PMID- 19442392 TI - Clinical inquiries. When should you suspect community-acquired MRSA? How should you treat it? AB - There are no clinical or epidemiologic features that will help you to clearly distinguish community-acquired methicillin-resistant Staphylococcus aureus infections (CA-MRSA) from methicillin-sensitive (CA-MSSA) infections. Incision and drainage is the primary therapy for purulent skin and soft tissue infections. There are inadequate data evaluating the role of oral antibiotics for MRSA. PMID- 19442393 TI - Clinical inquiries. Do nonmedicated topicals relieve childhood eczema? AB - Emollients are effective first-line treatment to decrease symptoms of eczema and reduce the need to use steroids in children. Tar preparations work, but compliance may be limited. Gamma-linoleic acid preparations, borage oil, and evening primrose oil show efficacy in small studies. MAS063DP cream (Atopiclair) is effective. Chamomile and bathing in acidic hot spring water may be effective, but these treatments have not been adequately evaluated. Wet wrap dressings may be effective but increase the risk of skin infections. Hamamelis distillate creams and massage with essential oils/aromatherapy are ineffective. PMID- 19442398 TI - Can the Swedish new variant of Chlamydia trachomatis (nvCT) be detected by UK NEQAS participants from seventeen European countries and five additional countries/regions in 2009? AB - In 2006, a new variant of Chlamydia trachomatis (nvCT) was reported in Sweden. The nvCT contains a deletion that includes the targets for the C. trachomatis genetic diagnostic single-target systems from Roche Diagnostics and Abbott Laboratories. Roche and Abbott have now developed certified dual-target assays that can detect the nvCT. This study examined the nucleic acid amplification tests (NAATs) currently used (in 2009) for C. trachomatis detection in laboratories from 17 European countries and five countries/regions outside Europe that are participating in the United Kingdom (UK) National External Quality Assessment Service (NEQAS). It further examined changes in these laboratories' testing strategy during the period from 2006 to 2009, and their performance regarding nvCT detection. A UK NEQAS blinded nvCT specimen was distributed to all 283 participating laboratories, which were asked to analyse the specimen according to their routine C. trachomatis diagnostic protocols for endocervical swabs. BD ProbeTec was the most commonly used NAAT, followed by Cobas Amplicor, Cobas TaqMan, and Aptima. From 2006 to 2009, the use of Cobas Amplicor, which does not detect the nvCT, decreased, but it was still used by 22% (n=57) of responding participants in 59% of the countries, 54 of these 57 used it as first assay. Virtually all of the other participants detected the nvCT correctly. Laboratories using commercial or in house NAATs that do not detect the nvCT are encouraged to carefully monitor their C. trachomatis incidence, participate in effective internal and external quality assurance and controls schemes, and to consider changing their testing system. PMID- 19442399 TI - Endemic hepatitis E in two Nordic countries. AB - Antibodies against hepatitis E virus (anti-HEV) were found in 248 Swedish and Danish patients between 1993 and 2007. Most patients were symptomatic and tested for anti-HEV due to travel abroad. Among patients with known country of infection, most were infected in Asia, mainly on the Indian subcontinent. However, 29 patients were infected in Europe, nine of these had HEV IgM and/or HEV RNA in serum. In sera from 65 of 141 tested patients HEV RNA could be detected, and 63 strains could be typed by limited sequencing within ORF2. HEV RNA was found in sera from 71% of the patients with HEV IgM and IgG and in 18% of the patients with only detectable HEV IgG. It was also found up to three weeks after the onset of disease in 67% of the patients with known date of onset. Patients infected in Europe were infected by genotype 3, and were older than those infected by genotype 1 (mean age 55.3 vs 30 years, p<0.001). Since it is known that genotype 3 can infect domestic pigs, HEV strains from 18 piglets in 17 herds in Sweden and Denmark were sequenced. Phylogenetic analyses of the genotype 3 strains showed geographical clades and high similarity between strains from patients and pigs from the same area. There are thus autochthonous hepatitis E cases in Scandinavia, and there are probably many undiagnosed ones. Patients with hepatitis of unknown etiology should therefore be investigated for anti-HEV even if they have not been outside Europe, since infections acquired from pigs or other animals should be taken into consideration. PMID- 19442400 TI - Anaphylaxis following unnecessary meningococcal chemoprophylaxis of a healthcare worker. AB - We report a case of anaphylaxis following meningococcal chemoprophylaxis of a healthcare worker, despite no history of direct contact with a patient who had meningococcal disease. The public health implications of this case are discussed. PMID- 19442401 TI - Sustained intensive transmission of Q fever in the south of the Netherlands, 2009. AB - The Netherlands is again facing a sharp increase in Q fever notifications, after the unprecedented outbreaks of 2007 and 2008. The most affected province of Noord Brabant has a high density of large dairy goat farms, and farms with abortion waves have been incriminated. Mandatory vaccination of small ruminants has started and should have an effect in 2010. A large multidisciplinary research portfolio is expected to generate better knowledge about transmission and additional control measures. PMID- 19442402 TI - A preliminary estimation of the reproduction ratio for new influenza A(H1N1) from the outbreak in Mexico, March-April 2009. AB - As of 12 May 2009, 5,251 cases of the new influenza A(H1N1) have been officially reported to the World Health Organization (WHO) from 30 countries, with most of the identified cases exported from Mexico where a local epidemic has been going on for the last two months. Sustained human-to-human transmission is necessary to trigger influenza pandemic and estimating the reproduction ratio (average number of secondary cases per primary case) is necessary for forecasting the spread of infection. We use two methods to estimate the reproduction ratio from the epidemic curve in Mexico using three plausible generation intervals (the time between primary and secondary case infection). As expected, the reproduction ratio estimates were highly sensitive to assumptions regarding the generation interval, which remains to be estimated for the current epidemic. Here, we suggest that the reproduction ratio was less than 2.2 - 3.1 in Mexico, depending on the generation interval. Monitoring and updating the reproduction ratio estimate as the epidemic spreads outside Mexico into different settings should remain a priority for assessing the situation and helping to plan public health interventions. PMID- 19442403 TI - Epidemiology of new influenza A(H1N1) in the United Kingdom, April-May 2009. AB - Following importations of cases from Mexico and the United States, by 11 May, United Kingdom surveillance activities had detected a total of 65 individuals with confirmed infections caused by the new influenza A(H1N1) virus. The infections were mainly in young people and younger adults and they spread within households and within schools. The illness in the United Kingdom is similar in severity to seasonal influenza and to date, besides one case of bacterial pneumonia, no clinically serious cases have occurred. PMID- 19442404 TI - New influenza A(H1N1) virus infections in Spain, April-May 2009. AB - An outbreak of infections with a new influenza A(H1N1) virus that was first detected in the United States and Mexico is currently ongoing worldwide. This report describes the initial epidemiological actions and outbreak investigation of the first 98 laboratory confirmed cases of infection with this new virus in Spain. PMID- 19442405 TI - Why are Mexican data important? PMID- 19442406 TI - The effect of gravel size fraction on the distribution coefficients of selected radionuclides. AB - This manuscript addresses the consequences of the common practice of assuming that the gravel fraction of sediments does not participate in sorption reactions and thus sorption quantified by the distribution coefficient (K(d)) construct can be estimated from laboratory tests on sediments less than 2 mm size fraction. However, this common assumption can lead to inaccurate estimates of the mobility and sorption affinity of many radionuclides (e.g., Tc, U, and Np) on gravel dominated sediments at the Hanford Site and other locations. Laboratory batch sorption experiments showed that the distribution coefficients measured using only sediment less than 2 mm size fraction and correcting for inert gravel fraction were not in agreement with those obtained from the bulk sediments including gravel (larger than 2 mm size fraction), depending on the radionuclide. The least reactive radionuclide, Tc had K(d) values for bulk sediment with negligible deviations from the inert gravel corrected K(d) values measured on less than 2 mm size fraction. However, differences between measured K(d) values using sediment less than 2 mm size fraction and the K(d) values on the bulk sediment were significant for intermediately and strongly reactive radionuclides such as U and Np, especially on the sediment with gravel fractions that contained highly reactive sites. Highly reactive sites in the gravel fraction were attributed to the presence of Fe oxide coatings and/or reactive fracture faces on the gravel surfaces. Gravel correction factors that use the sum of the K(d)(,<2 mm) and K(d)(,>2 mm) values to estimate the K(d) for the bulk sediment were found to best describe K(d) values for radionuclides on the bulk sediment. Gravel correction factors should not be neglected to predict precisely the sorption capacity of the bulk sediments that contain more than 30% gravel. In addition, more detailed characterization of gravel surfaces should be conducted to identify whether higher reactive sorbents are present in the gravels. PMID- 19442407 TI - Evaluating the fate of chlorinated ethenes in streambed sediments by combining stable isotope, geochemical and microbial methods. AB - The occurrence of chlorinated ethene transformation in a streambed was investigated using concentration and carbon isotope data from water samples taken at different locations and depths within a 15 x 25 m study area across which a tetrachloroethene (PCE) plume discharges. Furthermore, it was evaluated how the degree of transformation is related to groundwater discharge rates, redox conditions, solid organic matter content (SOM) and microbial factors. Groundwater discharge rates were quantified based on streambed temperatures, and redox conditions using concentrations of dissolved redox-sensitive species. The degree of chlorinated ethene transformation was highly variable in space from no transformation to transformation beyond ethene. Complete reductive dechlorination to ethane and ethene occurred at locations with at least sulfate-reducing conditions and with a residence time in the samples streambed zone (80 cm depth) of at least 10 days. Among these locations, Dehalococcoides was detected using a PCR method where SOM contents were >2% w/w and where transformation proceeded beyond ethene. However, it was not detected at locations with low SOM, which may cause an insufficient H(2) supply to sustain a detectably dense Dehalococcoides population. Additionally, it is possible that other organisms are responsible for the biodegradation. A microcosm study with streambed sediments demonstrated the potential of VC oxidation throughout the site even at locations without a pre exposure to VC, consistent with the detection of the epoxyalkane:coenzyme M transferase (EaCoMT) gene involved in the degradation of chlorinated ethenes via epoxidation. In contrast, no aerobic transformation of cDCE in microcosms over a period of 1.5 years was observed. In summary, the study demonstrated that carbon isotope analysis is a sensitive tool to identify the degree of chlorinated ethene transformation even in hydrologically and geochemically complex streambed systems. In addition, it was observed that the degree of transformation is related to redox conditions, which in turn depend on groundwater discharge rates. PMID- 19442408 TI - Effects and underlying mechanisms of human opiorphin on colonic motility and nociception in mice. AB - In the present study, we investigated the effects of human opiorphin on colonic motility and nociception in mice. In in vitro bioassay, opiorphin (10(-6) to 10( 4)M) caused colonic contraction in a concentration-dependent manner, which was completely blocked by naloxone and partially attenuated by beta-funaltrexamine and naltrindole. Moreover, opiorphin (10(-4)M) significantly enhanced the contractile response induced by Met-enkephalin. The data suggested that the effect of opiorphin on colonic contraction may be due to the protection of enkephalins. In in vivo bioassay, intracerebroventricular (i.c.v.) administration of opiorphin (1.25-10 microg/kg) dose- and time-dependently induced potent analgesic effect (ED(50)=3.22 microg/kg). This effect was fully blocked by naloxone and significantly inhibited by co-injection (i.c.v.) with beta funaltrexamine or naltrindole, but not by nor-binaltorphimine, indicating the involvement of both mu- and delta-opioid receptors in the analgesic response evoked by opiorphin. In addition, i.c.v. administration of 5 microg/kg opiorphin produced the comparative effect as 10 microg/kg morphine on the analgesia, suggesting that opiorphin displayed more potent analgesic effect than that induced by morphine. PMID- 19442409 TI - [Non-traumatic spontaneous intramural hematoma of the small bowel: an infrequent complication of anticoagulation therapy]. AB - Intramural hematoma of the small bowel is an infrequent complication of the use of oral anticoagulants. Diagnosis can only be performed when these symptoms are associated with a history of oral anticoagulant use and radiological tests. We report the case of a patient admitted for epigastric pain associated with oral anticoagulation therapy with warfarin and a 48-h history of retention vomiting. Ultrasound and abdominal computed tomography scans revealed a jejunal loop with diffuse parietal thickening, suggesting an intramural hematoma. Conservative therapy was provided with symptomatic regression on the second day and reabsorption of the jejunal intramural hematoma. Anticoagulation therapy was reintroduced with no recurrences. PMID- 19442410 TI - [Muehrcke's lines on nails after docetaxel/cisplatin/fluorouracil]. PMID- 19442411 TI - [Venlafaxine-induced cholestatic hepatitis]. PMID- 19442412 TI - [Ulcerative colitis associated with Vogt-Koyanagi-Harada disease]. AB - We report the case of a female patient who was diagnosed with Vogt-Koyanagi Harada disease at the age of 14 years and who developed myelopathy, resulting in paraparesis. A cerebral magnetic resonance imaging scan revealed the presence of T2-hyperintense lesions in the periventricular white matter, suggesting demyelinization. Twelve years later, ulcerative colitis was diagnosed during workup for abdominal pain associated with bloody diarrhea. The association of these two diseases has previously been reported anecdotically. The management of the ulcerative colitis was complicated by the patient's neurological manifestations. Even though recent reports support the use of anti-TNF drugs in the management of Vogt-Koyanagi-Harada-associated uveitis, because of the lack of experience in patients with neurological symptoms, and the presence of apparently demyelinating lesions in our patient, we did not use these drugs in this case. PMID- 19442413 TI - [Irritable bowel syndrome and inflammatory bowel disease: Is there a connection?]. AB - Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders and is that with the greatest socioeconomic impact worldwide. Diagnosis of IBS is based on clinical criteria that have been modified over time, the Rome II criteria being those that are currently followed. Some of the symptoms of IBS are similar to those in patients with inflammatory bowel disease (IBD), which can hamper or delay diagnosis. The use of inflammatory markers in stools (such as calprotectin) may help to distinguish between these two entities. A possible connection between IBS and IBD could be based on five points: (i) both disorders have similar symptoms; (ii) symptoms often overlap in the same patients; (iii) IBS and IBD have a common familial aggregation; (iv) some predisposing factors, such as a history of acute gastroenteritis, play a role in both disorders, and (v) importantly, signs of microinflammation are found in the bowels of patients with IBS. With regard to this latter point, an increase in inflammatory cells has been found in the intestinal mucosa of patients with IBS and, more specifically, mastocytes have been found to be increased in the jejunum and colon while CD3 and CD25 intraepithelial lymphocytes have be observed to be increased in the colon. Moreover, activated mastocytes are increased near to nerve endings in patients with IBS and this finding has been correlated with the intensity of both intestinal symptoms (abdominal pain) and psychological symptoms (depression and fatigue). A good model of microinflammation is post infectious IBS, since the timing of the onset of the infectious process is known. In patients with post-infectious IBS, an increase in intraepithelial lymphocytes and enterochromaffin cells is initially found, which is reduced over time; consequently, although the symptoms of IBS persist, after 3 years no differences are detected in the number of inflammatory cells between IBS patients and controls. Among the various factors that can favor the development of IBS in these patients, two host-dependent mechanisms are most closely implicated in the physiopathology of IBS: polymorphism of the genes codifying pro- or anti inflammatory cytokines and psychological factors such as anxiety, depression, somatization and neuroticism at the time of the acute infection. In view of all of the above, the similarities between IBS and IBD are probably more than mere coincidence and may reflect distinct manifestations of a broad spectrum of inflammation in the colon. PMID- 19442414 TI - [Infective endarteritis complicating aortic coarctation in a 66-year-old woman]. PMID- 19442415 TI - [Acute infective endocarditis due to Streptococcus suis serotype 2 in Spain]. PMID- 19442416 TI - [Bilateral gynecomastia in a patient with human immunodeficiency virus infection]. PMID- 19442417 TI - [Bacterial prostate abscess in chronic HIV-1 infected patients: case report and review of the literature]. PMID- 19442418 TI - [Utility of chromID ESBL medium for detection of cephalosporin-resistant enterobacteria in inoculated blood culture bottles]. PMID- 19442419 TI - Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrugs of 5-aminosalicylic acid for colon-specific drug delivery in inflammatory bowel disease. AB - Colon-specific mutual azo prodrugs of 5-aminosalicylic acid with essential amino acids were synthesized for the management of inflammatory bowel disease. The structures were confirmed by elemental and spectral analyses. 85-88% release of 5 aminosalicylic acid was achieved in rat fecal matter with half-lives ranging from 140 to 160 min, following first order kinetics. The prodrugs exhibited comparable ameliorating effect as that of sulfasalazine on trinitrobenzenesulfonic acid induced experimental colitis in rats with a better safety profile. PMID- 19442420 TI - Efficacy of a modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in pigs naturally exposed to a heterologous European (Italian cluster) field strain: Clinical protection and cell-mediated immunity. AB - The purpose of this study was to assess clinical protection in pigs vaccinated with a commercially available attenuated porcine reproductive and respiratory syndrome virus (PRRSV) vaccine (Porcilis) PRRS) and then naturally exposed under field conditions to a heterologous (Italian cluster) strain of virulent PRRSV. A total of 30, 4-week-old pigs seronegative for PRRSV were allocated to 1 of 3 groups (IM, ID, and C groups). At 5 weeks of age, pigs of groups IM (n=10 pigs) and ID (n=10 pigs) were vaccinated intramuscularly and intradermally, respectively, with modified live PRRSV-1 vaccine (Porcilis) PRRS). Pigs of group C (n=10 pigs) were kept as non-vaccinated controls. At post-vaccination (PV) days 0, 7, 14, 28, and 45, blood samples were collected for detection of vaccine virus (PCR) and antibody response (ELISA), identification of changes in lymphocyte subpopulations by cytometry, and IFN-gamma PRRSV-specific secreting cells (SC) by ELISpot. At PV day 45, pigs of A, B, and C groups were moved to a site 3 conventional finishing herd with a history of respiratory disease caused by PRRSV and the most common bacteria to be exposed to a natural challenge. The PRRSV field strain, belonging to the Italian cluster of the PRRSV-1, demonstrated a 84% identity with the vaccine virus (DV strain) at ORF5 sequencing. At 0 (exposure day=45 days PV), 4, 7, 11, 14, 19, 21, 28, and 34 days post-exposure (PE) blood samples were collected for detection and titration of PRRSV and antibody, as well as for lymphocyte and IFN-gamma measurement as described above. Throughout the post-exposure period, all pigs were observed daily for clinical signs. The overall clinical signs were reduced by 68 and 72%, respectively in the intramuscularly and intradermally vaccinated pigs compared to controls. Respiratory signs were reduced by 72 and 80%, respectively in the IM and ID groups. Clinical protection was associated with marked activation of cell mediated immune response. The highest levels of specific IFN-gamma production at 21-34 days PE were concomitant and associated to changes in natural killer (NK) cells, gamma/delta T, and cytotoxic T lymphocytes in the blood. In our field study, evidences of EU attenuated vaccine-induced clinical protection against natural exposure to a genetically diverse (84% homology) PRRSV-1 isolate (Italian cluster) was demonstrated by the statistically significant reduction in clinical signs in terms of incidence, duration and severity and by a more efficient cell mediated immune response in the vaccinated pigs as compared to the unvaccinated controls. PMID- 19442421 TI - Challenges in the evaluation and licensing of new pneumococcal vaccines, 7-8 July 2008, Ottawa, Canada. AB - The introduction of seven valent pneumococcal conjugate vaccine (7vPnC) into immunization programmes has led to a significant reduction in invasive disease due to Streptococcus pneumoniae. New conjugate pneumococcal vaccine formulations containing additional serotypes are at advanced stages of clinical development and are expected to be available in the near future. There are also a number of on-going initiatives to facilitate the introduction of pneumococcal conjugate vaccines into the immunization programmes of developing countries. These initiatives are dependent upon the vaccines being satisfactorily licensed and subsequently pre-qualified by the WHO for use by UN agencies. Recommendations for the production and control of pneumococcal conjugate vaccines were established by WHO in 2003 and have served as a basis for national requirements for the evaluation and licensing of these products. Much progress has been made since that time and a consultation held in Ottawa, Canada, in July 2008 aimed to provide regulators and manufacturers with further guidance on the criteria for evaluating and licensing of new pneumococcal conjugate vaccines taking account of recent developments. The principal conclusion of the meeting was that the current WHO recommendations, in which the demonstration of immunological non-inferiority to the licensed 7vPnC vaccine is proposed as the main basis for approval, continue to provide a solid basis for the evaluation of pneumococcal conjugate vaccines and may be referred to when assessing new vaccines for licensure and pre qualification. Uncertainties regarding serological criteria for assessing the efficacy of new conjugate vaccines against invasive pneumococcal disease were discussed in detail and proposals made for handling complex data. In particular, it was emphasized that all relevant immunological data should be taken into account when comparing new pneumococcal conjugate vaccines with licensed 7vPnC vaccine. These include the measurement of the total amount of anticapsular IgG as well as the demonstration of functionality of vaccine-induced antibodies, by verifying their ability to opsonize and promote the killing of pneumococcal serotypes, and the demonstration of immunological priming. It was agreed that new information on assay performance and on the effectiveness of currently licensed 7vPnC vaccine, as assessed in routine mass immunization programmes, should both be included in any update of the WHO recommendations. A detailed meeting report is available at the WHO web site for biologicals: http://www.who.int/biologicals/publications/meetings/areas/vaccines/pneumococcal/ n/index.html. PMID- 19442422 TI - Pediatric vaccination errors: application of the "5 rights" framework to a national error reporting database. AB - Little is known about vaccination errors. We analyzed 607 outpatient pediatric vaccination error reports from MEDMARX, a nationwide, voluntary medication error reporting system, occurring from 2003 to 2006. We used the "5 Rights" framework (right vaccine, time, dose, route, and patient) to determine whether vaccination error types were predictable. We found that "wrong vaccine" errors were more common among look-alike/sound-alike groups than among vaccines with no look alike/sound-alike group. Scheduled vaccines were more often involved in "wrong time" errors than seasonal and intermittent vaccines. "Wrong dose" errors were more common for vaccines whose dose is weight-based and age-based than for vaccines whose dose is uniform. "Wrong route" and "wrong patient" errors were rare. In this largest-ever analysis of pediatric vaccination errors, error types were associated with predictable vaccine-related human factors challenges. Efforts to reduce pediatric vaccination errors should focus on these human factors. PMID- 19442423 TI - Digital image-assisted microsurgery. PMID- 19442424 TI - Disseminated intravascular coagulation in obstetric disorders and its acute haematological management. AB - As activation of the coagulation pathway is a physiological response to injury, the development of disseminated intravascular coagulation (DIC) is a warning signal to the clinician that the primary pathological disease state is decompensating. In pregnancy, DIC can occur in several settings, which include emergencies such as placental abruption and amniotic fluid embolism as well as complications such as pre-eclampsia. Whilst the acuteness of the event and the proportionality in the coagulant and fibrinolytic responses may vary between these different conditions, a common theme for pregnancy-associated DIC is the pivotal role played by the placenta. Removal of the placenta is the linchpin to treatment in most cases but appropriate blood product support is also key to management. This is necessary because DIC itself can have pathological consequences that translate clinically into a worse prognosis for affected patients. This article will describe how pregnancy-associated DIC can be diagnosed promptly and how treatment should be managed strategically. It also discusses the latest developments in our understanding of haemostatic mechanisms within the placenta and how these may have relevance to new diagnostic approaches as well as novel therapeutic modalities. PMID- 19442425 TI - Rape treatment outcome research: empirical findings and state of the literature. AB - This article reviews empirical support for treatments targeting women sexually assaulted during adolescence or adulthood. Thirty-two articles were located using data from 20 separate samples. Of the 20 samples, 12 targeted victims with chronic symptoms, three focused on the acute period post-assault, two included women with chronic and acute symptoms, and three were secondary prevention programs. The majority of studies focus on posttraumatic stress disorder (PTSD), depression, and/or anxiety as treatment targets. Cognitive Processing Therapy and Prolonged Exposure have garnered the most support with this population. Stress Inoculation Training and Eye Movement Desensitization and Reprocessing also show some efficacy. Of the four studies that compared active treatments, few differences were found. Overall, cognitive behavioral interventions lead to better PTSD outcomes than supportive counseling does. However, even in the strongest treatments more than one-third of women retain a PTSD diagnosis at post treatment or drop out of treatment. Discussion highlights the paucity of research in this area, methodological limitations of examined studies, generalizability of findings, and important directions for future research at various stages of trauma recovery. PMID- 19442426 TI - Checking-in on the memory deficit and meta-memory deficit theories of compulsive checking. AB - The memory deficit theory and meta-memory deficit theory provide intuitive accounts for checking compulsions. According to these theories, deficits in memory and/or a lack of confidence in memory contribute to the compulsion to check. Our goal was to examine whether, as predicted by the theories, memory deficits and/or meta-memory deficits are unique to individuals with checking compulsions as opposed to being common to all OCD patients. The review revealed that previous investigations of these theories have focused almost exclusively on retrospective memory. More importantly, results of the review revealed similar patterns of deficits in the retrospective memory performance and meta-memory scores of OCD checkers and OCD non-checkers, indicating that deficits in retrospective memory are not unique to checkers and therefore are unlikely to contribute to the compulsion to check. The review also features results of the few studies that have examined the theories in the context of prospective memory, and it provides the results of some supplementary analyses which show that checkers demonstrate unique memory and meta-memory deficits related to prospective memory. Together these results indicate that the memory deficit and meta-memory deficit theories should be re-conceptualized and further examined in the context of prospective memory. PMID- 19442427 TI - On the role of dopamine replacement therapy in decision-making, working memory, and reward in Parkinson's disease: does the therapy-dose matter? AB - BACKGROUND: Dopaminergic therapy proved to ameliorate motor deficits in Parkinson's disease but its effects on behavior and cognition vary according to factors that include, among others, the evolution of the disease and the nature of the task that is tested. This study addressed the question of whether, in moderate to advanced Parkinson's disease (PD) with motor fluctuations, changes in decision-making and sensitivity to reward occur and to what extent dopaminergic therapy plays a role. METHODS: Fifteen PD patients (On and Off medication) and thirteen healthy controls were compared on two different tasks which analyzed decision-making processes (the Cambridge Gamble Task, CGT) and working memory abilities with and without the prospect of reward (modified N-back task). RESULTS: We found that the PD patients were unable to choose an optimal betting strategy and were impulsive in their choices relative to the control group. Further, a detrimental dose-dependent effect of dopaminergic therapy was detected, meaning that those patients who were taking higher doses of therapy were more impulsive in selecting bets and more impaired in making probabilistic choices. Such a dose-dependent effect was not found on the N-back task. However, the results of the PD group in this task supported indirect evidence of the amelioration of performance in rewarded conditions. CONCLUSION: Our results suggest that the detrimental effects of dopaminergic therapy may be dose-related and that the interaction between monetary reward and dopaminergic therapy can affect and improve some cognitive abilities, such as working memory. PMID- 19442428 TI - [Hypersensitivity pneumonitis caused by Trichoderma viride]. AB - Hypersensitivity pneumonitis (HP) can be induced by exposure to indoor molds contaminating humidifiers and heating or ventilation systems. A 54-year-old woman with dyspnea, cough, chest pain, and fever was seen in the emergency room. A chest radiograph revealed interstitial infiltrates and blood tests showed leukocytosis with neutrophilia and severe hypoxemia. A diagnosis of HP was made by a combination of clinical, radiologic, physiologic, and immunologic studies. Trichoderma viride was isolated in cultures of water samples from an ultrasonic humidifier installed in the patient's home a year earlier. Precipitating immunoglobulin G antibodies to T viride were detected in the patient's serum by enzyme-linked immunosorbent assay. The patient remained symptom free after the humidifier was removed from her home. Our findings strongly suggest that the patient developed HP due to T viride from the humidifier. To our knowledge, this is the first report of such a case. PMID- 19442429 TI - [Recommendations for end-of-life care in patients with chronic obstructive pulmonary disease]. PMID- 19442430 TI - Phase transition induced fission in lipid vesicles. AB - In this work we demonstrate how the first order phase transition in giant unilamellar vesicles (GUVs) can function as a trigger for membrane fission. When driven through their gel-fluid phase transition GUVs exhibit budding or pearl formation. These buds remain connected to the mother vesicle presumably by a small neck. Cooling these vesicles from the fluid phase (T>T(m)) through the phase transition into the gel state (Tor=200 min(-1). At 300 min( 1), increased MB discoloration was visibly accompanied by suspension of dissolution products of Fe(0)/MnO(2) and suspension of GAC fines. The results suggest that, shaking intensities aiming at facilitating contaminant mass transfer to the Fe(0) surface should not exceed 50 min(-1). PMID- 19442444 TI - Seasonal distribution of phthalate esters in surface water of the urban lakes in the subtropical city, Guangzhou, China. AB - Urban lakes are vulnerable to the accumulation of toxic and/or potentially toxic contaminants, such as phthalate esters (PAEs) from urban stormwater runoff, atmospheric deposition, as well as untreated discharge of industrial wastewater and municipal sewage. The concentrations of 16 PAEs in surface water from 15 urban lakes in the subtropical city, Guangzhou, were measured, respectively in spring, summer and winter 2006, to elucidate the effect of the seasonal variation in climate conditions on the distribution of PAEs. Seasonal variations of the Sigma(16)PAEs concentrations, ranging, respectively from 0.47 to 6.19 microg L( 1) and from 24.9 to 221 microg g(-1), were measured in the dissolved and suspended particulate matter (SPM) phases. The highest concentrations of PAEs were present in summer. The spatial distribution of PAEs was site-specific. Of the 16 PAEs, dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), di(4-methyl-2-pentyl) phthalate (DMPP), di(2-ethylhexyl) phthalate (DEHP) were present in all the samples analyzed, and dominated by DnBP, DiBP and DEHP. Composition profile of PAEs indicated that the application of DnBP/DiBP is relatively high in the Pearl River Delta (PRD). Longer/branching alkyl PAEs likely adsorb to SPM in aquatic environments. Normalized partition coefficient (K(OC)) between the dissolved water and SPM was correlated with n-octanol/water partition coefficient (K(OW)) to understand the environmental behavior of PAEs. PMID- 19442445 TI - Synthesis of AlPO4-5 and CrAPO-5 using aluminum dross. AB - AlPO(4)-5 and its chromium-containing analogue, CrAPO-5, were prepared using aluminum dross in the presence of triethylamine as a structure directing agent; both Al dross powder and an extracted precipitate from Al dross in an alkali solution were used as an aluminum source. These materials were characterized by XRD, BET surface area measurement, SEM, EDX, XRF, ESR, and UV-vis spectroscopy. Their textural properties were found close to those of the corresponding reference samples prepared using pure Al(OH)(3). CrAPO-5 samples prepared from the aluminum dross were tested as a catalyst for liquid phase oxidation of tetralin using t-butyl hydroperoxide as an oxidizing agent, which showed virtually identical catalytic performances to that obtained by a reference CrAPO 5 catalyst. PMID- 19442446 TI - Transdermal fentanyl in cachectic cancer patients. AB - Fentanyl is an opioid with high lipid solubility, suitable for intravenous, spinal, transmucosal and transdermal administration. The transdermal fentanyl patch has become widely used in the treatment of both malignant and non-malignant chronic pain. The absorption of fentanyl from the patch is governed by the surface area of the patch, by skin permeability and by local blood flow. The aim of this study is to find out whether absorption of fentanyl in cachectic patients with cancer-related pain is different from that of normal weight cancer patients. We recruited ten normal weight (mean body mass index (BMI) 23 kg/m(2)) and ten cachectic (mean BMI 16 kg/m(2)) cancer pain patients. A transdermal fentanyl patch with a dose approximately equianalgesic to the patients' previous opioid dose was administered to the upper arm of the patient for 3 days. Prior to patch application, the height, weight and BMI of the patient, as well as upper arm skin temperature, local sweating, thickness of skin fold and local blood flow were measured. Plasma fentanyl concentrations were analyzed from blood samples taken at baseline, 4, 24, 48 and 72 h. Plasma fentanyl concentrations adjusted to dose were significantly lower at 48 and 72 h in cachectic patients than normal weight patients. The cachectic patients had a significantly thinner upper arm skin fold, but no differences were found in local blood flow, sweating, or skin temperature. Absorption of transdermal fentanyl is impaired in cachectic patients compared with that of normal weight cancer pain patients. PMID- 19442447 TI - A retrospective descriptive study of electrocution deaths in Gauteng, South Africa: 2001-2004. AB - There is a paucity of data with regards to non-lightning, electrical-related injuries in sub-Saharan Africa. A review of the South African medical literature also shows a dearth of electrocution-related information. This study aimed to retrospectively review all high- and low-voltage-electrocution-fatality cases in Gauteng, South Africa for the period 2001-2004. Altogether, 126 electrocution related deaths were identified, of which 91 cases represented low-voltage electrocution deaths and 35 represented high-voltage-electrocution deaths. All cases were reviewed from a demographic and pathology-of-trauma point of view. This study serves to illustrate the high number of electrocution-related fatality cases in the region as compared with the rest of the world. It also serves to highlight the need for more active research and attention in this field. PMID- 19442448 TI - Delayed response in 'BURNS'. PMID- 19442449 TI - Lower limb functional outcome assessment following burn injury: a novel use for 3D laboratory-based movement analysis. PMID- 19442450 TI - Adherence to pressure garment therapy in adult burn patients. AB - Pressure garment therapy (PGT) is a generally accepted procedure to prevent hypertrophic scarring after severe burns. Wearing pressure garments is uncomfortable and challenging for the patient and, consequently adherence is low. In order to improve adherence, precise knowledge about the advantages and disadvantages of PGT is necessary. In this study we investigated specific aspects which inhibit or reinforce the application of PGT on the patients' part. Twenty one patients participated in a semi-structured interview concerning their experiences with PGT. The complaints most frequently mentioned were 'physical and functional limitations' caused by the garments, 'additional effort' created by the need to care for garments and 'perceived deficiencies' of the treatment. At the same time, most of the patients reported coping strategies used to persevere with the therapy. Coping can be categorised into 'behavioural' and 'cognitive coping strategies'. Besides the 'expectation of success', 'emotional' as well as 'practical support' and experiencing 'good outcome' were motivating factors for the patients. Based on the analyses of limitations and resources, recommendations for future interventions enhancing adherence are outlined. PMID- 19442451 TI - Childhood parental divorce and cortisol in young adulthood: evidence for mediation by family income. AB - Childhood parental divorce has been linked with negative physical and psychological health in adulthood, potentially due to alterations in adrenocortical activity resulting from chronic stress. The current study evaluated cortisol in 94 young adults (mean age 19.9) from families characterized by parental divorce (n=43) or intact parental marriages (n=51). Salivary cortisol was assessed prior to and at 3 time points after a challenging speech task. Participants from divorced families had significantly lower cortisol across the experimental period than those from intact families, even after controlling for family conflict and current depression and anxiety. Lower family income was also associated with lower cortisol, and partially mediated the relationship between parental divorce and cortisol. Findings suggest that childhood parental divorce is associated with attenuated cortisol in young adulthood, which may be explained by lower income in divorced families. PMID- 19442452 TI - Initiation of alcohol use in early adolescence: links with exposure to community violence across time. AB - Early alcohol use initiation has been linked with exposure to community violence, but the direction of these associations and the roles of witnessing violence vs. victimization are not clear. This study used a cross-lagged structural equation model to examine the prospective relationships between alcohol use initiation and witnessing community violence and victimization in early adolescence. A sample of 603 boys and girls provided two waves of data 16 months apart. After controlling for continuity in alcohol use and violence exposure, early initiation of alcohol use predicted later victimization in the community. Witnessing community violence increased and victimization decreased the risk of subsequent alcohol use. Prevention programs targeting early alcohol initiation may result in decreased victimization, while interventions addressing constructive ways of coping with witnessing community violence may also reduce early adolescents' alcohol use. PMID- 19442453 TI - Why do humans have such a prominent nose? The final result of phylogenesis: a significant reduction of the splanchocranium on account of the neurocranium. AB - During the last few decades several authors tried to clarify the anthropological aspects of the shape of the human nose and why it has so emphasized projection. Our hypothesis suggests the essentiality of the role of morphologic changes of the human skull which occurred during the phylogenesis. It seems that erectile posture of the man caused remarkable morphological changes of the skull base shape thus being a part of morphologic evolution. The changes in the shape of the human spine from birth to adulthood show a philogenesis in short: a newborn has an almost flat spine like quadrupeds (except in the sacro-coccigeal region), but the spine gets increasingly bent as the person grows (lumbar lordosis, thoracic kyphosis, cervical lordosis). It is well known that the sphenoidal angle was less emphasized in prehistoric man than in modern man. In addition, the cervical spine position in the gorilla, Neanderthal man and modern man is quite different in terms of anterior inclination. Accordingly, there is a great degree of maxillary and mandible reduction in humans. The same differences can be seen when comparing the skull shapes of gorilla, gibbons, Neanderthals and modern man. A major reason for the maxillary and mandible reduction in humans is that their way of feeding has changed remarkably with time. In lower primates and other animals, nasal function, particularly olfaction, may be essential for day-to day survival. In humans, however, this is less important although both impaired nasal breathing and olfaction may affect the function in the other body organs and, of course, influence the quality of life. Nasal configuration in recent humans seems to be associated with the internal nasal cavity wideness and nasal bridge elevation which just happened because of newly developed physiological needs. The skull base angulation leads directly to obvious changes in splanchocranium on the account of neurocranium, since previous is getting "squeezed", by angulation of the surrounding bones, and the other one gets more room for the further development according to human's intellectual needs. The final morphologic result of the squeezing of the splanchocranium, in fact a side-effect of these phylogenetic changes, is a protrusion of its most anterior parts more anteriorly, that is a prominent nose in humans which is a hallmark of the modern man. PMID- 19442454 TI - Angioimmunoblastic T-cell lymphoma with autoimmune thrombocytopenia: a report of two cases. AB - We report two patients, a 68-year-old man (Case 1) and a 66-year-old man (Case 2), with polyclonal gammopathy, lymphadenopathy, thrombocytopenia, and high platelet-associated IgG (PAIgG) level. We initially diagnosed them as having angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). From confirmation of clear cells by careful observation and detection of rearrangement bands of T cell receptors by Southern blot hybridization analysis, we finally concluded that their diagnoses were compatible with angioimmunoblastic T-cell lymphoma (AILT). AILT with autoimmune thrombocytopenia (AIT) is very rare, and all the reported cases were Japanese ones. PMID- 19442455 TI - Symptomatic nonunion of a distal phalanx fracture: treatment with a percutaneous compression screw. AB - Fractures of the distal phalanx caused by crush injuries occur frequently but rarely result in nonunions. This article describes 2 patients with a symptomatic hypertrophic nonunion after a fracture of the waist of the distal phalanx of the thumb. Following the general principles of nonunion treatment, both patients were successfully treated with a single compression screw inserted by a minimally invasive approach. PMID- 19442456 TI - Treatment of a little finger synovial cyst by repair of an opening in the wrist capsule: case report. AB - As synovial fluid from the wrist may leak into the ulnar bursa and from there into the flexor synovial sheath in the little finger, the origin of a synovial cyst of the pulp of the little finger may be in the wrist. Here we present the surgical treatment of a patient with a synovial cyst of the pulp of the little finger by surgery of the wrist and palm of the hand after failed conservative treatment. PMID- 19442457 TI - Distal biceps tendinosis: evidence-based review. PMID- 19442458 TI - Smoking and smoking cessation in disadvantaged women: assessing genetic contributions. AB - Abundant evidence from family, adoption and twin studies points to large genetic contributions to individual differences in vulnerability to develop dependence on one or more addictive substances, including tobacco. Twin data suggests that much of this genetic vulnerability is shared by individuals who are dependent on a variety of addictive substances. Interestingly, some twin data also supports substantial differences in the apparent heritability of nicotine dependence in women as environmental conditions become more permissive for their smoking. In addition, twin studies also support the idea that ability to quit smoking displays substantial heritability, and that this heritable influence overlaps partially with genetic influences on nicotine dependence. Candidate gene molecular genetic studies and genome wide association studies of substance dependence and ability to quit smoking each document apparent polygenic influences that identify lists of genes that display partial overlap, as expected from classical genetic studies. More of these genes are expressed in the brain than would be anticipated by chance. These lists of genes overlap significantly with those identified in molecular genetic studies of individual differences in cognitive abilities, frontal lobe brain volumes as well as personality and psychiatric phenotypes. Though most available genome wide association data do not separate results by gender, it may be notable that few of these genes lie on sex chromosomes. These data provide a substrate to improve understanding of nicotine dependence, the ability to quit smoking, the potential for less permissive environments to restrict the expression of genetic influences on smoking and the possibility that brain features that underlie phenotypes such as individual differences in cognitive abilities might interact with environmental features that are especially prominent for disadvantaged women to provide special circumstances that should be considered in prevention and treatment efforts to reduce smoking. PMID- 19442459 TI - Is socioeconomic status associated with awareness of and receptivity to the truth campaign? AB - BACKGROUND: The truth campaign is credited with preventing approximately 450,000 youth from starting to smoke, from 2000 through 2004 [Farrelly, M.C., Nonnemaker, J., Davis, K.C., Hussin, A., 2009. The Influence of the National Truth Campaign on Smoking Initiation. Am. J. Prev. Med. February 9 [Epub ahead of print]]. However, no research has been conducted to determine whether lower socioeconomic status (SES) youth benefit equally from the campaign. This study examines whether socioeconomic status is associated with awareness of and receptivity to the truth campaign among youth ages 12-17. METHODS: This study is based on seven waves of Legacy Media Tracking Survey (LMTS) data, collected from September 2000 through January 2004 (n=30,512). LMTS is a nationally representative, cross-sectional telephone survey. Median household income and median household education at the zip code level were appended to the LMTS data. RESULTS: Females had lower levels of confirmed awareness of the truth campaign as compared with males. Youth who lived in lower education zip codes were less likely to have confirmed campaign awareness as compared with those in higher education zip codes. Zip code level median household income was not associated with confirmed awareness. Receptivity to the campaign was not associated with zip code level median household income or education. CONCLUSIONS: These findings suggest that the effectiveness of the truth campaign could be enhanced by developing strategies to increase campaign awareness among females and youth from lower education zip codes. Increased campaign exposure within these populations could result in lower smoking rates and, ultimately, lower rates of tobacco-related disease. PMID- 19442460 TI - Educational disadvantage and cigarette smoking during pregnancy. AB - This study examined the influence of education on smoking status in a cohort (n=316) of pregnant women who were smokers at the time they learned of the current pregnancy. Subjects were participants in clinical trials examining the efficacy of monetary-based incentives for smoking-cessation and relapse prevention. In multivariate analyses, educational achievement was a robust predictor of smoking status upon entering prenatal care, of achieving abstinence antepartum among those still smoking at entry into prenatal care, and of smoking status at 6-month postpartum in the entire cohort and the subsample who received smoking-cessation treatment. In addition to educational attainment, other predictors of smoking status included smoking-related characteristics (e.g., number of cigarettes/day smoked pre-pregnancy), treatment, maternal age, and stress ratings. We suggest that strategies to increase educational attainment be included with more conventional tobacco-control policies in efforts to reduce smoking among girls and young women. PMID- 19442461 TI - In vitro survival and development of goat preantral follicles in two different oxygen tensions. AB - The aim of the present study was to evaluate the effect of two different oxygen (O(2)) concentrations on survival and development of preantral follicles of goats cultured in vitro. Preantral ovarian follicles (> or =150 microm) were isolated from ovarian cortex fragments of goats and individually cultured for 30 days under two different O(2) concentrations (5% and 20% O(2)). Follicle development was evaluated on the basis of antral cavity formation, increase in follicular diameter, presence of healthy cumulus oocyte complexes and fully grown oocytes. Results showed with progression of culture period from 6 to 12 days, a decrease in follicular survival was observed in both O(2) concentrations (P<0.05). When the O(2) tensions were compared to each other in the different days of culture, 20% O(2) was more efficient in promoting an increase in follicular diameter from day 24 of culture onward than 5% O(2) (P<0.05). However, follicles cultured with 5% O(2) had an increased percentage of antrum formation from 12 days to the end of culture, compared with 20% O(2) (P<0.05). Moreover, there was no difference in percentage of fully developed oocytes with the different O(2) tensions. However, only oocytes (16.7%) from follicles cultured in 20% O(2) resumed meiosis. In conclusion, concentration of 20% O(2) was more efficient in promoting follicular growth and oocyte meiosis resumption from preantral follicles of goats when grown in vitro. PMID- 19442462 TI - High mobility group box 1 protein enhances polyethylenimine mediated gene delivery in vitro. AB - The relatively low efficiency of transgene expression is a major drawback of non viral gene delivery systems despite it being a safer alternative for gene therapy. Modifications of non-viral carriers with peptides have been utilized to improve their gene transfer efficiency. In this study, we described a new combined carrier, which was comprised of a cationic polymer, polyethylenimine (PEI), and a nuclear protein, high mobility group box 1 (HMGB1) containing nuclear localization sequences (NLS). The HMGB1/branched or linear PEI (b-PEI or l-PEI) combined carriers have been investigated for their cytotoxicity and ability to condense and deliver plasmid DNA (pDNA) to mammalian cells in vitro. Both HMGB1 and PEI formed complexes with pDNA are revealed by a gel-retardation assay. Compared with pDNA/l-PEI complexes, a reduction in particle size was observed for pDNA/HMGB1/l-PEI ternary complexes. In MTT assay the results of cell viability suggested lower cytotoxicity for HMGB1/PEI combined carriers. Transfection efficiencies of pDNA/HMGB1/PEI ternary complexes were evaluated by green fluorescent protein expression level measured by fluorescence spectroscopy and flow cytometry. Transfection efficiencies for pDNA/HMGB1/l-PEI ternary complexes and pDNA/HMGB1/b-PEI ternary complexes showed more than 2.9-fold and 4.0-fold greater than that for pDNA/l-PEI complexes and pDNA/b-PEI complexes, respectively. Thus, our results showed that HMGB1/PEI combined carriers may be a versatile non-viral carrier for pDNA with high transfection efficiency. PMID- 19442463 TI - Antiplasmodial activity of extracts from seven medicinal plants used in malaria treatment in Cameroon. AB - AIM OF THE STUDY: In a search for new plant-derived biologically active compounds against malaria parasites, we have carried out an ethnopharmacological study to evaluate the susceptibility of cultured Plasmodium falciparum to extracts and fractions from seven Cameroonian medicinal plants used in malaria treatment. We have also explored the inhibition of the Plasmodium falciparum cysteine protease Falcipain-2. MATERIALS AND METHODS: Plant materials were extracted by maceration in organic solvents, and subsequently partitioned or fractionated to afford test fractions. The susceptibility of erythrocytes and the W2 strain of Plasmodium falciparum to plant extracts was evaluated in culture. In addition, the ability of annonaceous extracts to inhibit recombinant cysteine protease Falcipain-2 was also assessed. RESULTS AND DISCUSSION: The extracts showed no toxicity against erythrocytes. The majority of plant extracts were highly active against Plasmodium falciparumin vitro, with IC(50) values lower than 5 microg/ml. Annonaceous extracts (acetogenin-rich fractions and interface precipitates) exhibited the highest potency. Some of these extracts exhibited modest inhibition of Falcipain-2. CONCLUSION: These results support continued investigation of components of traditional medicines as potential new antimalarial agents. PMID- 19442464 TI - Geometric morphometric approach to sex estimation of human pelvis. AB - Sex estimation of skeletal remains is an important issue in both forensics and bioarchaeology. The chance of attaining a high level of accuracy regarding sex allocations is related to the skeletal component analyzed and the ability of the techniques employed to describe shape and size differences among the sexes. Current opinion regards the hip bone as the most reliable sex indicator because it is the most dimorphic bone, particularly in adult individuals. The aim of this study was therefore to analyze the greater sciatic notch and the ischiopubic complex morphology by employing geometric morphometric techniques, based on semilandmark and multivariate statistical methods, in order to develop a reliable and accurate technique for adult sex estimation. The sample analyzed consisted of 121 adult left hip bones randomly selected from the collection of documented skeletons housed at the Museu Antropologico de Coimbra. Morphometric analysis was based on coordinates of landmarks and semilandmarks of the ilium and ischiopubic regions that were digitized on 2D photographic images. Discriminant analysis with leave-one-out cross-validation and k-means clustering of shape and shape-size variables were used in order to classify individuals by sex. For the greater sciatic notch, average accuracy of 90.9% was achieved with both multivariate analyses based on shape variables. For the ischiopubic complex, the values obtained with shape variables were 93.4% and 90.1% for discriminant and k-means, respectively. Females were misclassified more frequently than males, especially for the ischiopubic complex. When multivariate statistical analyses were performed using shape-size variables, the percentages of correct classifications were lower than those obtained with shape variables. We conclude that the use of geometric morphometrics and multivariate statistics is a reliable method to quantify pelvic shape differences between the sexes and could be applied to discriminate between females and males. PMID- 19442465 TI - [Hospital LOS, medical complexity and deprivation indicators]. AB - BACKGROUND: Several studies have shown that socioeconomic deprivation is associated with increased hospitalization lengths of stay (LOS) and costs. Yet, the French DRG-based information system (PMSI) does not take deprived situations into account. Hence, we aimed at extracting routinely available variables measuring deprivation from the Hospital Information System and at assessing their association with severity of illness and hospital LOS. METHODS: We performed record linkage between the PMSI database concerning stays of patients aged more than 16years in the short-stay sector of Assistance publique-Hopitaux de Paris in 2007 and an administrative database which provided the following deprivation measures: recipients of Couverture Medicale Universelle (basic or complementary health insurances adapted for underprivileged French citizens) or Aide Medicale d'Etat (health and medical emergency insurances adapted for underprivileged non French citizens living in France) and homeless patients. We compared length of stays showing a deprivation measure to others after adjustment on morbidity, age and sex. RESULTS: Among 352,721 stays, the prevalence of the deprivation measures ranged from 0.71% for "homelessness" to 6.24% for complementary Couverture Medicale Universelle. Stays showing a deprivation measure had specific illnesses and had more frequently associated comorbidities or complications than others. After adjustment, deprivation measures were associated with significantly increased LOS (by 5% for Couverture Medicale Universelle to 48% for emergency Aide Medicale d'Etat. CONCLUSION: Routine extraction of deprivation measures from Hospital Information Systems is feasible. Age, sex and illness being equal, these deprivation measures were associated with more complicated cases and increased LOS. We recommend that case mix-based hospital prospective payment systems take socioeconomic deprivation into account. PMID- 19442466 TI - The utility of diffusion-weighted MR imaging in cervical cancer. AB - PURPOSE: To investigate the value of diffusion-weighted MR imaging (DWI) in detection of cervical cancer, and to determine the diagnostic accuracy of apparent diffusion coefficient (ADC) values for evaluating cervical cancer before and after chemoradiotherapy. MATERIALS AND METHODS: Thirty-three patients with cervical squamous carcinoma and 20 patients with other pelvic abnormalities underwent diffusion-weighted imaging (DWI) in addition to routine MR imaging. The ADC values of normal cervical tissue, cervical area before and after chemoradiotherapy were measured and compared. Receiver operating characteristic (ROC) analysis was employed to investigate whether ADC values could help in discrimination among normal cervical tissue, cervical cancer before and after therapy, and to obtain the optimal ADC threshold value. RESULTS: Cervical cancer lesion demonstrated obviously hyperintensity on DWI images. The mean ADC value of cervical carcinoma (1.110+/-0.175 x 10(-3)mm(2)/s) was significantly lower than that of normal cervical tissue (1.593+/-0.151 x 10(-3)mm(2)/s) (P<0.001). The mean ADC value of the cervical area in 22 patients treated by chemoradiotherapy (1.436+/-0.129 x 10(-3)mm(2)/s) was significantly higher than that before therapy (1.013+/-0.094 x 10(-3)mm(2)/s) (P<0.001). The difference of ADC values between normal cervical tissue and cervical area after therapy was statistically significant (P<0.01). The optimal ADC threshold values for distinguishing between normal cervical tissue and cervical carcinoma was 1.359 x 10(-3)mm(2)/s, between cervical area before and after therapy was 1.255 x 10(-3)mm(2)/s, between normal cervical tissue and cervical area after therapy was 1.525 x 10(-3)mm(2)/s. The sensitivity and specificity were 100% and 84.8%, 95.5% and 100%, 70% and 81.8%, respectively. CONCLUSION: DWI can be applied for the detection of cervical cancer because of its superior disease contrast with normal tissue. The measurement of the ADC values can be a useful tool to monitor the response to therapy for cervical carcinoma. PMID- 19442467 TI - Effect of cardiac function on aortic peak time and peak enhancement during coronary CT angiography. AB - PURPOSE: To examine the manner in which cardiac function affects the magnitude and timing of aortic contrast enhancement during coronary CT angiography (CTA). MATERIALS AND METHODS: Twenty-nine patients (21 men, 8 women; mean age, 64.4+/ 13.4 years; mean weight, 59.4+/-10.3 kg) underwent measurement of cardiac output within 2 weeks of coronary CTA. The cardiac output of each patient was measured by the thermodilution technique and the cardiac index was calculated from the body surface area. During coronary CTA, attenuation of the descending aorta was measured at the workstation every 3s. The aortic peak time (APT) and aortic peak enhancement (APE) of each patient were calculated. Pearson's correlation coefficient analysis was used to investigate the relationships between the cardiac output or cardiac index and APT or APE. Furthermore, the relationship between patient factors or parameters on test bolus injection and APT or APE was also evaluated. RESULTS: The range of cardiac output, cardiac index, APT, and APE was 1.55-10.46 L/min (mean: 4.77+/-2.13), 1.11-5.30 L/(min-m(2)) (mean: 3.28+/ 1.08), 25-51 s (mean: 38.3+/-7.5), and 273.1-598.1 HU (mean: 390.4+/-72.1), respectively. With an increase in the cardiac index, both APT (r=-0.698, p<0.0001) and APE (r=-0.573, p=0.0009) decreased. There were significant correlations between the patient body weight and APT and APE with the test bolus injection, and with APT and APE during coronary CTA. CONCLUSION: The APT and APE during coronary CTA are closely related to cardiac function. PMID- 19442468 TI - Cardiovascular whole-body MRI. AB - Cardiovascular diseases still rank number one in mortality statistics in the industrialized world. In these countries the five most common causes of death are associated to atherosclerotic changes of the arterial vasculature. Due to its often long lasting treatment and the possible loss of ability to work atherosclerotic disease constitutes an economic factor which should not be disregarded. Thus screening for atherosclerotic disease seems to be reasonable because as known the potential to influence atherosclerotic changes is higher in an early stage of the disease. Not in every case it is possible to cure the disease but sometimes progression can be controlled and decelerated. Imaging of the arterial vasculature was limited to invasive procedures associated with ionizing radiation for a long time. Non-invasive exams like the "ankle-brachial index" (ABI) can indicate the presence of PAOD, an exact localization of the pathologic changes is only possible with imaging methods. For cardiac imaging likewise the only non-invasive exams have been ECG and auscultation. Certainly echocardiography is an excellent technique to access cardiac function but it depends very much on both, the examining physician and the patient. MRI constitutes a non-invasive imaging modality without ionizing radiation offering excellent reproducible image quality. PMID- 19442469 TI - Recovery of opthalmoplegia associated with cavernous sinus dural arteriovenous fistulas after transvenous cavernous sinus packing. AB - BACKGROUND: We report the recovery of ophthalmoplegia in 11 patients with cavernous sinus dural arteriovenous fistula (CSDAVF) after sinus packing at follow-up. METHODS: Of 18 patients with CSDAVF treated with transvenous cavernous sinus packing between August 2002 and December 2007 at Beijing Tiantan Hospital, there were 9 patients with initial CNIII or CNVI dysfunction and 2 patients with CNVI dysfunction immediately after cavernous sinus packing selected and reevaluated. RESULTS: Of 11 patients with CNIII or CNVI palsy, recovery was complete in 10. In 1 patient, complete CNVI palsy was unchanged because the CSDAVF was not cured. There were 6 men and 5 women with a mean age of 52.9 years. In 5 patients, CNVI palsy was associated with chemosis, proptosis and pulsatile tinnitus. Timing of treatment after onset of symptoms was from 4 to 35 days in 9 patients. All CSDAVFs were Barrow type D. Mean follow-up after treatment was 17.7 months (range, 2-54 months). CONCLUSION: CSDAVF-induced CNIII or CNVI palsies can be cured after cavernous sinus packing transvenously in most patients. PMID- 19442470 TI - The additional value of three time point color coding in dynamic contrast enhanced MRI of the breast for inexperienced and experienced readers. AB - PURPOSE: To evaluate the additional value of the color coding of dynamic data using the 3TP method in the evaluation of contrast-enhanced breast MRI for readers with different levels of experience. MATERIALS AND METHODS: A total of 52 lesions were included in this study, 25 malignant and 27 benign. All lesions were evaluated by four readers on two different workstations for the evaluation of dynamic breast MRI; one displaying the subtracted images and relative enhancement versus time curves and one displaying the subtracted images together with the 3TP color coding projected onto pre-contrast T1 images. Readers with different levels of experience were used. The diagnostic performance of both workstations was evaluated using ROC curve analyses. Interobserver variations were evaluated using kappa statistics. RESULTS: All lesions were detected by all four readers on both workstations. The diagnostic performance found in the inexperienced readers improved significantly when using the 3TP evaluations (p=0.04 and p=0.03). No significant difference was found for the more experienced readers (p=0.94 and p=0.54). The level of agreement between the readers improved significantly when using the 3TP evaluation method (p=0.01). CONCLUSION: Even though the 3TP color coding did not improve the diagnostic performance of the more experienced readers, this study clearly shows its value for inexperienced readers. The use of 3TP color coding is therefore recommended for inexperienced readers. PMID- 19442471 TI - 1-Minute quality control tests for positron emission tomography radiopharmaceuticals. AB - An ultra-fast, sensitive and versatile radio-liquid chromatographic (LC) procedure was developed and validated for quality control (QC) tests of PET radiopharmaceuticals. For a wide variety of radio-probes, the usual LC conditions were used: (1) column: Waters XBridge RP(18) (50 mm x 3.0 mm ID, 2.5 microm), (2) mobile phase: a mixture of three modifiers (90% CH3CN, ammonium phosphate at pH 2.1 and pH 9.3), and (3) detection: UV absorption and NaI(Tl) scintillation. The introduction of a short column packed with small particles of 2.5 microm allowed excellent separation of target analytes within a very short run time of 1 min; only a 3% decline of radioactivity was observed during QC analysis of (11)C labelled pharmaceuticals. Combining ammonium-phosphate buffer as the mobile-phase component and low-wavelength UV detection led to an improvement in the applicability and sensitivity. All 34 pharmaceuticals investigated could be successfully applied to determine the specific radioactivity, radiochemical and chemical purity with 10-times better sensitivity than traditional LC. We could analyze different pharmaceuticals in a short period since this system utilized a common column and mobile phase. The proposed procedure fulfils the requirements for routine QC tests in terms of rapidity, sensitivity, simplicity and applicability. PMID- 19442472 TI - Antioxidant evaluation of O-methylated metabolites of catechin, epicatechin and quercetin. AB - Catechins and quercetin are major polyphenols in many plant foods that have been related to health promotion. In the human organism they are largely metabolized to different metabolites, which are further found in plasma and should contribute to the biological effects associated to the intake of the parent compounds. An important step in quercetin and catechins metabolism is the O-methylation of the catechol group, which can be expected to have an effect on their antioxidant and scavenging properties. In the present work, the 3'- and 4'-methylethers of catechin and epicatechin have been prepared and characterised and their antioxidant activity evaluated and compared to that of the corresponding quercetin derivatives. The antioxidant activity was assessed using the ferric reducing power (FRAP) assay and two methods based on the ability to scavenge the ABTS(+) radical cation at different pH values. In these assays the three flavonoids behave as better radical scavengers and reducing compounds than usually recognised antioxidants like alpha-tocopherol. The O-methylation of the hydroxyls of the catechol B-ring resulted in a decrease of the antioxidant activity with regard to the parent compounds. However, the methylated metabolites still retain significant radical scavenging activity at pH 7.4, suggesting that they could act as potential antioxidants in physiological conditions. Quercetin and its methylated metabolites showed, in general, greater activity than (epi)catechin and their O-methyl derivatives, although a relatively high antioxidant activity was found in the case of 3'-O-methyl catechin at pH 7.4, comparable to those of its parent compound and the quercetin metabolites. It was confirmed that the antioxidant activity of the flavonoids assayed was strongly dependent on the pH of the medium, showing higher activity at greater pH values. The results obtained are expected to contribute to the understanding of the mechanisms involved in the biological effects attributed to the intake of flavonoid-rich diets. PMID- 19442473 TI - A high-throughput LC-MS/MS method for the quantitation of posaconazole in human plasma: Implementing fused core silica liquid chromatography. AB - A rapid and robust liquid chromatographic tandem mass spectrometric (LC-MS/MS) method for the determination of posaconazole concentrations in human plasma was validated. Posaconazole was extracted from human plasma using mixed-mode cation exchange solid phase extraction in a 96-well plate format followed by gradient separation on a fused-core Halo C18 column. The analyte and its corresponding internal standard were detected using a Sciex API 4000 triple quadrupole LC-MS/MS system equipped with a TurboIonSpray ionization source operated in the positive ion mode. The calibration range of the method was 5.00-5000ng/mL using a 50microL aliquot of plasma. The assay inter-run accuracy and precision were-4.6-2.8% and 2.3-8.7%, respectively (n=18). The results from method validation indicate the method to be sensitive, selective, accurate, and reproducible. The method was successfully applied to the routine analysis of clinical samples with the fused core silica columns providing excellent reproducibility for greater than 1000 injections per column. PMID- 19442474 TI - Nontraumatic pneumocephalus due to nosocomial Enterobacter cloacae infection. AB - Nosocomial meningitis is rare, and routine cerebrospinal fluid study is seldom recommended for hospitalized patients with fever and acute delirium. We present a case of Enterobacter cloacae meningitis complicated with a nontraumatic pneumocephalus. Maintaining a high index of suspicion of nosocomial meningitis is crucial in patients with acute delirium and multiple underlying comorbid conditions. PMID- 19442475 TI - Virulence features of atypical enteropathogenic Escherichia coli identified by the eae(+) EAF-negative stx(-) genetic profile. AB - This study characterized 76 atypical enteropathogenic Escherichia coli (aEPEC) strains, previously classified by the eae(+) EAF-negative stx(-) genotype, isolated from children with diarrhea in Brazil. Presence of bfpA and bfpA/perA was detected in 2 and 6 strains, respectively. The expression of bundle-forming pilus (BFP), however, was observed by immunofluorescence in 1 bfpA and 3 bfpA/perA strains, classifying them as typical EPEC (tEPEC). The remaining 72 aEPEC strains were characterized by serotyping, intimin typing, adherence patterns to HEp-2 cells, capacity to induce actin aggregation (fluorescent actin staining test), and antimicrobial resistance. Our results show that aEPEC comprise a very heterogeneous group that does not present any prevalence or association regarding the studied characteristics. It also suggest that tEPEC and aEPEC must not be classified only by the reactivity with the EAF probe, and that the search of other markers present in pEAF, as well as the BFP expression, must be considered for this matter. PMID- 19442476 TI - Manubriosternal joint dislocation: an unusual risk of trampolining. AB - BACKGROUND: Manubriosternal joint (MSJ) dislocation is a rare but potentially serious injury that can be associated with concurrent injuries to ribs, lungs, or myocardium. Two distinct types of MSJ dislocation have been described in the literature: type I, involving posterior dislocation of the sternum due solely to direct trauma; and type II, involving the sternum being pushed anteriorly as a result of indirect trauma. Until now, the relationship between the nature of the forces acting on the sternum and the type of MSJ dislocation that results has been absolute, whereby indirect forces never cause a type I dislocation, and direct forces never result in a type II dislocation. OBJECTIVES: To describe a case demonstrating that type I MSJ dislocation can occur without direct trauma. CASE REPORT: A 14-year-old boy developed sternal pain accompanied by an audible crack while executing a maneuver on a trampoline that required hyperflexion of the thorax. A lateral chest radiograph demonstrated a type I manubriosternal dislocation normally associated with direct trauma, as opposed to the more typical type II dislocation pattern one would expect to find in a hyperflexion injury. CONCLUSION: MSJ dislocations are classified into two groups, depending on the position of the sternum in relation to the manubrium. Each type of dislocation has been ascribed to either direct forces (for type I dislocation) or indirect forces (for type II dislocation). This case highlights that it is possible to have a type I dislocation in the absence of any direct sternal trauma. PMID- 19442477 TI - Education, literacy, and health: Mediating effects on hypertension knowledge and control. AB - OBJECTIVE: To determine whether literacy mediates the association between education, hypertension knowledge and control. METHODS: In-person interviews with a literacy assessment and chart review were conducted with 330 hypertensive patients from six primary care safety net clinics. Mediational analysis was used to test the role of literacy skills in explaining the relationship between education and hypertension knowledge and control. RESULTS: In multivariate analyses that did not make an adjustment for the other variable, both lower educational attainment and more limited literacy were found to be significant independent predictors of poorer hypertension knowledge and control. When literacy was entered into models that included education only, the association between education and knowledge was fully attenuated and no longer significant (Grades 1-8: beta=-0.30, 95% CI=-1.44-0.83), while the relationship between education and blood pressure control was only minimally reduced (AOR 2.46, 95% CI 2.10-2.88). More limited literacy skills also was associated with hypertension control in the final model (AOR 2.68, 95% CI 1.54-4.70). CONCLUSION: Patient literacy mediated the relationship between education and hypertension knowledge. Literacy was a significant independent predictor of blood pressure control, but only minimally explained the relationship between education and blood pressure. PRACTICE IMPLICATIONS: Health literacy is critical to the design of educational tools to improve knowledge acquisition. However, in order to impact health outcome, future health literacy studies should also address other psychosocial factors that impact motivation and capability to manage disease. PMID- 19442478 TI - Unraveling the relationship between literacy, language proficiency, and patient physician communication. AB - OBJECTIVE: To examine whether the effect of health literacy (HL) on patient physician communication varies with patient-physician language concordance and communication type. METHODS: 771 outpatients rated three types of patient physician communication: receptive communication (physician to patient); proactive communication (patient to physician); and interactive, bidirectional communication. We assessed HL and language categories including: English speakers, Spanish-speakers with Spanish-speaking physicians (Spanish-concordant), and Spanish-speakers without Spanish-speaking physicians (Spanish-discordant). RESULTS: Overall, the mean age of participants was 56 years, 58% were women, 53% were English-speakers, 23% Spanish-concordant, 24% Spanish-discordant, and 51% had limited HL. Thirty percent reported poor receptive, 28% poor proactive, and 56% poor interactive communication. In multivariable analyses, limited HL was associated with poor receptive and proactive communication. Spanish-concordance and discordance was associated with poor interactive communication. In stratified analyses, among English-speakers, limited HL was associated with poor receptive and proactive, but not interactive communication. Among Spanish-concordant participants, limited HL was associated with poor proactive and interactive, but not receptive communication. Spanish-discordant participants reported the worst communication for all types, independent of HL. CONCLUSION: Limited health literacy impedes patient-physician communication, but its effects vary with language concordance and communication type. For language discordant dyads, language barriers may supersede limited HL in impeding interactive communication. PRACTICE IMPLICATIONS: Patient-physician communication interventions for diverse populations need to consider HL, language concordance, and communication type. PMID- 19442480 TI - [Autosomal recessive cerebellar ataxias]. AB - Friedreich ataxia is the most frequent recessive cerebral ataxia d should always be researched first. Ataxia with isolated vitamin E deficiency and abetalipoproteinemia have a specific treatment. Associated neurological signs such polyneuroapthy, ophtalmologic or oculomotor signs, pyramidal signs, and cerebellar MRI can lead to the etiological diagnosis. Biological tests should be: vitamin E, cholesterol, alpha-fetoprotein levels, acanthocytes, than phytanic acid, cholestanol, lysosomal enzymes. Numerous autosomal recessive cerebellar ataxia remain without etiology. PMID- 19442481 TI - [Gossypiboma in the abdomen: don't forget this diagnosis]. PMID- 19442479 TI - Colorectal cancer screening by primary care physicians: recommendations and practices, 2006-2007. AB - BACKGROUND: Primary care physicians (hereafter, physicians) play a critical role in the delivery of colorectal cancer (CRC) screening in the U.S. This study describes the CRC screening recommendations and practices of U.S. physicians and compares them to findings from a 1999-2000 national provider survey. METHODS: Data from 1266 physicians responding to the 2006-2007 National Survey of Primary Care Physicians' Recommendations and Practices for Breast, Cervical, Colorectal, and Lung Cancer Screening (cooperation rate=75%) were analyzed in 2008. Descriptive statistics were used to examine physicians' CRC screening recommendations and practices as well as the office systems used to support screening activities. Sample weights were applied in the analyses to obtain national estimates. RESULTS: Ninety-five percent of physicians routinely recommend screening colonoscopy to asymptomatic, average-risk patients; 80% recommend fecal occult blood testing (FOBT). Only a minority recommend sigmoidoscopy, double-contrast barium enema, computed tomographic colonography, or fecal DNA testing. Fifty-six percent recommend two screening modalities; 17% recommend one. Nearly all physicians who recommend endoscopy refer their patients for the procedure. Four percent perform sigmoidoscopy, a 25-percentage-point decline from 1999-2000. Although 61% of physicians reported that their practice had guidelines for CRC screening, only 30% use provider reminders; 15% use patient reminders. CONCLUSIONS: Physicians' CRC screening recommendations and practices have changed substantially since 1999-2000. Colonoscopy is now the most frequently recommended test. Most physicians do not recommend the full menu of test options prescribed in national guidelines. Few perform sigmoidoscopy. Office systems to support CRC screening are lacking in many physicians' practices. Given ongoing changes in CRC screening technologies and guidelines, the continued monitoring of physicians' CRC screening recommendations and practices is imperative. PMID- 19442482 TI - [Peripheral occlusive arterial disease in the young patient]. AB - Lower limb arterial disease has unusual features when occurring before 50 years old. The most important one is the number of causes: atherosclerosis in 2/3 cases, Leo Buerger's disease in 1/4, but also sometimes embolic cardiopathies, antiphospholipid syndrome, myeloproliferative disorders, genetic or compressive diseases, inflammatory arterial disease. When peripheral arterial disease occurs before 50, explorations have to be performed according to anamnesis: duplex echography, EKG, blood sample. Afterwards other explorations may be performed such as other vascular imaging techniques, echocardiography or more complete biological investigation. Results from an ongoing multicenter study should be soon available and give more knowledge about these special peripheral arterial diseases. PMID- 19442483 TI - Acetabular cup revision with the use of the medial protrusio technique at an average follow-up of 6.6 years. AB - A significant rim defect encountered during revision surgery can make stable cementless cup fixation difficult. One approach to this problem is to medialize the acetabular cup to improve the degree of rim contact. In this study, we investigate this technique, termed the medial protrusio technique, for acetabular fixation in revision hip arthroplasty. A retrospective review of 25 patients (25 hips) who underwent medialization was performed. Clinical and radiographic evaluation was performed. At an average follow-up of 6.6 years, the overall patient function and satisfaction were good to excellent, with a mean Harris hip score of 85.2. This demonstrates that the medial protrusio technique can be a valuable option in addressing acetabular cup failure. PMID- 19442484 TI - Minimal radiation dose computed tomography for measurement of cup orientation in total hip arthroplasty. AB - We studied a computed tomography (CT) protocol with minimal radiation dose for measurements of cup orientation after total hip arthroplasty. Inclination and version angles were measured directly on cadaver pelvis fixed with an acetabular component. We performed the CT scanning on the phantom made of this model in 6 protocols as follows: tube current of 300, 100, 50, 30, 20, and 10 mA. The 30 mA protocol maintained good image quality for measurements with the smallest dose (1.1 millisievert), which corresponds to less than 2 times that of an anteroposterior radiograph of the pelvis. The differences of measured angles between direct and CT measurements on the phantom were less than 1 degrees. Measurements of cup orientation were possible by this protocol in 26 hips in 22 patients after total hip arthroplasty. PMID- 19442485 TI - Removing a well-fixed nonmodular large-bearing cementless acetabular component: a simple modification of an existing removal device. AB - Removing well-fixed cementless acetabular components while minimizing bone loss has been facilitated by the use of a removal device featuring sharp curved gouges, specific to the outside diameter of the existing acetabular shell, mated to a femoral head designed to sit inside the acetabular liner. Nonmodular acetabular components with inner bearing diameters greater than 36 mm are to date not accommodated by femoral head sizes in this system. A simple modification, placement of a bipolar head matching the inner diameter of the fixed shell, allows use of this removal device for nonmodular shells. PMID- 19442486 TI - Disentangling cellular proliferation and differentiation in the embryonic stem cell test, and its impact on the experimental protocol. AB - The mouse embryonic stem cell test (EST) was designed to predict embryotoxicity based on the inhibition of the differentiation of embryonic stem cells (ESC) into beating cardiomyocytes in combination with cytotoxicity data in monolayer ESC cultures and 3T3 cells. In the present study, we have tested a diverse group of chemicals in the EST, applying different exposure durations, in an attempt to discriminate between effects on proliferation and differentiation within the EST protocol. Chemicals tested were monobutyl phthalate (MBP), 6-aminonicotinamide (6 AN), 5-fluorouracil (5-FU) and 5-bromo-2'-deoxyuridine (BrdU). We showed that 5 FU and BrdU behaved principally different from MBP and 6-AN. 5-FU and BrdU specifically affected cell proliferation during the first three days of the EST protocol, as shown by EB size, protein concentration and cell cycle stage analysis. In addition, we studied the differentiation state of cells in the EST protocol with time to elucidate the transition of pluripotent ESC to more differentiated cell types. Analysis by flow cytometry of the pluripotency marker SSEA-1 in EST showed that although total SSEA-1 positive cells remained unchanged up to and including day 5, the signal intensity already decreased from day 3 onwards. Furthermore, RT-PCR data showed an upregulation of the mesodermal marker T at day 3, whereas the cardiac muscle marker Myh6 was upregulated from day 5 onwards. These findings confirm that proliferation and differentiation of ESC in the EST are highly intertwined processes. Based on these findings we suggest an amended EST protocol which could more clearly discriminate between proliferation and differentiation effects of chemicals within the same EST differentiation protocol. This proposal includes a cytotoxicity assessment in EB at day 3 of the EST after day 0-3 exposure, and cardiac muscle foci counts after exposure from day 3-10 in the EST. PMID- 19442487 TI - Existence and global exponential stability of periodic solution of a cellular neural networks difference equation with delays and impulses. AB - A class of cellular neural networks difference equation with delays and impulses are considered. Sufficient conditions for the existence and global exponential stability of periodic solution are obtained by using contraction mapping theorem and inequality techniques. The results of this paper are completely new. A numerical example and its simulations are offered to show the effectiveness of our new results. PMID- 19442488 TI - Anterior segmental distraction of the hypoplastic maxilla by a tooth borne device: a study on the movement of the segment. AB - The aim of this study is to determine the relative movement of the teeth and bone after premaxillary distraction with a tooth-borne device constructed in the authors' centre. To evaluate the effects of this device on the anterior segment and teeth, the space formed between the anterior and posterior segments of the maxilla was measured on computerized tomography images from 10 patients. The average differences were 3.5mm at the apex level, 5.5 mm at alveolar ridge level and 7.4 mm at crown level on the right side. On the left side, the average differences were 3.2, 5.2 and 7.1 mm, respectively. There were statistically significant differences between all these measurements (p<0.05), but the difference between right and left sides was not statistically significant (p>0.05). The ratio between the movements at apex and crown levels was 46%. These results showed that the tooth-borne distractor was able to distract the anterior segment of the maxilla but it also caused anchorage loss of the maxillary incisors. PMID- 19442489 TI - The electrophysiological "delayed effect" of focal interictal epileptiform discharges. A low resolution electromagnetic tomography (LORETA) study. AB - Collating the findings regarding the role of focal interictal epileptiform discharges (IEDs) on CNS functions raises the possibility that IEDs might have negative impact that outlasts the duration of the spike-and-wave complexes. The aim of this study was the electrophysiological demonstration of the "delayed effect" of the IEDs. 19-channel, linked-ears referenced, digital waking EEG records of 11 children (aged 6-14 years, eight with idiopathic, three with cryptogenic focal epilepsy, showing a single spike focus) were retrospectively selected from our database. A minimum of 20 (preferably, 30), 2-s epochs containing a single focal spike-and-wave complex were selected (Spike epochs). Thereafter, Postspike-1 (Ps1), Postspike-2 (Ps2) and Postspike-3 (Ps3) epochs were selected, representing the first and second seconds (Ps1), the third and fourth seconds (Ps2) and the fifth and sixth seconds (Ps3) after the Spike epoch, respectively. Interspike epochs (Is) were selected at a distance at least 10s after the Spike epoch. Individual analysis: the frequency of interest (FOI=the individual frequency of the wave component of the IEDs), and the region of interest (ROI=the site of the IEDs) were identified by reading the raw EEG waveform and the instant power spectrum. Very narrow band LORETA (low resolution electromagnetic tomography) analysis at the FOI and ROI was carried out. Age adjusted, Z-transformed LORETA "activity" (=current source density, amperes/meters squared) was compared in the Spike, Ps1, Ps2, Ps3 and Is epochs. FINDINGS: the greatest (uppermost pathological) Z-scores and the greatest spatial extension of the LORETA-abnormality were always found in the Spike epochs, followed by the gradual decrease of activity in terms of severity and spatial extension in the Ps1, Ps2, Ps3 epochs. The lowest (baseline) level and extension of the abnormality was found in the Is epochs. Group analysis: average values of activity across the patients were computed for the temporal decrease of the abnormality. FINDINGS: a clear tendency for the decrease of abnormality was demonstrated. CONCLUSION: the "delayed effect" of the IEDs was demonstrated electrophysiologically and quantified. The method may be utilized in the individual assessment of the effect of IEDs on cortical activity, the degree and temporo-spatial extension of the abnormality. PMID- 19442490 TI - Delusions, illusions and hallucinations in epilepsy: 2. Complex phenomena and psychosis. AB - In this second paper the clinical features and electrophysiological underpinnings of more complex psychotic states associated with epilepsy are reviewed. (a) Complex partial status epilepticus, in particular of temporal lobe origin, may result in mental states remarkably similar to those seen in the primary psychoses. This non-convulsive state is associated with prolonged epileptic discharges on intracranial stereoelectroencephalography (SEEG) in hippocampal and other mesial temporal structures, sometimes without abnormalities on the scalp EEG. Where hallucinatory or psychotic symptomatology does occurs, it can be considered an examples of an ictal psychosis. The phenomenology and electrophysiological features of this condition are reviewed. (b) Postictal psychosis is noted for its similarity to schizophrenia-like/paranoid and affective psychoses and there is convincing SEEG evidence that, for some cases at least, the psychosis is not in fact postictal but rather an ictal psychosis due to ongoing limbic seizure activity and a form of non-convulsive status epilepticus. It has been suggested that postictal psychosis should be divided into two sub-groups: the classical 'nuclear' postictal type and an atypical periictal type. (c) Interictal hallucinosis in epilepsy has been poorly studied, but is probably commoner than appreciated. To what extent it represents subclinical epileptic discharges (i.e. auras) is not known. It may interestingly also be associated with abnormal affective states in epilepsy. (d) The interictal psychosis of epilepsy is often indistinguishable from primary schizophrenia. It occurs more commonly in temporal lobe (limbic) epilepsy, in those with frequent seizures and only in patients with a long history of epilepsy (usually over 10 years). There is convincing SEEG evidence of frequent, semi-continuous and sometimes continuous epileptic activity in limbic structures at the time of psychotic and hallucinatory ideation and behaviour, suggesting that in some cases at least, the epileptic activity is the cause of the symptoms. Whether the psychosis is directly 'driven' by subclinical electrographic activity or is indirectly a consequence of function change induced by such activity is not clear. An intriguing question also arises as to whether similar electrophysiological changes could underpin psychosis in patients without epilepsy but evidence on this point is sparse. The effects of temporal lobe surgery on the psychoses of epilepsy are described and these might throw light on the mechanisms of epileptic psychosis. The principles of pharmacological therapy of epileptic hallucinosis and psychosis are outlined. PMID- 19442491 TI - Immediate versus gradual suspension of previous treatments during switch to aripiprazole: results of a randomized, open label study. AB - The aim of the present work was to investigate possible differences in terms of efficacy and tolerability between different switching options to aripiprazole. 77 subjects were randomly assigned to (1) administration of aripiprazole (10 mg) with simultaneous discontinuation of current antipsychotic; (2) administration of aripiprazole (10 mg) and tapering off current antipsychotic over 4 weeks with half dose after the first 2 weeks; (3) administration of aripiprazole (10 mg) and tapering off current antipsychotic over 6 weeks with half dose after the first 2 weeks. Efficacy assessments included CGI-S, CGI-I, BPRS and SANS. Safety assessments included SAS, BAS and AIMS. Severity of symptoms significantly decreased from baseline over the 12 weeks of treatment. Patients switched to aripiprazole with immediate discontinuation of the previous antipsychotic showed an increase of symptoms' severity at week 1. However, severity of side effects did not overall change significantly during the 12-weeks follow-up. Previous treatment's tapering off strategy for switching patients to aripiprazole could be preferable as compared to abrupt discontinuation, in order to prevent early worsening of symptoms and premature discontinuation of treatment, though this results has to be considered with caution given the limitations of the study. PMID- 19442493 TI - Dysfunctional, but not functional, impulsivity is associated with a history of seriously violent behaviour and reduced orbitofrontal and hippocampal volumes in schizophrenia. AB - Aggression and violent acts have been linked with impulsive responding. We investigated whether impulsive personality trait, especially suggestive of dysfunctional impulsivity (i.e. fast and inaccurate responding where this is non optimal), is associated with a history of seriously violent behaviour and specific brain deficits in schizophrenia. Twenty-four male participants with schizophrenia, of whom 10 had a history of serious physical violence, and 14 healthy male participants were assessed on impulsiveness (dysfunctional impulsivity), venturesomeness (functional impulsivity), and empathy. All participants underwent magnetic resonance imaging. The results revealed that participants with schizophrenia and a history of violence showed elevated impulsiveness but had comparable scores on venturesomeness and empathy dimensions. Impulsiveness scores correlated negatively with reduced orbitofrontal grey matter volume in both the patient and healthy control groups, and with hippocampal volume in the patient group. Our findings suggest that dysfunctional, but not functional, impulsivity is elevated in patients with schizophrenia with a propensity for repetitive violence, and this in turn appears to be associated with reduce volumes of both the orbitofrontal cortex grey matter and the hippocampus. Violence risk prediction and management strategies in schizophrenia may benefit from including specific measures of dysfunctional impulsive traits. PMID- 19442494 TI - Reduced brain activation in euthymic bipolar patients during response inhibition: an event-related fMRI study. AB - Deficits in inhibitory control have been reported in euthymic bipolar disorder patients. To date, data on the neuroanatomical correlates of these deficits are exclusively related to cognitive inhibition. This study aimed to examine the neural substrates of motor inhibitory control in euthymic bipolar patients. Groups of 20 patients with euthymic bipolar disorder and 20 demographically matched healthy subjects underwent event-related functional magnetic resonance imaging while performing a Go-NoGo task. Between-group differences in brain activation associated with motor response inhibition were assessed by using random-effects analyses. Although euthymic bipolar patients and healthy subjects performed similarly on the Go-NoGo task, they showed different patterns of brain activation associated with response inhibition. Specifically, patients exhibited significantly decreased activation in the left frontopolar cortex and bilateral dorsal amygdala compared with healthy subjects. There were no brain regions that were significantly more activated in patients than in healthy subjects. The findings suggest that euthymic bipolar patients have deficits in their ability to engage the left frontopolar cortex and bilateral dorsal amygdala during response inhibition. Further research should ascertain the role that such deficits may play in the emergence of impulsive behaviors that characterize bipolar disorder. PMID- 19442492 TI - Tract-Based Spatial Statistics (TBSS) of diffusion tensor imaging data in alcohol dependence: abnormalities of the motivational neurocircuitry. AB - Previous diffusion tensor imaging (DTI) studies indicated microstructural disruption of white matter in alcohol dependence. To investigate the microstructure of primary neurocircuitry involved in alcohol use disorders, the present study used Tract-Based Spatial Statistics (TBSS) of DTI measures as well as probabilistic tractography. Eleven recovering alcoholics in their first week of abstinence from alcohol were compared with 10 light-drinking controls; diffusion measures were correlated with measures of neurocognition and drinking severity. Regions characterized by low fractional anisotropy and high mean diffusivity included cortico-striatal fibers and those in frontal white matter and limbic pathways. Greater diffusion abnormalities in sections of commissural fibers (inter-hemispheric connections) were associated with greater drinking severity, and lower fractional anisotropy measures in frontal and limbic fiber tracts correlated with lower visuospatial memory performance. These study findings provide direct evidence of compromised integrity of the motivational brain circuitry in alcohol use disorders. These abnormalities in fiber connections could be partially responsible for deficiencies in executive functions, behavioral regulation, and impulse control commonly described in alcohol dependence. PMID- 19442495 TI - The effect of acute tryptophan depletion on performance and the BOLD response during a Stroop task in healthy first-degree relatives of patients with unipolar depression. AB - Previous research has shown that low central serotonin, induced by acute tryptophan depletion (ATD), results in depressed mood and impairs cognition in healthy volunteers with a predisposition for depression. It remains unknown whether ATD affects emotional processing via mood changes or directly. In the present study we investigated the interaction between vulnerability for depression and the effect of ATD on mood, cognition and the associated brain activation. In a previous functional MRI study, we tested the effect of ATD during a combined cognitive and emotional Stroop task in healthy women without a family history of depression (FH-). In this study, we present the data of an additional group of 12 healthy women with a positive family history of unipolar depression (FH+). The effect of ATD on mood and Stroop performance was different for the FH+ group as compared with the FH- group. Scores on the depression sub scale of the Profile of Mood States (POMS) did not correlate with performance changes, but did correlate with the anterior cingulate cortex response during Stroop interference. This study showed that a family history of unipolar depression interacts with the effect of ATD. PMID- 19442496 TI - Diffusion tensor changes in patients with amnesic mild cognitive impairment and various dementias. AB - White matter damage and its contribution to clinical manifestations in patients with dementia have been increasingly recognized. To explore white matter changes in different types of dementia, we examined brain water diffusivity with diffusion tensor imaging (DTI). We measured fractional anisotropy and mean diffusivity of multiple white matter regions in patients with amnesic mild cognitive impairment (MCI, n=10), Alzheimer's disease (AD, n=30), subcortical ischemic vascular dementia (SIVD, n=18), frontotemporal dementia (FTD, n=7), and control subjects (n=20). We performed pairwise comparisons in each region of interest between patients and controls. MCI patients showed diffusion tensor change (DTC) in the left anterior periventricular (PV) area, possibly in the right posterior PV area, and the genu of the corpus callosum. AD patients showed DTC in the corpus callosum, and in frontal and parieto-occipital subcortical and anterior PV areas. In SIVD patients, DTC occurred in the genu of the corpus callosum, and in bilateral frontal subcortical and PV areas. FTD patients differed from controls in showing DTC in the temporal and frontal subcortical areas, the genu of the corpus callosum and PV areas. The degree of DTC correlated with the clinical severity of dementia as assessed by the clinical dementia rating (CDR). Mean diffusivity was diffusely and positively associated with the CDR scores. Fractional anisotropy of the PV areas was negatively associated with the CDR scores, suggesting a critical role of the lateral cholinergic pathways. PMID- 19442497 TI - Impact factors and thermodynamic characteristics of aquatic humic acid loaded onto kaolin. AB - The adsorption of humic acid (HA) on kaolin particles was studied at various conditions of initial solution pH, ionic strength and solid-to-liquid ratio. The resulting affinity of interactions between humic acid and kaolin was attributed to the surface coordination of HA in ambient suspensions of mineral particles and the strong electrostatic force at low pH. Addition of inorganic salt can also influence the adsorption behavior by affecting the HA molecular structure, the clay particle zeta potential and so on. Equilibrium data were well fitted by the Freundlich model and implied the occurrence of multilayer adsorption in the process. In addition, the enthalpy dependent of system temperature was 79.17 kJ/mol, which proved that the mechanism of HA adsorption onto kaolin was comprehensive, including electrostatic attraction, ligand complexation and hydrogen bonding. PMID- 19442498 TI - Tissue surface tension measurement by rigorous axisymmetric drop shape analysis. AB - Certain behaviours of embryonic cell aggregates can be modelled by ascribing to them a tissue surface tension, with each cell analogous to a liquid molecule. Under normal gravity, aggregates are nearly spherical, but they can be partially flattened in a centrifuge. This allows measurement of their tissue surface tensions by a drop shape method such as axisymmetric drop shape analysis (ADSA). We study ectodermal embryonic cells from the frog Xenopus laevis subjected to centrifugation at 100 x g and 200 x g. We show that ADSA can be applied to irregular aggregate profiles and compare results with those from a previous, simpler version called ADSA-IP. With a modification in the experimental method, the two algorithms give similar results and the aggregate profiles more closely follow Laplacian curves. The ADSA fitting error allows an estimate of the relative uncertainty in the results. PMID- 19442499 TI - [Asthma and obesity in childhood: what is the link?]. AB - According to the definition (body mass index>97 degrees percentile), overweight and obesity concern 15% of French children. The parallel trends in the increase in asthma and obesity may indicate a potential link between these two conditions. The purpose of this study was to review the epidemiological data indicating a relationship between asthma and obesity, to evaluate the consequences of obesity on asthma and to assess the mechanisms of this association. We conclude with the implications for treatment strategies. PMID- 19442500 TI - On the evolution of 'Indian Bison type' strains of Mycobacterium avium subspecies paratuberculosis. AB - Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne's disease (JD) in animals, has also been linked with Crohn's disease in human beings. Lack of indigenous diagnostics and vaccine hampered control of JD in India. Designing effective control strategies require thorough understanding of the etiological agent at phenotypic and molecular levels. On the basis of cultural phenotypes and IS1311 PCR-REA typing, MAP strains have been genotyped as 'Cattle type', 'Sheep type' and 'Bison type'. Information exists on genetic differences and comparative evolution of 'Cattle type' and 'Sheep type' strains after divergence from M. avium; however, emphasis has been little on 'Bison type' strains. Recently, a new 'Indian Bison type' genotype has been reported as principal strain infecting different animal species and human beings in India. The study analyzed few genetic markers to have inferences on the molecular evolution of native MAP isolates belonging to 'Bison type' genotype. Results pointed towards recent evolution of 'Bison type' genotype. PMID- 19442501 TI - Maternal dietary n-3 fatty acids alter cardiac ventricle fatty acid composition, prostaglandin and thromboxane production in growing chicks. AB - The effects of feeding n-6 and n-3 fatty acids to broiler hens on cardiac ventricle fatty acid composition, and prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) production of hatched chicks were investigated. Fertile eggs obtained from hens fed diets supplemented with 3.5% sunflower oil (Low n-3), 1.75% sunflower+1.75% fish oil (Medium n-3), or 3.5% fish oil (High n-3) were incubated. The hatched chicks were fed a diet containing 18:3 n-3, but devoid of longer chain n-6 and n-3 fatty acids for 42 days. Arachidonic acid content was lower in the cardiac ventricle of High n-3 and Medium n-3 compared to Low n-3 birds for up to 2 weeks (P<0.002). Long chain n-3 fatty acids were higher in the cardiac ventricle of chicks from hens fed High and Medium n-3 diets when compared to chicks from hens fed the Low n-3 diet. Differences in long chain n-3 fatty acids persisted up to four weeks of age (P<0.001). Peripheral blood mononuclear cells (PBMNC) of 7-day-old High n-3 broilers produced significantly lower PGE2 and TXA2 than PBMNC from Low n-3 and Medium n-3 birds. These results indicate that maternal dietary n-3 fatty acids increases cardiac ventricle n-3 fatty acids while reducing arachidonic acid and ex vivo PGE2 and TXA2 production during growth in broiler chickens. PMID- 19442502 TI - Genetic control of resistance to human malaria. AB - The term 'innate resistance' covers mechanisms of resistance that operate early in the course of infections, preceding adaptive immune responses which exert effects after several days. The first example of genetically controlled innate resistance to human malaria was the demonstration in 1954 that sickle-cell heterozygotes have less severe Plasmodium falciparum infections than do children with normal adult hemoglobin. This observation has been repeatedly confirmed, most recently by independent studies of genome-wide associations in severe falciparum malaria, which have identified the HBB locus as the major signal of association. Other abnormal hemoglobins, glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency also confer some degree of resistance against falciparum malaria. A second early example of inherited innate resistance to malaria was the finding that nonexpression of the Duffy antigen/chemokine receptor (DARC) on erythrocytes confers resistance to P. vivax. However, this parasite can enter nonhuman primate red cells independently of DARC, and in some human populations P. vivax has been observed in persons lacking DARC. Hence DARC is not the only receptor for P. vivax, but it is likely to be a major one for human transmission. Innate resistance to malaria is rapidly reinforced by adaptive immune responses, both cell-mediated and humoral. Among the factors influencing the efficacy of adaptive immune responses to malaria is the MHC complex constitution of hosts. This differs among populations, presumably because of variations in the structure of parasite antigens recognized by the immune systems of hosts. PMID- 19442503 TI - Membrane injury by pore-forming proteins. AB - The plasma membrane defines the boundary of every living cell, and its integrity is essential for life. The plasma membrane may, however, be challenged by mechanical stress or pore-forming proteins produced by the organism itself or invading pathogens. We will here review recent findings about pore-forming proteins from different organisms, highlighting their structural and functional similarities, and describe the mechanisms that lead to membrane repair, since remarkably, cells can repair breaches in their plasma membrane of up to 10,000 microm(2). PMID- 19442504 TI - Exosomes--vesicular carriers for intercellular communication. AB - Cells release different types of vesicular carriers of membrane and cytosolic components into the extracellular space. These vesicles are generated within the endosomal system or at the plasma membrane. Among the various kinds of secreted membrane vesicles, exosomes are vesicles with a diameter of 40-100 nm that are secreted upon fusion of multivesicular endosomes with the cell surface. Exosomes transfer not only membrane components but also nucleic acid between different cells, emphasizing their role in intercellular communication. This ability is likely to underlie the different physiological and pathological events, in which exosomes from different cell origins have been implicated. Only recently light have been shed on the subcellular compartments and mechanisms involved in their biogenesis and secretion opening new avenues to understand their functions. PMID- 19442505 TI - Ecotoxicological characterisation of 12 incineration ashes using 6 laboratory tests. AB - In the European Waste List (2000/532/EC as amended) the ash of municipal waste incineration is defined as a so called mirror entry. This waste can be classified as hazardous or non-hazardous depending on the content of hazardous substances and other risk properties. For the assignment of waste in mirror entries, 14 criteria are defined. One of the criteria is H14 "ecotoxic". In the presented study, the ecotoxicological potential of 12 ashes from different incineration plants has been assessed using biological test systems. The test battery included aquatic tests with eluates (algae, daphnids, and luminescent bacteria) and terrestrial tests with solid waste (plants, earthworms and bacteria). The test results revealed a clear ecotoxicological hazard potential for some of the MWI ashes. Despite the fact that fresh ashes were several times more toxic than aged ashes both groups did not differ consistently in terms of toxicity. The results show also that there is no correlation between the biological effects and the analyzed chemical compounds of the ash samples. PMID- 19442506 TI - Pt nanoparticle-based highly sensitive platform for the enzyme-free amperometric sensing of H2O2. AB - Highly sensitive electrochemical platform based on polymer supported Pt nanoparticles (nPts) for the amperometric sensing of H(2)O(2) at sub-nanomolar level without any redox mediator or enzyme is developed. The nPts are generated by the chemical reduction of precursor pre-organized on the electrode surface and characterized by field emission scanning electron microscopy, X-ray diffraction, spectral and electrochemical measurements. The cationic polymer poly(diallyldimethylammonium) chloride was used to assist the pre-organization of metal precursor. nPts on the electrode surface have an average size of 17 nm. The nanoparticles show excellent electrocatalytic activity towards oxidation of H(2)O(2) at less positive potential than the polycrystalline Pt electrode. Unlike the polycrystalline Pt electrode, the nanoparticle-based electrode does not undergo deactivation by surface oxides and other species in solution. Particle loading on the electrode surface controls the electrocatalytic activity. The nanoparticle-based electrode is highly sensitive (9.15 microA/mM) and display linear response up to 3 mM. It could detect 0.5 nM (S/N=5) of H(2)O(2) under hydrodynamic condition in neutral solution and the electrode is highly stable. The detection limit achieved is significantly lower than the other nanoparticle based electrodes. The excellent performance of the electrode is ascribed to the good catalytic activity of the particle and ensemble behavior of the nanoparticle modified electrode. The analytical performance of the electrode in the development of glucose biosensor is demonstrated. The biosensor is used for the sensing of glucose in the micromolar level in neutral pH. PMID- 19442507 TI - Fluorescence lifetime spectroscopy and imaging of nano-engineered glucose sensor microcapsules based on glucose/galactose-binding protein. AB - We aimed to develop microsensors for eventual glucose monitoring in diabetes, based on fluorescence lifetime changes in glucose/galactose-binding protein (GBP) labelled with the environmentally sensitive fluorophore dye, badan. A mutant of GBP was labelled with badan near the binding site, the protein adsorbed to microparticles of CaCO(3) as templates and encapsulated in alternating nano layers of poly-L-lysine and heparin. We used fluorescence lifetime imaging (FLIM) with two-photon excitation and time-correlated single-photon counting to visualize the lifetime changes in the capsules. Addition of glucose increased the mean lifetime of GBP-badan by a maximum of approximately 2 ns. Analysis of fluorescence decay curves was consistent with two GBP states, a short-lifetime component (approximately 0.8 ns), likely representing the open form of the protein with no bound glucose, and a long-lifetime component (approximately 3.1 ns) representing the closed form with bound glucose and where the lobes of GBP have closed round the dye creating a more hydrophobic environment. FLIM demonstrated that increasing glucose increased the fractional proportion of the long-lifetime component. We conclude that fluorescence lifetime-based glucose sensing using GBP encapsulated with nano-engineered layer-by-layer films is a glucose monitoring technology suitable for development in diabetes management. PMID- 19442508 TI - Conjugated polymer as a signal amplifier for novel silica nanoparticle-based fluoroimmunoassay. AB - Immunoassays are conventional methods for protein detection, which rely on specific antibody-antigen recognition. Very few strategies have been developed for signal amplification of immunoassays. In this work, we report a conjugated polymer amplified silica nanoparticle (NP)-based immunoassay for IgG detection. After immobilization of the prime antibody on the NP surface, the NPs are used to capture antigen and Cy3 labeled secondary antibody in a sandwich assay format. The presence of target antigen in solution brings the fluorescent Cy3 molecules to the NP surface. Addition of a cationic conjugated polymer further amplifies the fluorescence signal of the dye, which improves the assay sensitivity and selectivity. Within the tested concentration range, a linear response for IgG detection is observed from 0 to 1 microg/mL with a detection limit of approximately 1.1 ng/mL. Due to the pink color of Cy3 molecules, the assay also allows naked eye detection of IgG with a detection limit of 50 ng/mL. The polymer amplified NP assay represents a simple strategy for antigen detection with high sensitivity and selectivity. PMID- 19442509 TI - A solid-state electrochemiluminescence biosensing switch for detection of thrombin based on ferrocene-labeled molecular beacon aptamer. AB - A solid-state electrochemiluminescence (ECL) biosensing switch system based on special ferrocene-labeled molecular beacon aptamer (Fc-MBA) has been developed successfully for thrombin detections. Such special switch system includes two main parts, an ECL substrate and an ECL intensity switch. The ECL substrate was made by modifying the complex of Au nanoparticle and Ruthenium (II) tris (bipyridine) (Ru(bpy)(3)(2+)-AuNPs) onto Au electrode. A molecular beacon aptamer labeled by ferrocene acted as the ECL intensity switch. The loop bases of the ECL intensity switch are designed with special anti-thrombin aptamer sequence which could be combined with its target protein via the reaction between aptamer and thrombin. During the reactions, the molecular beacon aptamer opened its stem loop, and the labeled Fc was consequently kept away from the ECL substrate. Such structural change resulted in an obvious ECL intensity increment due to the decreased quenching effect of Fc to the ECL substrate. The analytic results are sensitive and specific. PMID- 19442510 TI - Implantable diagnostic device for cancer monitoring. AB - Biopsies provide required information to diagnose cancer but, because of their invasiveness, they are difficult to use for managing cancer therapy. The ability to repeatedly sample the local environment for tumor biomarker, chemotherapeutic agent, and tumor metabolite concentrations could improve early detection of metastasis and personalized therapy. Here we describe an implantable diagnostic device that senses the local in vivo environment. This device, which could be left behind during biopsy, uses a semi-permeable membrane to contain nanoparticle magnetic relaxation switches. A cell line secreting a model cancer biomarker produced ectopic tumors in mice. The transverse relaxation time (T(2)) of devices in tumor-bearing mice was 20+/-10% lower than devices in control mice after 1 day by magnetic resonance imaging (p<0.01). Short term applications for this device are numerous, including verification of successful tumor resection. This may represent the first continuous monitoring device for soluble cancer biomarkers in vivo. PMID- 19442511 TI - Selective calcium ion detection with functionalized ZnO nanorods-extended gate MOSFET. AB - Zinc oxide nanorod-extended gate field effect transistor (MOSFET) is demonstrated for the detection of calcium (Ca(2+)) ions. ZnO nanorods were grown on the surface of a silver wire to produce an electrochemical nanosensor for selectively detecting Ca(2+). The electrochemical response from the interaction between the ZnO nanorods and Ca(2+) in an aqueous solution is coupled directly to the gate of a field effect transistor (MOSFET). The induced voltage change on the gate results in a measureable current response. In order to adapt the sensors for Ca(2+) ions measurements in biological fluids with sufficient selectivity and stability, a plastic membrane coating containing ionophores was applied on the nanorods. The sensor exhibited a linear response within the range of interest from 1 microM to 1 mM. This work demonstrates a simple technique for sensitive detection of Ca(2+) ions by efficient transfer of the chemical response directly to a standard electronic component producing a low impedance signal. PMID- 19442512 TI - Lipid-modified morphogens: functions of fats. AB - Despite their location in the aqueous extracellular environment, a number of secreted proteins carry hydrophobic lipid modifications. These modifications include glycosylphosphatidylinositol, cholesterol, and both saturated and unsaturated fatty acids, and they are attached in the secretory pathway by different classes of enzymes. Lipid attachments make crucial contributions to protein function in vivo through a diverse array of mechanisms. They can promote protein maturation and secretion, membrane tethering, targeting to specific membrane subdomains, or receptor binding and activation. Additionally, secretion of lipid-modified morphogens of the Wnt and Hh families requires dedicated accessory proteins and may involve their packaging into lipoprotein particles for long-range transport. PMID- 19442514 TI - Steroidogenesis inhibitors alter but do not eliminate androgen synthesis mechanisms during progression to castration-resistance in LNCaP prostate xenografts. AB - In castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. We and others have recently reported that CRPC tumor cells can de novo synthesize androgens from adrenal steroid precursors or cholesterol and that high levels of progesterone exist in LNCaP tumors after castration serving perhaps as an intermediate in androgen synthesis. Herein, we compare androgen synthesis from [(3)H-progesterone] in the presence of specific steroidogenesis inhibitors and anti-androgens in steroid starved LNCaP cells and CRPC tumors. Similarly, we compare steroid profiles in LNCaP tumors at different stages of CRPC progression. Steroidogenesis inhibitors targeting CYP17A1 and SRD5A2 significantly altered but did not eliminate androgen synthesis from progesterone in steroid starved LNCaP cells and CRPC tumors. Upon exposure to inhibitors of steroidogenesis prostate cancer cells adapt gradually during CRPC progression to synthesize DHT in a compensatory manner through alternative feed-forward mechanisms. Furthermore, tumors obtained immediately after castration are significantly less efficient at metabolizing progesterone ( approximately 36%) and produce a different steroid profile to CRPC tumors. Optimal targeting of the androgen axis may be most effective when tumors are least efficient at synthesizing androgens. Confirmatory studies in humans are required to validate these findings. PMID- 19442513 TI - ATP-dependent chromatin remodeling in neural development. AB - Recent advances have revealed that modification of chromatin structure is an important determinant of cell fate and function. DNA methylation and covalent modifications of histone tails contribute to changes in chromatin architectures, either enhancing or repressing gene expression. Another mechanism underlying the modification of chromatin structure relies on the activity of the SWI/SNF-related ATP-dependent chromatin remodeling complexes that control the accessibility of DNA sequences to transcription factors. There is increasing evidence that ATP dependent chromatin remodeling complexes based on the alternative DNA-dependent ATPases, Brg1 and Brm, plays essential roles during neural development in both vertebrates and invertebrates. This remodeling complex has dedicated functions at different stages of neural development that appear to arise by combinatorial assembly of its subunits. PMID- 19442515 TI - Potential advantage of preoperative three-dimensional mapping of sentinel nodes in breast cancer by a hybrid single photon emission CT (SPECT)/CT system. AB - OBJECTIVE: This study aims to assess the role of three-dimensional single-photon emission computed tomography (3D-SPECT/CT) in sentinel node (SN) identification, and to analyze the impact of such information on estimating metastases to SNs. BACKGROUND: Nodal status is a key factor for breast cancer. SN biopsy has been established as the alternative to routine axillary dissection these days. We investigated both the anatomical location of SNs demonstrated by our 3D-SPECT/CT system and the correlation to SN positivity. METHODS: Two hundred and twenty three clinically node-negative patients underwent SN biopsy. All of the axillary structures, including SNs, were visualized by a SPECT/CT combined system after subcutaneous injection of (99m)Tc-phytate. By plotting the visualized SNs, the most frequent SN location 'Pedestal area (PA)' was designated. RESULTS: SPECT/CT detected (99m)Tc uptake in 217 cases (97.3%). 3D-SPECT/CT images visualized the accurate location of SNs in each case. In patients whose SNs were histopathologically negative (SN-), 228 (98.3%) SNs were found in the PA, and 4 (1.7%) were in other zones. In those with histopathologically positive SNs (SN+), 65 (78.3%) SNs were in the PA and 18 (21.7%) were outside it. The difference in SN distribution (i.e., in or out of the PA) between SN+ and SN- patients was statistically significant (p<0.001, chi-square test). CONCLUSIONS: SN biopsy navigated by 3D-SPECT/CT can clarify the preoperative anatomical localization of SNs in patients with breast cancer. Atypical distribution of SNs out of the PA may suggest SN positivity, reflecting failure of the lymphatic drainage systems. PMID- 19442516 TI - Non-surgical treatment of localised prostate cancer. AB - The non-surgical treatment of localised prostate cancer depends on a number of factors including: PSA, stage, Gleason score, age, fitness for treatment and life expectancy, and is individualised depending on risk. Patients who present with early localised (stage T1 or T2) tumours with low risk features (PSA <10 ng/ml, Gleason score 3+4 or below) and who have a life expectancy of more than 10 years may consider radiotherapy or active surveillance. Permanent brachytherapy seed implantation is suitable for low risk patients who have minimal lower urinary tract symptoms, with equivalent results to external beam radiotherapy Conformal high-dose external beam radiotherapy is effective for patients with high risk disease, and consideration should be given to the use of neoadjuvant and adjuvant anti-androgens. Prophylactic pelvic nodal irradiation is indicated for patients with high risk of lymph node disease, followed by a boost to the prostate using either a smaller external beam volume, or brachytherapy. The definitive treatment depends on both clinical parameters such as the clinical staging, prognostic risk, and the likelihood of acute and late toxicity and the patient's personal choice based on their life style. PMID- 19442517 TI - Thermochemical conversion of livestock wastes: carbonization of swine solids. AB - Slow pyrolysis or carbonization promotes the conversion of animal manures such as swine manure into charcoal. In this paper, the carbonizing kinetics of swine solids taken from different treatment stages were investigated with a thermogravimetric analyzer. Compared to their biologically stabilized counterpart (lagoon sludge) with an activation energy of 160 kJ mol(-1), the activation energies for fresh swine solid samples such as homogenized flushed manure and dewatered solids were much lower between 92 and 95 kJ mol(-1). Compared to the kinetics of first order decomposition of cellulose, the pyrolytic decomposition of the swine manures were more complex with the reaction orders varying at 3.7 and 5.0. The two different mathematical methods employed in this paper yielded the similar values of activation energy (E) and pre-exponential factor (A), confirming the validity of these methods. The results of this study provide useful information for development of farm-scale swine solid carbonization process. PMID- 19442518 TI - Expression of multi-functional cellulase gene mfc in Coprinus cinereus under control of different basidiomycete promoters. AB - Multi-functional cellulase gene mfc was expressed in Coprinus cinereus under naturally non-inductive conditions using three heterologous promoters. Endo-beta 1,4-glucanase expression was achieved in solid and liquid media with promoter sequences from the Lentinula edodesgpd gene, the Flammulina velutipes gpd gene and the Volvariella volvaceagpd gene. As measured by enzyme activity in liquid cultures, a 613-bp gpd promoter fragment from L. edodes was most efficient, followed by a 752-bp gpd fragment from F. velutipes. The V. volvacea gpd promoter sequence was less active, in comparison. Irrespective of the promoter used, enzymatic activities increase 34-fold for highly active transformants and 29-fold for less active one by using cellulase-inducing medium. The highest activities of endo-beta-1,4-glucanase (34.234 U/ml) and endo-beta-1,4-xylanase (263.695 U/ml) were reached by using the L. edodesgpd promoter. PMID- 19442519 TI - The discovery of novel calcium sensing receptor negative allosteric modulators. AB - The design and profile of a series of zwitterionic calcium sensing receptor negative allosteric modulators is described. Evaluation of key analogues using a rat model demonstrate a robust response, significantly improved potency over ronacaleret and have the potential as an oral, anabolic treatment for osteoporosis. PMID- 19442520 TI - Synthesis, biological evaluation of prenylflavonoids as vasorelaxant and neuroprotective agents. AB - A series of prenylflavonoids with multiple hydroxyl groups were synthesized and evaluated for their vasorelaxant activities against rat aorta rings pre contracted by phenylephrine (PE), as well as their neuroprotective effects against OGD induced PC12 cell injury. The results indicated that the prenyl group at A-ring of prenylflavonoids, as well as hydroxyl groups at B-ring was important for their activities. (+/-)Leachianone G 1b, bearing 8-prenyl and 2',4'-dihydoxyl groups, exhibited the most potent vasorelaxant and neuroprotective effects. PMID- 19442521 TI - WITHDRAWN: Two new cytotoxic labdane diterpens from Alpinia zerumbet. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 19442522 TI - An efficient preparation of N-alkyl-2-benzazepine derivatives and investigation of their biological activity. AB - N-Alkyl-2-benzazepine derivatives are readily prepared through N-alkylation of secondary 2-benzazepines that are constructed via 7-endo selective cyclization of radical cyclization of N-boc-N-(2-bromo-5-methoxyphenylmethyl) methacrylamides. The structure and activity relationship of these derivatives are examined. PMID- 19442523 TI - The effect of botulinum toxin injections on gait control in spastic stroke patients presenting with a stiff-knee gait. AB - INTRODUCTION: Botulinum toxin type A (BoNT-A) injections are known to improve walking impairments and activity in spastic hemiparetic stroke patients presenting with a stiff-knee gait [Caty GD, Detrembleur C, Bleyenheuft C, Deltombe T, Lejeune TM. Effect of simultaneous botulinum toxin injections into several muscles on impairment, activity, participation, and quality of life among stroke patients presenting with a stiff knee gait. Stroke 2008;39(October (10)):2803-8]. The aim of the present study was to understand how the improvement of mechanical variables during gait is controlled by the central nervous system after BoNT-A injections. Therefore, we used Kinematic Segmental Coordination (KSC), i.e. the kinematic covariation law of elevation angles between lower limb segments, to assess their effect on gait control. As far as we know, this has never been studied before. METHODS: Twenty chronic hemiparetic stroke patients presenting with a stiff-knee gait performed an instrumented gait analysis at the same walking speed before and 2 months after BoNT-A injection in several spastic muscles. We used the kinematic recordings previously obtained by Caty et al. [Caty GD, Detrembleur C, Bleyenheuft C, Deltombe T, Lejeune TM. Effect of simultaneous botulinum toxin injections into several muscles on impairment, activity, participation, and quality of life among stroke patients presenting with a stiff knee gait. Stroke 2008;39(October (10)):2803-8] and computed KSC following Borghese's methodology. The treatment effect was tested using a repeated measures ANOVA. RESULTS: BoNT-A injections allowed a statistically significant improvement in KSC of both lower limbs (p=0.004). Moreover, the unaffected side KSC reached normal values after BoNT-A injections. CONCLUSION AND DISCUSSION: BoNT-A allowed an improvement in KSC of the affected lower limb and a normalization of KSC of the unaffected limb. This improvement could either be due to a mechanical effect or a central effect of BoNT-A via the spinal central pattern generators (CPGs). PMID- 19442524 TI - The human sacrum and safe approaches for screw placement. AB - The human sacrum is the target of lumbosacral instrumentation and decompression procedures. Such surgical interventions require detailed knowledge of the anatomy of the human sacrum. The aim of this study was to measure surgically relevant parameters. Several factors, including the one-piece composition of the sacrum, the angles of the sacral pedicles and the anteroposterior diameter of the sacral vertebral bodies distinguish the sacrum from other parts of spine. Thirty-two measurements of shape, angles and distances between parts were taken of the sacra of 100 adult West Anatolian people using a Vernier caliper accurate to 0.1 mm and goniometer. According to this morphometric study, when measured from the sagittal, the S1 facet angle was measured as 35.71 degrees +/-9.59 and 34.70 degrees +/-9.66, the sacral pedicle anteromedial screw trajectory angle was 35.65 degrees +/-4.73 and 31.95 degrees +/-3.95 and the anterolaterally oriented sacral wing screw trajectory angle was 32.65 degrees +/-3.51 and 29.10 degrees +/-3.14, on the right and left sides, respectively. The distance of the midline oriented S1 pedicle screw was 51.12 mm and 51.26 mm on the right and left side, respectively. The distance for sacral wing oriented screw placement was 50.13 mm and 50.46 mm on the right and left side, respectively. The anteroposterior and transverse diameter of the sacral spinal canal were 21.81 mm and 31.31 mm, respectively. Thus, this study describes anatomical specifications of the sacrum. These defined morphometric details should be taken into consideration during surgical procedures. This study also describes anatomical landmarks which will allow injury of the sacrum during surgery to be avoided. PMID- 19442525 TI - A novel photoaffinity ligand for the dopamine transporter based on pyrovalerone. AB - Non-tropane-based photoaffinity ligands for the dopamine transporter (DAT) are relatively unexplored in contrast to tropane-based compounds such as cocaine. In order to fill this knowledge gap, a ligand was synthesized in which the aromatic ring of pyrovalerone was substituted with a photoreactive azido group. The analog 1-(4-azido-3-iodophenyl)-2-pyrrolidin-1-yl-pentan-1-one demonstrated appreciable binding affinity for the DAT (K(i)=78+/-18 nM), suggesting the potential utility of a radioiodinated version in structure-function studies of this protein. PMID- 19442526 TI - Synthesis and antiviral activity evaluation of acyclic 2'-azanucleosides bearing a phosphonomethoxy function in the side chain. AB - Acyclic 2'-azanucleosides with a phosphonomethoxy function in the side chain were obtained by coupling of diethyl {2-[N-(pivaloyloxymethyl)-N-(p toluenesulfonyl)amino]ethoxymethyl}phosphonate with the pyrimidine nucleobases via the Vorbruggen-type protocol. The compounds were evaluated in vitro for activity against a broad variety of RNA and DNA viruses. PMID- 19442528 TI - Effects of background suppression of gamma counts on signal estimation. AB - Gamma detectors at border crossings are intended to detect illicit nuclear material. One of their performance challenges is the fact that vehicles suppress the natural background and, thus, potentially reduce probability of detection of threat items. Here we test several methods to adjust the detection to background suppression in the context of signal estimation. We show that, for the small-to moderate suppression magnitudes, suppression adjustment leads to higher detection probability. However, for signals triggering alarm without an adjustment, adjustment does not improve estimation of the signal location, only moderately improves estimation of the signal magnitude, and does not improve estimation of the signal width. PMID- 19442527 TI - Building of scientific information system for sustainable development of BNCT in Bulgaria. AB - Building a boron neutron capture therapy (BNCT) facility is foreseen within the reconstruction of the Research Reactor IRT (IRT) of the Institute for Nuclear Research and Nuclear Energy of the Bulgaria Academy of Sciences (INRNE). The development of BNCT at IRT plays a very significant role in the plan for sustainable application of the reactor. A centralized scientific information system on BNCT is being built at the INRNE with the purpose to collect and sort new information as knowledge accumulated during more than thirty years history of BNCT. This BNCT information system will help the creation and consolidation of a well informed and interconnected interdisciplinary team of physicists, chemists, biologists, and radio-oncologists for establishing BNCT cancer treatment in Bulgaria. It will strengthen more intensive development of the national network as well as its enlargement to the Balkan region countries. Furthermore, to acquaint the public at large with the opportunity for BNCT cancer treatment will be addressed. Human, social, and economics results due to BNCT for many patients from Balkan region are expected. PMID- 19442529 TI - The long-term stability of the DSPEC PLUS spectrometer at the Reactor Institute Delft. AB - In the 1990s, digital spectrometry became feasible as very fast ADCs became available. In a digital spectrometer, the signal from the detector is no longer shaped by analog circuitry before it is handed over to the ADC that determines the channel number-it is digitized to begin with. High count rates that vary within the acquisition time are dealt with satisfactory in these spectrometers. The gain of analog amplifiers is known to be temperature sensitive. Digital spectrometers supposedly do not exhibit such sensitivity. In general, very high gain stability is expected because of this. Stability tests of a DSPEC(PLUS) digital spectrometer were performed at Ortec over a period of seven months. Also, the performance of such a digital spectrometer was monitored during seven years in the reactor containment building of the Delft research reactor--where no climate control is present. It is concluded that the long term gain stability of the digital systems tested is about 0.2%--almost as good as the 0.1% of the analog system used before. The FWHMs as observed are quite a bit better with the digital spectrometer. PMID- 19442530 TI - Quality of life of grown-up congenital heart disease patients after congenital cardiac surgery. AB - BACKGROUND: Due to better early and long-term outcome, the increasing population of grown-ups with congenital heart disease (GUCH) brings up unexpected quality of life (QoL) issues. The cardiac lesion by itself is not always the major problem for these patients, since issues pertaining to QoL and psychosocial aspects often predominate. This study analyses the QoL of GUCH patients after cardiac surgery and the possible impact of medical and psychosocial complications. PATIENTS AND METHODS: A questionnaire package containing the SF-36 health survey (health related QoL), the HADS test (anxiety/depression aspects) and an additional disease specific questionnaire was sent to 345 patients (mean 26+/-11 years) operated for isolated transposition of the great arteries (TGA), tetralogy of Fallot (TOF), and ventricular septal defect (VSD). The scores were compared with age- and gender-matched standard population data and in relation to the underlying congenital heart disease (CHD). RESULTS: In all SF-36 and HADS health dimensions the GUCH patients showed excellent scores (116+/-20), which are comparable to the standard population (100+/-15), regardless of the initial CHD (p=0.12). Eighty-two percent of the patients were found to be in NYHA class I and 83% patients declared that they do not consider their QoL to be limited by their malformation. Complications like reoperations (p=0.21) and arrhythmias (p=0.10) do not show significant impact on the QoL. The additional questionnaire revealed that 76% of adult patients have a fulltime job, 18% receive a full or partial disability pension, 21% reported problems with insurances, most of them regarding health insurances (67%), and 4.4% of adult patients declared to have renounced the idea of having children due to their cardiac malformation. CONCLUSION: QoL in GUCH patients following surgical repair of isolated TOF, TGA and VSD is excellent and comparable to standard population, this without significant difference between the diagnosis groups. However, these patients are exposed to a high rate of complications and special psychosocial problems, which are not assessed by standardized questionnaires, such as the SF-36 and HADS. These findings highlight the great importance for a multidisciplinary and specialized follow-up for an adequate management of these complex patients. PMID- 19442531 TI - Total thoracoscopic pulmonary segmentectomy. AB - OBJECTIVE: In lung resection, thoracoscopy has been mainly used for wedge resection and lobectomy. There have been very few reports on pulmonary segmentectomy, mainly because of its complex nature. The present report evaluates the safety and efficacy of thoracoscopic pulmonary segmentectomy for the treatment of benign lung diseases or small lung carcinomas. METHODS: The study involved 30 patients who underwent thoracoscopic segmentectomy without a minithoracotomy from September 2004 to March 2008. The median age of the patients was 69 years (range, 16-81 years). Four 5-20 mm ports were used. The pulmonary vessels were ligated, and the bronchi were closed using a stapler. An electrocautery was used for intersegmental dissection. Chest tubes were inserted in all cases. RESULTS: Twenty-eight patients underwent complete thoracoscopic segmentectomy. A minithoracotomy was created in one case because of arterial bleeding, and open lobectomy was performed in another case owing to the diagnosis of small cell carcinoma. The operative time ranged from 147 to 425 min (median time, 216 min). The inserted chest tubes were maintained in position for 1-7 days (median duration, 1 day). One patient developed subcutaneous emphysema that spontaneously resolved. No mortality was observed for 30 days after the surgery. Further, no local recurrence or metastases were observed during follow-up in cases of malignancy. CONCLUSIONS: Thoracoscopic pulmonary segmentectomy is a feasible and safe technique. Reduced postoperative pain and an improved cosmetic outcome are considered advantages of this minimally invasive procedure. PMID- 19442532 TI - When parents opted not to perform surgery for a long-segment congenital tracheal stenosis child: flexible bronchoscopic balloon tracheoplasty as the primary treatment. AB - Congenital tracheal stenosis is a rare airway disorder characterized by a fixed tracheal narrowing. Surgical intervention is usually considered as the treatment of choice for long-segment type. However, due to wide spectrum of this disease, treatment modalities need to be individualized. The long-segment type has the most unfavorable outcome because it is often associated with multiple anomalies and, thus, the most difficult to manage. Here we present a case of long-segment congenital tracheal stenosis (LSCTS) that was managed by several sessions of flexible bronchoscopic balloon tracheoplasty as the primary treatment. In this particular situation, we had to deal with the parents' request of a 'non surgical' approach for an infant who had respiratory distress that also required a way to increase his tracheal diameter simultaneously. Having done this particular experience, we would like to show that this non-surgical approach can be viable for long-segment tracheal stenosis in selected cases. PMID- 19442533 TI - What is the most effective palliation for esophagorespiratory fistulas? PMID- 19442534 TI - Novel photosensitizer-protein nanoparticles for photodynamic therapy: photophysical characterization and in vitro investigations. AB - In this work two types of pheophorbide-HSA (Pheo-HSA) nanoparticles, PHSA40 and PHSA100, were prepared and their photophysical and photosensitizing properties were investigated. Due to intramolecular interactions the singlet oxygen quantum yield of PHSA40 and PHSA100 is very low (less than 0.1). Intracellular uptake and phototoxicity of pheophorbide a as well as of the Pheo-HSA nanoparticles were studied in Jurkat cells. The HSA nanoparticles do not influence the amount of dye accumulation in cells. After 24h incubation, PHSA40 and PHSA100 showed a higher phototoxicity than Pheo. The reason for this behavior is an efficient nanoparticle decomposition in the cellular lysosomes. The process of drug release during incubation of cells with Pheo-HSA nanoparticles was illustrated by fluorescence lifetime imaging (FLIM) and confocal laser scanning microscopy (CLSM). The final phototoxicity of Pheo-HSA is at the same scale as induced by free Pheo. The drug release ability of HSA nanoparticles shows the possibility to use such formulations as drug carriers in PDT treatment. Therefore, this work constructs a standard for further investigation and optimization of photosensitizer-HSA drug carrier system. PMID- 19442535 TI - Male breast cancer. Evolution of treatment and prognostic factors. Analysis of 489 cases. AB - BACKGROUND: Infiltrating MBC represents less than 1% of all male cancers. Our study details clinico-pathological features, treatments and prognostic factors in a large French cohort. MATERIAL AND METHODS: Four hundred and eighty-nine patients were collected from 1990 to 2005. Median age was 66 years (34% over 70 years) and median follow-up 58 months. RESULTS: According to TN classification, we found T(1): 39%, T(2): 41%, T(3)T(4): 9%, T(x): 11% and N(1)N(2): 27%. Lumpectomy (L) and mastectomy (M) were performed in 8.6% and 91.4% of the cases. Axillary dissection (AD), sentinel node biopsy or both were performed in 90%, 2% and 5% of the cases, respectively. Ninety-five percent of tumours were ductal carcinomas; 47% were pT(1), 20% pT(2) and 33% pT(3)-T(4). Axillary nodal involvement was present in 52.8% cases. ER and PgR were positive in 92% and 89% cases. Radiotherapy (RT) was performed in 85% of the patients. Hormonal treatment (HT) was delivered in 72% of the cases. Tamoxifen and aromatase inhibitors were used in 85% and 12% of the cases; 34% of the patients received chemotherapy (CT). Local recurrence (LR), nodal recurrences (NR) and metastases occurred in 2%, 5% and 22% of the cases; 2% and 10% developed contralateral BC and second cancer. The 5- and 10-year overall survival (OS) rates were 81% and 59%; disease-specific survivals (DSS) were 89% and 72%. Death causes were BC 56%, second cancer 8%, complications 3%, intercurrent disease 15% and unknown 18%. In a univariate analysis, metastatic risk factors were T stage (T1: 19%, T(2): 26%, T(3)T(4): 40%; p=0.013), pN status (pN(0): 12% pN(1-3): 26% pN(>3): 44%; p<0.0001) and presence of locoregional recurrence (62% versus 18% p<0.0001). In a multivariate analysis, axillary nodal involvement and high SBR remain prognostic factors. CONCLUSION: Earlier diagnosis and wide use of adjuvant treatments (RT/HT/CT) widely decreased LR and increased survival rates in MBC, reaching female ones. Prognostic factors were also very similar to female ones. PMID- 19442536 TI - Cannabinoids in intestinal inflammation and cancer. AB - Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids - via direct or indirect activation of CB(1) and/or CB(2) receptors exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer. PMID- 19442537 TI - Implicit working memory. AB - Working Memory (WM) plays a crucial role in many high-level cognitive processes (e.g., reasoning, decision making, goal pursuit and cognitive control). The prevalent view holds that active components of WM are predominantly intentional and conscious. This conception is oftentimes expressed explicitly, but it is best reflected in the nature of major WM tasks: All of them are blatantly explicit. We developed two new WM paradigms that allow for an examination of the role of conscious awareness in WM. Results from five studies show that WM can operate unintentionally and outside of conscious awareness, thus suggesting that the current view should be expanded to include implicit WM. PMID- 19442538 TI - Comparison of various imaging modalities in localization of epileptogenic lesion using epilepsy surgery outcome in pediatric patients. AB - PURPOSE: We employed the results of imaging modalities from pediatric patients who received successful epilepsy surgery to determine the accuracy of each imaging tool in identifying epileptic zones in youngsters. METHODS: All Engel class I pediatric patients who received epilepsy surgery between October 2003 and April 2008 were selected. Their pathology, EEG, MRI, PET, and subtraction ictal SPECT coregistered to MRI (SISCOM) results were compared for accuracy in locating the epileptic foci, defined as "area that resulted in seizure ablation after resection". RESULTS: Forty-two patients were enrolled (23 temporal lobectomy, 19 extratemporal resections). MRI showed concordance in 84.2% of extratemporal cases, all of which had precise localization of lesions. In temporal cases, lateralization was 91.3% and localization was 82.6%. PET showed a concordance rate of 95.5% and localization was 72.7% for temporal lesions. For extratemporal lesions, concordance was only 68.4%. SISCOM showed concordance in 100% of temporal and 92.3% of extratemporal cases, with localization in 66.7% of temporal and 84.6% of extratemporal cases. Most temporal lobe cases had hippocampal sclerosis, and cortical dysplasia was observed in extratemporal cases. DISCUSSION: MRI was invariably reliable in all cases. PET results were as reliable in lateralizing the temporal epileptic area, while its efficacy was lower for extratemporal cases. SISCOM effectively localized lesions in extratemporal cases, but its efficacy was lower in temporal lesions. In cases of conflicting pre-surgical results, MRI, with supplementary data from PET, helped to establish correct decisions in temporal epilepsies, while utilization of SISCOM and MRI data is advised for extratemporal cases. PMID- 19442539 TI - An assessment of the likelihood, frequency, and content of verbal communication between radiologists and women receiving screening and diagnostic mammography. AB - RATIONALE AND OBJECTIVES: Research on communication between radiologists and women undergoing screening and diagnostic mammography is limited. We describe community radiologists' communication practices with patients regarding screening and diagnostic mammogram results and factors associated with frequency of communication. MATERIALS AND METHODS: We received surveys from 257 radiologists (70% of those eligible) about the extent to which they talk to women as part of their health care visit for either screening or diagnostic mammograms, whether this occurs if the exam assessment is positive or negative, and how they use estimates of patient risk to convey information about an abnormal exam where the specific finding of cancer is not yet known. We also assessed characteristics of the radiologists to identify associations with more or less frequent communication at the time of the mammogram. RESULTS: Two hundred and forty-three radiologists provided complete data (95%). Very few (<6%) reported routinely communicating with women when screening mammograms were either normal or abnormal. Fewer than half (47%) routinely communicated with women when their diagnostic mammograms were normal, whereas 77% often or always communicated with women when their diagnostic exams were abnormal. For positive diagnostic exams, female radiologists were more likely to be frequent communicators compared to males (87.1%-72.8%; P=.02) and those who spend 40%-79% of their time in breast imaging (94.6%) were more likely to be frequent communicators compared to those who spend less time (67.2%-78.9%; P=.02). Most radiologists convey risk information using general rather than numeric statements (57.7% vs. 28.5%). CONCLUSIONS: Radiologists are most likely to convey information about diagnostic mammographic findings when results are abnormal. Most radiologists convey risk information using general rather than numeric statements. PMID- 19442540 TI - In vitro effects of detergent sclerosants on antithrombotic mechanisms. AB - OBJECTIVES: To investigate the in vitro effects of detergent sclerosants on antithrombotic pathways. MATERIALS AND METHODS: Proteins C, S and antithrombin (AT) were assayed in normal plasma treated with increasing concentrations of sodium tetradecyl sulphate (STS) and polidocanol (POL). Activated protein C (APC) was investigated by mixing normal plasmas with sclerosants and testing with the activated partial thromboplastin time (APTT) and dilute Russell's viper venom time in the presence and absence of APC. The effect on factor Xa (FXa), heparin and enoxaparin was investigated using chromogenic anti-FXa and APTT methods. RESULTS: High concentration (>0.6%) STS significantly destroyed proteins C, S and AT whereas POL only caused a mild reduction in PC and AT and a moderate (60%) reduction in PS levels. STS potentiated the anticoagulant effect of APC while POL increased APC resistance. STS mimicked AT and demonstrated significant anti-Xa and anti-IIa activity. STS demonstrated a similar anticoagulant profile to heparin but was 1000x weaker. It also significantly potentiated the anticoagulant effect of heparin while POL had less effect. CONCLUSION: STS and POL demonstrated quite distinct and sometimes opposite effects on the antithrombotic mechanisms assayed. These effects were concentration-dependent and in general, STS had the greatest effect on antithrombotic proteins. PMID- 19442541 TI - Tissue damage after sodium hypochlorite extrusion during root canal treatment. AB - Sodium hypochlorite solution is toxic to vital tissues, causing severe effects if extruded during endodontic treatment. This paper presents a report on the tissue damage related to inadvertent extrusion of concentrated sodium hypochlorite solution during root canal treatment. A 65-year-old woman was referred with moderate pain, ecchymosis, and severe swelling of the right side of the face. These symptoms appeared immediately after a root canal treatment of the maxillary right canine, which had been started 21 hours earlier. It was diagnosed as air emphysema related to sodium hypochlorite solution extravasation during the endodontic treatment. To avoid this, an initial radiograph should be taken to determine the correct canal working length and confirm root canal integrity. PMID- 19442543 TI - Molecular mechanisms of projection neuron production and maturation in the developing cerebral cortex. AB - The cerebral cortex is a brain structure unique to mammals and highly adapted to process complex information. Through multiple developmental steps, the cerebral cortex is assembled as a huge diversity of neurons comprising a complex laminar structure, and with both local and long-distance connectivity within the nervous system. Key processes must take place during its construction, including: (i) regulation of the correct number of neurons produced by progenitor cells, (ii) temporal and spatial generation of neuronal diversity, and (iii) control of neuron migration and laminar positioning as well as terminal differentiation within the mature cortex. Here, we seek to highlight recent cellular and molecular findings underlying these sequential steps of neurogenesis, cell fate specification and migration during cortical development, with particular emphasis on cortical projection neurons. PMID- 19442542 TI - Microarray analysis of prothrombin knockdown in zebrafish. AB - The serine protease thrombin is generated from its precursor, prothrombin, in the coagulation cascade and plays a central role in fibrin deposition and platelet activation mediated through the protease activated receptors. Knockdown of prothrombin in the zebrafish was previously shown to recapitulate the phenotype observed in prothrombin knockout mice, such as an absence of blood pericardial edema, and hemorrhage. However, the role of thrombin during embryogenesis is not fully understood. To find genes affected by potential thrombin signaling in embryogenesis before blood circulation, microarray analysis was performed using total RNA prepared from antisense-injected, knockdown embryos versus mismatch injected at 20 h post fertilization. A total of 63 upregulated and downregulated genes were identified with duplicate microarrays using dye reversal and a two fold difference limitation. Real time RT-PCR for 10 selected genes identified by the microarray confirmed the expression changes in these genes. One particular gene, phlda3, was at least eleven fold upregulated, and in situ hybridization revealed expansion of phlda3 expression in the central nervous system, branchial arches, and head endoderm in knockdown embryos. The identification of these genes regulated by thrombin according to microarray analysis should provide a greater understanding of the effects of thrombin activity in the early vertebrate embryo. PMID- 19442544 TI - Intestinal mucosal immune response in ducklings following oral immunisation with an attenuated Duck enteritis virus vaccine. AB - To investigate the intestinal mucosal immune responses in ducklings orally inoculated with attenuated Duck enteritis virus (DEV), the kinetics of the viral load, the specific humoral immune responses, and the distribution of immunoglobulin (Ig)A-secreting cells in the intestine were evaluated. Oral inoculation with attenuated DEV stimulated an IgA-dominant response in intestinal secretions and a IgY-dominant response in the serum. The dramatic increase in virus-specific mucosal IgA 15 days after inoculation was accompanied by reductions in the DEV intestinal load, suggesting that the IgA response has a role in controlling viral replication. The kinetics of virus-specific IgA production closely correlated with the presence of IgA+ plasma cells in the intestinal lamina propria. PMID- 19442545 TI - Structural features for homodimer folding mechanism. AB - The homodimers have essential role in catalysis and regulation. The homodimer folding mechanism through 2-state without stable intermediate (2S), 3-state with monomer intermediate (3SMI) and 3-state with dimer intermediate (3SDI) is fascinating. 23MI and 3SDI constitute 3-state (3S). Hence, it is important to differentiate 2S, 3SMI and 3SDI homodimers using structural features. We used the dataset of Li et al. [L. Li, K. Gunasekaran, J.G. Gan, C. Zhanhua, P. Shapshak, M.K. Sakharkar, P. Kangueane, Structural features differentiate the mechanisms between 2S and 3S folding of homodimers, Bioinformation 1 (2005) 42-49] consisting of twenty-five 2S, ten 3SMI and six 3SDI homodimer structures for the study. Interface to total (I/T) residues ratio is large for 2S than 3SMI and 3SDI. Interface to total residues ratio is similar for 3SMI (mean monomer length (ML)=208) and 3SDI (mean monomer length (ML)=404) despite difference in mean monomer size. Interface residues correlate with monomer size in 2S (Pearson's correlation coefficient (r); r(2)=0.41) and 3SMI (r(2)=0.52). This is not true for 3SDI with interface residues and monomer length (r(2)=0.17). Interface area (B/2) does not correlate with interface residues (r(2)<0.001) and monomer size (r(2)=0.023) in 2S. This is despite a relationship with interface residues and monomer size (r(2)=0.41) in 2S. However, this is not true for 3SMI (r(2)=0.61 with interface residues and r(2)=0.25 with monomer size). In 3SDI, a different relationship is seen (r(2)=0.28 with interface residues and r(2)=0.09 with size). The mean hydrophobicity factor (H(f)) is 3-fold less in 3S than 2S. H(f) does not correlate with interface area in 2S (r(2)=0.03) and 3SDI (r(2)=0.0). However, a weak causal relation is seen in 3SMI (r(2)=0.23). Hydrophilic amino acid residues (E, R, K, S and Q) are prominent in 2S than 3S. Charged negative amino acid residues (D, E) are more than positive amino acid residues (R, K, H) in 2S and charged positive amino acid residues (R, K, H) are more than negative amino acid residues (D, E) in 3S. These features help to distinguish 2S, 3SMI and 3SDI providing insights to homodimer folding and binding. PMID- 19442546 TI - New intercellular lipid mediators and their GPCRs: an update. AB - Intercellular lipid mediators such as prostaglandins and lysophosphatidic acid (LPA) interact with their G-protein-coupled receptors (GPCR) in the plasma membrane to modulate functions of target cells or tissues. Discovery of new members of intercellular lipid mediators and their GPCRs have been milestones in lipid biology and the foundation for drug development. Recent advances in intercellular lipid mediators are very interesting. New lipid molecules have been recognized as intercellular signaling mediators acting on GPCRs including resolvin E1, eoxin, acylethanolamides (arachidnonylethanolamide and oleoylethanolamide), fatty acids, bile acids, lipoamino aicd (N-palmitoyl glycine and N-arachidonyl glycine), estrogen, 5-oxo-ETE and 9-hydroxyoctadecadienoic acid, among others. Also new GPCRs for LPA have been identified. New intercellular lipid mediators and their GPCRs are reviewed. PMID- 19442547 TI - [Medicinal plants in nursing: an educational experience aimed at filling an training gap]. PMID- 19442549 TI - [Nursing care in patients undergoing interventional neuroendovascular procedures]. AB - Vascular interventional radiology (VIR) procedures have increased markedly, partly due to the current healthcare context, which encourages the use of less invasive procedures that reduce pressure on surgery departments and decrease hospital stays. In most patients, these techniques can be carried out in a single intervention. VIR procedures are based on the possibility of gaining access to vascular structures through a catheter inserted percutaneously without the need for open surgery. Due to the complexity of these procedures, hospitalization is required before and after the technique is performed but length of stay is short compared with that associated with surgery. As the health workers closest to patients, nurses must respond to their information needs. The provision of comprehensive nursing care should include all the care required before, during and after the procedure and all aspects related to the quality of the healthcare process. Knowledge of how diagnostic and therapeutic VIR techniques are performed in the neurovascular section is essential. Based on the authors' experience, the present article aims to provide nurses with knowledge of some neurointerventional procedures (cerebral angiography and embolization of intracranial aneurysms) and of the care provided in RVI rooms. PMID- 19442548 TI - [The most common causes of admission and related variables in the resuscitation room of the emergency service]. AB - OBJECTIVE: To identify the most common causes of admission to the resuscitation room of the emergency service and to determine which variables modify this frequency. METHODS: An observational retrospective study was performed during the months of July-August, 2004 and January-February, 2005. A sample of 1346 patients obtained from the registration book of the resuscitation room was analyzed. Information on age and sex was obtained from the hospital's internal database. The variables analyzed were age, sex, shift, date, and patient destination. RESULTS: The most frequent causes of admission were heart disease, respiratory disease and polytrauma. Although there was a higher percentage of males (59.5%), the percentages among the causes of admission changed according to the sex of the patient. There was a higher number of patients during the morning period (37.8%), on Mondays (17.7%), and in January (30.5%), with some variations according to cause and sex. The most common patient destination was the observation area of the emergency service. CONCLUSION: The causes and frequency of admission were influenced by the variables studied. PMID- 19442550 TI - Staphylococcal pneumonia with multiple muscle abscesses in an immunocompetent patient. PMID- 19442551 TI - [Some considerations on "regulation, practices and public health stakes" in blood transfusion]. PMID- 19442552 TI - Pluripotent stem cells. AB - The isolation of human embryonic stem cells (ESC) in 1998 has created the hope that stem cells will one day be used to regenerate tissues and organs, even though it is obvious that a number of hurdles will need to be overcome for such therapies to become reality. The cloning of "Dolly" in 1997, more than 40 years after the first frogs were cloned, combined with the very fast progress made in our understanding of the molecular processes that govern the pluripotency of ESC has lead to the ability of scientists to recreate a pluripotent state in fibroblasts and other cells from mouse, rat and man, named induced pluripotent stem cells (iPSC). This feat makes it theoretically possible to create patient specific pluripotent stem cells whose differentiated progeny could be used in an autologous manner obviating the need for immunosuppression that would be needed to use allogeneic ESC-derived differentiated cells. In addition, the ability to generate custom made pluripotent stem cells will no doubt lead to the development of protein or small molecule drugs that can induce differentiation not only of iPSC or ESC to mature tissue cells, but also endogenous tissue stem cells. Moreover, it allows scientists to create models of human diseases and may aid the pharmaceutical industry in testing more rigorously toxicity of drugs for human differentiated cells. Thus, there is little doubt that progress in stem cell biology will change many aspects of medicine as we know it in the next one to two decades. PMID- 19442553 TI - [What plans need to be carried out to increase the plasma collection by the EFS?]. AB - The need of plasma derivatives increases in France. The Etablissement francais du sang (EFS) carries out plans for supplying plasma to the Laboratoire francais du fractionnement et des biotechnologies (LFB). Different kinds of actions are taken or will be taken according to the way of plasma processing. For plasma issued from whole blood, the increase is correlated with the increase of whole blood collection for the patients' need of red cells concentrates and the optimized plasma volume of plasma concentrate. For plasma issued from combined aphaeresis and the production of pooled platelets concentrates, synthetic media is favoured. Plasma aphaeresis is a specific way to satisfy requirements of the LFB. Communication choice of the blood collection's place, effects of the new law on blood donors selection, the process of aphaeresis collection, blood tests qualification are subjects of study and actions. PMID- 19442554 TI - [Roles of an independent national Society of Blood Transfusion in the European Union]. AB - Learned societies are a reality in the medical sector. They are currently tending to become a federation of professionals, which targets are to secure the independence of training programs and perpetuate the scientific knowledge of blood transfusion. This is the way the French Society of Blood Transfusion (SFTS) built its role and scope of action in the service of patients. PMID- 19442556 TI - [Review of the main haemovigilance systems in the world]. AB - Since 2002, major progress has occurred worldwide in the context of haemovigilance and significant improvement of the blood chain has come out as a result. Nevertheless different scenarios exist throughout the European Union and outside of Europe: the systems are mandatory or voluntary, notification is required for recipients, donors, processes or activities in the broad context of blood component transfusion. Differing from country to country, notification is mandatory for all adverse reactions or only for serious ones; and so it is with adverse events. Under-reporting is generally considered to be the most important single problem. But there is no doubt that haemovigilance will continue to help improve quality and safety of blood transfusion. PMID- 19442555 TI - [Tranfusion counseling]. AB - In this article, we present transfusion counseling; its organization, actors, their formations and we deal with factual positions. Transfusion counseling needs better identification, tending to a homogeneous organization between every bloodbank centre. PMID- 19442557 TI - [Biobanks and blood transfusion in France: a tool for public health]. AB - Donor and recipient sample biobanks are a precious tool in hemovigilance studies as well as in epidemiological and biological research, in particular with regards to safety against blood-borne agents. This paper describes the main transfusion biobanks existing in France and gives their advantages and limits. The National blood donation biobank, organized for medicolegal reasons, preserves samples of each blood donation for a 5-year period. The biobank of the Blood and Organ Transmissible Infectious Agents (BOTIA) project stocks paired donor-recipient samples with a research objective. Preserved over a long period of time, such transfusion biobanks will be useful in terms of public health, as a reflection of the biological state of a population at a given moment. PMID- 19442558 TI - [TRALI and TACO: diagnostic and clinical management of patients]. AB - Transfusion-related acute lung injury (TRALI) is the inflammatory, exudative form and Transfusion-associated cardiac overload (TACO) is the hydrostatic, transudative form of transfusion-induced acute pulmonary edema. The distinction between these two entities may be difficult, but important because of different clinical management strategies and different implications. There is no unique diagnostic tool. The diagnostic search should gather several clinical information and may be helped by various techniques listed in this article. PMID- 19442559 TI - Allele frequencies and haplotypes for 28 Y-STRs in Ovambo population. AB - Y-chromosomal 28 short tandem repeat (STR) loci were investigated in unrelated healthy individuals of the Ovambo population from Namibia (n=54). Sixteen Y chromosome short tandem repeat (Y-STR) polymorphic loci (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385, DYS393, DYS391, DYS439, DYS635, DYS392, GATAH4, DYS437, DYS438, and DYS448) were analyzed using AmpFISTR Yfiler Polymerase Chain Reaction (PCR) Amplification Kit. DYS441-445 and DYS446, DYS447, DYS449, DYS450, DYS459a/b, DYS463 and DYS464a/b/c/d were investigated using a multiplex PCR system. Fifty-one haplotypes were identified in 54 Ovambos. The STR diversity values for Y-STRs loci ranged from 0.036 (DYS392) to 0.900 (DYS 385). PMID- 19442560 TI - Ultrasound-promoted a green protocol for the synthesis of 2,4-diarylthiazoles under ambient temperature in [bmim]BF(4). AB - A mild, efficient, facile and eco-friendly procedure for the synthesis of 2,4 diarylthiazoles from arylthioamides and alpha-bromoacetophenones in 1-n-butyl-3 methylimidazolium tetrafluoroborate as a "green" media under ultrasound irradiation at room temperature is described. It is interesting to mention that only one product was obtained when two different alpha-bromoacetophenones were reacted with 1,3-phenyl dithioamide as the substrate. Work-up is very simple and there is no need to purify the product. A recycling study confirmed that the ionic liquid can be reused multiple times without a significant loss in its activity. PMID- 19442561 TI - The prognosis of fixed dystonia: a follow-up study. AB - BACKGROUND: The syndrome of fixed dystonia includes both CRPS-dystonia and psychogenic dystonia. The underlying mechanisms are unclear, but a high prevalence of neuropsychiatric illness has previously been reported. METHODS: Clinical and neuropsychiatric follow-up study by telephone and self-administered instruments (HADS, SDQ-20, DES II, EQ-5D), on 41 patients with fixed dystonia after a mean of 7.6 (+/-3.6) years. RESULTS: We obtained information on clinical outcome in 35 (85.4%) patients and neuropsychiatric questionnaire data in 22 (53.7%). Eighty-three percent were women. Thirty-one percent had worsened, 46% were the same and 23% had improved, of whom 6% had major remissions. At follow up, mean duration of illness was 11.8 (+/-4.9) years and mean age 43.2 (+/-14.8) years. Except for 1 patient who was re-diagnosed with corticobasal degeneration, the diagnosis remained unchanged in others. Forty-one percent had scores indicating anxiety and 18% indicating depression; 18% scored within the range of dissociative/somatoform disorders on DES II and 19% on SDQ-20. The mean EQ-5D index and VAS scores were 0.34 and 56.1%. Comparison between the 3 outcome groups revealed significant difference only in the EQ-5D (p=0.003). Only baseline CRPS predicted a worse outcome (chi(2)=0.006). CONCLUSIONS: Our findings revealed that the prognosis of this syndrome is poor, with improvement in less than 25% of patients, major remission in only 6% and continued worsening in a third. A high rate of neuropsychiatric findings was noted and new neuropsychiatric features had occurred in some. Average health status was poor. Of the baseline parameters, only CRPS predicted poorer outcome. PMID- 19442562 TI - The therapeutic and optical application of a rigid gas permeable semi-limbal diameter contact lens. AB - PURPOSE: To evaluate the therapeutic and optical application of a semi-limbal diameter (S-LIM) rigid gas permeable (RGP) contact lens. METHOD: A retrospective non-comparative case series of 14 consecutive patients (22 eyes) who were referred to one senior optometrist for the fitting of S-LIM contact lenses at Moorfields Eye Hospital. The cases comprised of 11 patients (17 eyes) with keratoconus, 1 patient (2 eyes) post-surgical ectasia from previous LASIK, 1 (1 eye) post-graft patient, and 1 patient (2 eyes) who required corneal protection secondary to lagophthalmos. These patients had failed previously with other lens designs because of lens intolerance, unstable vision, chronic 3 and 9 o'clock corneal staining, and inadequate corneal protection for the patient with lagophthalmos. A conventional method of using diagnostic lenses with fluorescein assessment was adopted in fitting the S-LIM lenses. RESULTS: The median duration of problems encountered with previous lenses was 4 years (range 0.5-10 years). The median visual acuity with the S-LIM lens was 6/9 (range 6/5-6/24). A median of 1 diagnostic lens (range 1-3 lenses) was required to achieve a satisfactory fit. At the last recorded follow-up, 10 patients (14 eyes) had no clinically observable problem and were wearing their lenses with a median wearing time of 8h per day (range 1-18 h). The median duration of follow up was 6 months (range 2-18 months). One patient (1 eye) abandoned lens wear because of satisfactory unaided vision. CONCLUSION: The use of a semi-limbal diameter lens can be an effective modality in patients with intolerance to other lens designs. However, lens modification from the standard design and the use of ocula lubricants are often required to optimise lens fit and to enhance tolerance. PMID- 19442563 TI - Biomarkers in dysplasia of the oral cavity: a systematic review. AB - Oral dysplasia is a potentially precancerous lesion diagnosed histologically. While the risk of progression is associated with histological grade, it is currently impossible to predict accurately which lesions will progress. More accurate markers predicting progression to cancer would enable the targeting of these lesions for more aggressive treatment and closer follow-up. We have performed a systematic review with pooling of data to assess the evidence for the use of biomarkers in predicting transformation of oral dysplasia into cancer. We systematically searched the Cochrane library, MEDLINE, EMBASE, AMED, Cinahl and the Kings Fund electronic databases using the terms: oral dysplasia, leukoplakia, erythroplakia, biomarkers and genetic markers. The following a priori selection criteria were used: longitudinal cohort or case-controlled studies of oral dysplasia that progressed to cancer. Cross-sectional studies and studies reporting only on leukoplakia were excluded. Data were extracted by two reviewers. Quality assessment was carried out using validated tools. We assessed the relative risk of progression form oral dysplasia to cancer and pooled data where possible. 2550 studies were identified, from which 288 were scrutinised in greater detail. Of these, 247 were excluded, mainly due to cross-sectional design. Of the 41 studies containing follow-up data, 28 were excluded, most commonly due to data only being available for lesions once they had progressed to cancer. A lack of clear histological definition of oral lesions was also a common finding. Data were extracted from 13 longitudinal studies. The evidence consists mainly of small, single centre, retrospective studies. In oral dysplasia, loss of heterozygosity (LOH), particularly at the 3p+/-9p loci, increases the risk of progression to cancer (RR 17.60 (2.77, 108.37) p<0.001), as does survivin (RR 30 (4.25, 197.73), p0.001), matrix metalloproteinase (MMP 9), (RR 19.00 (1.56, 209.38) p=0.02) and DNA content (RR 12.00 (1.17, 82.10) p=0.03). Other markers identified by this review including p53, p73, MMP 1 and 2 and cathepsin L mRNA, did not predict progression. LOH, survivin, MMP 9 and DNA content are potential markers for increased risk of progression from oral dysplasia to cancer. Many methodological limitations have been identified by this review, however, and we recommend these results are interpreted with caution. Research into this field should concentrate on longitudinal design, with pooling of data from multiple centres to achieve larger cohorts. We recommend standardisation of definitions to allow appropriate comparisons to be made. PMID- 19442564 TI - CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients. AB - Head and neck squamous cell carcinoma (HNSCC) is associated with environmental factors, especially tobacco and alcohol consumption. Most of the carcinogens present in tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYPs) enzymes and detoxification of these substances is performed by glutathione S-transferases (GSTs). It has been suggested that genetic alterations, such as polymorphisms, play an important role in tumorigenesis and HNSCC progression. The aim of this study was to investigate CYP1A1, CYP1A2, CYP2E1, GSTM1, and GSTT1 polymorphisms as risk factors in HNSCC and their association with clinicopathologic data. The patients comprised 153 individuals with HNSCC (cases) and 145 with no current or previous diagnosis of cancer (controls). Genotyping of the single nucleotide polymorphisms (SNPs) of the CYP1A1, CYP1A2, and CYP2E1 genes was performed by PCR-RFLP and the GSTM1 and GSTT1 copy number polymorphisms (CNPs) were analyzed by PCR-multiplex. As expected, a significant difference was detected for tobacco and alcohol consumption between cases and controls (P<0.001). It was observed that the CYP1A2*1D (OR=16.24) variant and GSTM1 null alleles (OR=0.02) confer increased risk of HNSCC development (P<0.001). In addition, head and neck cancer alcohol consumers were more frequently associated with the CYP2E1*5B variant allele than control alcohol users (P<0.0001, OR=190.6). The CYP1A2*1C polymorphism was associated with tumor recurrence (log-rank test, P=0.0161). The CYP2E1*5B and GSTM1 null alleles were significantly associated with advanced clinical stages (T3+T4; P=0.022 and P=0.028, respectively). Overall, the findings suggested that the genetic polymorphisms studied are predictors of risk and are also associated with tumor recurrence, since they are important for determining the parameters associated with tumor progression and poor outcomes in HNSCC. PMID- 19442565 TI - Immunotherapy for head and neck cancer. AB - Overall survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has not improved appreciably over the past few decades. Novel therapeutic approaches, such as immunotherapy, are under clinical investigation since the standard treatments are toxic and have not successfully controlled this disease with sufficiently high success rates. Cancer immunotherapy describes various techniques to expand and activate the immune system to control tumor growth in vivo, and clinical evaluation has so far demonstrated low toxicity. Immunotherapy appears to have the most applicability in settings of minimal residual disease and to reduce distant metastases after other therapeutic interventions, and its potential clinical value is now receiving intensive evaluation. Emerging forms of SCCHN immunotherapy involve both the use of monoclonal antibodies (mAb) that target growth factor receptors where immune activation appears to contribute to tumor cell lysis, as well as various forms of active vaccination strategies which activate and direct the patient's cellular immunity against the tumor. This article reviews immunotherapeutic strategies currently in clinical trials or under development for patients with SCCHN. PMID- 19442566 TI - The influence of different irradiation doses and desensitizer application on demineralization of human dentin. AB - The aim of the present study was to evaluate the effect of different irradiation doses after desensitizer application on the onset of initial demineralization of human dentin in situ. The root surfaces of 45 freshly extracted caries-free human molars were cleaned, thereby removing the cementum. From each tooth two root dentin specimens were prepared. The specimens were distributed among the following experimental groups: 0, 0.5, 1, 2 and 5Gy. The irradiation dose was fractionally applied (0.5Gy/day). One dentin specimen of each group was inserted into both buccal aspects of nine intraoral mandibular appliances. On one side the specimens were additionally coated with the desensitizer Hyposen (H). On the other side, the specimens were left untreated (C). The appliances were worn by nine persons for five weeks day and night. During meals, the appliance was stored in 10% sucrose solution. After the in situ period, slabs (150microm) were ground and studied using a polarized light microscope. Concerning radiation dose, significant differences were observed between the control and 5Gy group (p<0.05, Tukey s test). Pairwise comparison showed that lesion depths in groups treated with Hyposen were significantly decreased. Within the limitations of this study it can be concluded that higher radiation doses seem to increase the caries susceptibility of dentin. The additional application of a desensitizer hampers the demineralization and might have a caries-protective effect on exposed irradiated root surfaces. PMID- 19442567 TI - The psychometric and clinical validity of the SWAL-QOL questionnaire in evaluating swallowing problems experienced by patients with oral and oropharyngeal cancer. AB - The aim of this study was to evaluate feasibility, reliability, validity of the SWAL-QOL (a questionnaire on swallowing problems in daily life), and to define sample size calculations and a clinically relevant cut-off score. One hundred and two patients were treated for cancer of the oral cavity or pharynx and 111 healthy subjects completed the SWAL-QOL and the EORTC H and N35 questionnaire. A randomly selected subset of patients (n=29) completed the SWAL-QOL twice to assess test-retest stability. For the patient sample, data on tumor site (oral or oropharyngeal) and stage (I-IV), treatment modality (surgery, radiation, surgery+radiation, chemoradiation), and presence of a PEG tube were abstracted from medical records. Reliability of the SWAL-QOL was high with high internal consistency and test-retest stability. Feasibility was good, except for patients with tube feeding, of whom 38% did not complete the questionnaire (versus 9% of those with oral feeding). A cut-off score of 14 points (or higher) was defined regarding the total SWAL-QOL score to identify patients with swallowing problems with 94% sensitivity and 84% specificity. A difference score of 12 points or more is proposed to be used in study designs with multiple groups. It can be concluded that the SWAL-QOL is a feasible, reliable, and valid questionnaire to assess patients' swallowing impairment. It can be used in future comparative studies for oral and oropharyngeal cancer and in clinical practice to identify patients in need of further diagnostics and/or swallowing rehabilitation services. PMID- 19442568 TI - Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines. AB - Concomitant chemoradiotherapy is a common treatment for advanced head and neck squamous cell carcinomas (HNSCC). Cisplatin is the backbone of chemotherapy regimens used to treat HNSCC. Therefore, the aim of this study was to identify predictive markers for cisplatin treatment outcome in HNSCC. The intrinsic cisplatin sensitivity (ICS) was determined in a panel of tumour cell lines. From this panel, one sensitive and two resistant cell lines were selected for comparative transcript profiling using microarray analysis. The enrichment of Gene Ontology (GO) categories in sensitive versus resistant cell lines were assessed using the Gene Ontology Tree Machine bioinformatics tool. In total, 781 transcripts were found to be differentially expressed and 11 GO categories were enriched. Transcripts contributing to this enrichment were further analyzed using Ingenuity Pathway Analysis (IPA) for identification of key regulator genes. IPA recognized 20 key regulator genes of which five were differentially expressed in sensitive versus resistant cell lines. The mRNA level of these five genes was further assessed in a panel of 25 HNSCC cell lines using quantitative real-time PCR. Among these key regulators, MMP-7 and MMP-13 are implicated as potential biomarkers of ICS. Taken together, genome-wide transcriptional analysis identified single genes, GO categories as well as molecular networks that are differentially expressed in HNSCC cell lines with different ICS. Furthermore, two novel predictive biomarkers for cisplatin resistance, MMP-7 and MMP-13, were identified. PMID- 19442569 TI - CEACAM1 distribution and it's effects on angiogenesis and lymphangiogenesis in oral carcinoma. AB - To investigate the expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its effects on angiogenesis and lymphangiogenesis in oral carcinoma. Immunohistochemistry was used to study the expression of CEACAM1, LYVE1 and CD31, double-labelling immunofluorescence was used to detect the co expression of CEACAM1 and LYVE1, and double-labelling immunohistochemistry was performed to observe the co-expression of LYVE1 and CD31 in vessels. Membranous CEACAM1 was expressed in well-differentiated squamous cell carcinoma and cytoplastic CEACAM1 in poorly and moderately differentiated carcinoma (P<0.05). More CEACAM1-positive vessels were observed in CEACAM1-positive tumors with cytoplasmic expression than with membranous expression (P<0.001). Co-expression of CEACAM1 and LYVE1, LYVE1 and CD31 in vessels was more common in CEACAM1 positive tumors with cytoplasmic expression than with membranous expression (P<0.001). CEACAM1 has different distribution in oral carcinoma. Membranous CEACAM1 inhibits angiogenesis and lymphangiogenesis, but cytoplasmic CEACAM1 promotes angiogenesis, and even promotes lymphangiogenesis by mediating the transformation of vascular endothelial cells (VECs) into lymphatic endothelial cells (LECs). PMID- 19442570 TI - Feasibility of transoral lateral oropharyngectomy using a robotic surgical system for tonsillar cancer. AB - Conventional surgical approaches for tonsillar carcinomas have a great risk for developing treatment-related morbidity. To minimize this morbidity, transoral lateral oropharyngectomy (TLO) using the robotic surgical system was performed, and the efficacy and feasibility of this procedure was evaluated. TLO was performed using the da Vinci surgical robot (Intuitive Surgical, Inc., Sunnyvale, CA). It consists of a surgeon's console and a manipulator cart equipped with three robotic arms. The surgeon is provided with three-dimensional magnified images from the endoscopic arm and can control two instrument arms for delicate operations from the console. Safe resection of tonsillar carcinoma was possible with the three-dimensional magnified images. When proceeding with resection of the buccopharyngeal fascia, we could prevent damage to the carotid artery, which is located posterolateral to the tonsillar fossa, since the joint at the distal part of the robotic arm can be bent freely from side to side. By using the 30 degrees endoscope, we can achieve a better surgical view of the base of the tongue area. TLO was performed successfully in all five patients without surgical complications. The mean operating time was 44 min, and an average of 19 min was required for setting up the robotic system. TLO using the robotic system will be a good option for organ preservation therapy in the treatment of carcinomas of the tonsil and the tonsillar fossa in the future. PMID- 19442571 TI - Enhancing epidemiologic research on head and neck cancer: INHANCE - The international head and neck cancer epidemiology consortium. PMID- 19442572 TI - The azo dyes Disperse Red 1 and Disperse Orange 1 increase the micronuclei frequencies in human lymphocytes and in HepG2 cells. AB - The use of azo dyes by different industries can cause direct and/or indirect effects on human and environmental health due to the discharge of industrial effluents that contain these toxic compounds. Several studies have demonstrated the genotoxic effects of various azo dyes, but information on the DNA damage caused by Disperse Red 1 and Disperse Orange 1 is unavailable, although these dyes are used in dyeing processes in many countries. The aim of the present study was to evaluate the mutagenic activity of Disperse Red 1 and Disperse Orange 1 using the micronucleus (MN) assay in human lymphocytes and in HepG2 cells. In the lymphocyte assay, it was found that the number of MN induced by the lowest concentration of each dye (0.2 microg/mL) was similar to that of the negative control. At the other concentrations, a dose response MN formation was observed up to 1.0 microg/mL. At higher dose levels, the number of MN decreased. For the HepG2 cells the results were similar. With both dyes a dose dependent increase in the frequency of MN was detected. However for the HepG2, the threshold for this increase was 2.0 microg/mL, while at higher doses a reduction in the MN number was observed. The proliferation index was also calculated in order to evaluate acute toxicity during the test. No differences were detected between the different concentrations tested and the negative control. PMID- 19442573 TI - Investigations of molecular interactions in propionic acid-N,N-dimethyl formamide binary system--FTIR study. AB - FTIR spectra of propionic acid (PA), N,N-dimethyl formamide (DMF) and its binary mixtures with varying molefractions of the PA were recorded in the region 500 3500 cm(-1), to investigate the formation of hydrogen bonded complexes in a mixed system. The observed features in nu(C=O), delta(O=C-N) and nu(as)(CN) of DMF, nu(C=O) and nu(CO) of PA have been explained in terms of the hydrogen bonding interactions between DMF and PA and dipole-dipole interaction. The intrinsic bandwidth for the vibrational modes nu(as)(CN) and nu(CO) has been elucidated using Bondarev and Mardaeva model. PMID- 19442574 TI - A novel time-resolved laser fluorescence spectroscopy system for research on complexation of uranium(IV). AB - To date only a small number of studies have investigated the chemical speciation of complexes and the fluorescence properties of metal ions whose emitted fluorescence lifetime is in the range of only few nanoseconds. This is due to a lack of advanced methods which allow the conduction of these measurements. In the current study we set up a new time-resolved laser fluorescence spectroscopy system with which the fluorescence properties of metal ions with very short fluorescence lifetimes such as uranium(IV) and its compounds can be investigated. By studying the fluorescence properties of uranium(IV) in perchloric acid, we showed uranium(IV) to have a detection limit of 5 x 10(-7)M and a fluorescence decay time of 2.74+/-0.36 ns. We further investigated the fluorescence properties of uranium(IV) during the reaction with fluoride and applied our novel laser system to study the complexation of uranium(IV) with fluoride. Our data revealed the formation of a 1:1 complex of uranium(IV) and fluoride. The corresponding complex formation constant of uranium(IV) fluoride UF(3+) was found to be log beta(0)=9.43+/-1.94. Our results demonstrate that our novel time-resolved laser fluorescence spectroscopy system can successfully conduct speciation measurements of metal ions and their compounds with very short-lived fluorescence lifetimes. Using this laser system, it is possible to analytically investigate such elements and compounds in environmentally relevant concentration ranges. PMID- 19442575 TI - Geometrical and vibrational features of phosphate, phosphorothioate and phosphorodithioate linkages interacting with hydrated cations: a DFT study. AB - The effect of hexahydrated monovalent and divalent cations on the geometrical and vibrational features of dimethyl phosphate, dimethyl phosphorothioate and dimethyl phosphorodithioate anions (simple suitable model compounds representing the anionic moieties of natural and some modified nucleic acids) was studied. For this purpose, density functional theory (DFT) calculations were carried out at the B3LYP/6-31++G* level. Our results indicate that only K(+) and Mg(2+) prefer to be located in the bisector plane of the PO(2)(-) angle, whereas Li(+) and Na(+) deviate from this plane. Monovalent and divalent cations are slightly deviated from the OPS(-) bisector plane and are found closer to the free oxygen atom. Moreover, the present calculations have shown that in contrast to the general belief, the g(-)g(-) conformer (with respect to the torsion angles defined around the P-O ester bonds) is not always the energetically most favorable. For instance, the g(-)t conformer presents the lowest energy in the case of dimethyl phosphorothioate. The calculated vibrational wavenumbers obtained for dimethyl phosphate and dimethyl phosphorothioate interacting with hydrated sodium counterion, were compared with those previously recorded by Raman scattering and infrared absorption (IR) in aqueous solutions. It has been evidenced that the use of explicit solvent versus dielectric continuum, considerably improves the agreement between the theoretical and observed characteristic wavenumbers. PMID- 19442576 TI - Dengue and Chikungunya virus co-infection in a German traveller. PMID- 19442577 TI - Agrypnia Excitata: a microneurographic study of muscle sympathetic nerve activity. AB - OBJECTIVE: Agrypnia Excitata (AE) is characterized by autonomic over-activity and cardiovascular fluctuations but direct evidence of sympathoexcitation is lacking. AE is a common feature of acquired (i.e. Morvan's syndrome--MS) and genetic (i.e. fatal familial insomnia--FFI) conditions where a dysfunction of the thalamo limbic system has been suggested. The aim of this study is to report the first microneurographic recordings of sympathetic activity in acquired and genetic AE to investigate the pattern of sympathetic activation. METHODS: We describe two patients presenting acquired AE (MS) as demonstrated by elevated serum antibody levels to voltage-gated potassium channels and one patient with genetically confirmed FFI. Patients and fifteen sex and age-matched healthy controls underwent microneurography from peroneal nerve to assess muscle sympathetic nerve activity (MSNA) and heart rate (HR). RESULTS: Mean level of resting awake MSNA and HR was significantly increased in patients compared to controls. Patients presented a similar pattern of MSNA with a normal cardiac rhythmicity and a very high burst incidence expressed in approximately each cardiac beat. CONCLUSIONS: Acquired and genetic AE presented a resting awake sympathetic over-activity. SIGNIFICANCE: AE patients may develop high blood pressure and/or cardiovascular instability potentially increasing the morbidity/mortality of the underlying disorders. PMID- 19442578 TI - Executive function deficits and neural discordance in children with Autism Spectrum Disorders. AB - OBJECTIVE: This study examined neurophysiologic activities, executive dysfunctions, and their association in children with Autism Spectrum Disorders (ASD). METHODS: Thirty-eight normal and 16 children with ASD participated with parental consent. Executive functions were measured using neuropsychological tests and parent ratings, and neurophysiologic activities were measured using EEG to yield cordance values, an indirect measure of brain perfusion. RESULTS: Children with ASD made significantly more intrusion errors and False Alarms on the Hong Kong List Learning Test (HKLLT) and Object Recognition Test (OR) than normal children, but were comparable to normal children on the Rey-Osterrieth Complex Figure Test and Continuous Performance Test. They also showed significantly poorer executive functions in everyday activities as shown on the Behavior Rating Inventory of Executive Function (BRIEF), and had lower frontal perfusion patterns than normal children as shown in the neurophysiologic cordance measures. Frontal cordance values were found to be significantly associated with executive dysfunctions in HKLLT Delayed Intrusions, OR False Alarms and BRIEF. CONCLUSIONS: Children with ASD were impaired in everyday executive functioning and response inhibition. The cordance value, which has been shown to correlate with brain perfusion in a number of studies, was significantly correlated with executive dysfunctions. SIGNIFICANCE: Exploration of this measure as an index for response to intervention is warranted. PMID- 19442579 TI - Working memory function in post-traumatic stress disorder: an event-related potential study. AB - OBJECTIVE: Previous studies using event-related potentials (ERPs) in post traumatic stress disorder (PTSD) have demonstrated reduced P3 amplitude during target detection and working memory (WM) processes. This study investigated effects of psychotropic medication (primarily antidepressants) on these ERP components. METHODS: ERPs were recorded from 26 scalp sites in 34 PTSD patients (20 unmedicated, 14 medicated) with age- and gender-matched controls during a WM paradigm that involved detection of target letters on a visual display. RESULTS: As expected, PTSD patients showed a reduced amplitude P3wm component during WM updating and a reduced and delayed target P3 component. Contrary to expectation, these ERP effects were most apparent in the medicated subgroup of PTSD patients. The medicated PTSD subgroup showed a trend towards reduced P3wm amplitude compared with controls and a significant amplitude reduction and delay of target P3 component, while there was little difference between the non-medicated PTSD subgroup and controls. Neither ERP nor behavioural measures were related to Clinician Administered PTSD Scale (CAPS) symptom severity measures. CONCLUSIONS: These results are consistent with research that suggests antidepressant medication may impair working memory performance. SIGNIFICANCE: The present study illustrates the importance of monitoring medication effects on cognitive performance during clinical efficacy studies. PMID- 19442580 TI - Relationships of sleep duration with sleep disturbances, basic socio-demographic factors, and BMI in Chinese people. AB - OBJECTIVE: This study aimed at determining the mean total sleep time (TST) and the relationship between sleep duration and basic socio-demographic factors and BMI sleep problems in Chinese subjects. METHOD: A total of 5926 subjects were randomly selected and interviewed using standardized assessment tools. RESULTS: The reported mean TST was 7.76 h. Short sleepers were significantly older than medium and long sleepers. There were more urban residents who were short sleepers than medium and long sleepers. Short sleepers reported more sleep problems than medium and long sleepers. Short and long sleepers reported more psychiatric disorders than medium sleepers in both sexes, and short sleepers also had more major medical conditions in women. Short sleepers had a lower BMI than medium and long sleepers after controlling for the effects of age and psychiatric disorders in women. CONCLUSIONS: Nationwide epidemiologic surveys in China are needed to further explore the relationship between sleep duration and sleep problems. PMID- 19442581 TI - Evidence of sensorimotor deficits in functional ankle instability: a systematic review with meta-analysis. AB - Functional ankle instability (FAI) has been associated with impaired sensorimotor function; however individual studies have produced conflicting results. In an attempt to reduce this ambiguity, a systematic review with meta-analysis was undertaken to determine which sensorimotor deficits exist with FAI. Fifty-three studies assessing sensorimotor factors in subjects with FAI were included from 465 identified articles. Studies were rated for methodological quality and data were pooled for peroneal reaction time, joint position sense, and postural sway during single-leg stance and time to stabilisation from a single-leg jump. Data on joint movement sense were unable to be pooled. When subjects with unstable ankles were compared to healthy controls, sensorimotor impairments were demonstrated for passive joint position sense (mean difference (MD)=0.7 degrees , 95% confidence interval (CI): 0.2-1.2 degrees , p=0.004), active joint position sense (MD=0.6 degrees , 95% CI: 0.2-1.0 degrees , p=0.002), postural sway in single-leg stance (standardised MD (SMD)=0.6, 95% CI: 0.2-1.0, p=0.002), the star excursion balance test (SMD=0.4, 95% CI: 0.1-0.7, p=0.009), and time to stabilisation from a single-leg jump in a medio-lateral (MD=0.6 ms, 95% CI: 0.4 0.8, p<0.0001) and an antero-posterior direction (MD=0.7 ms, 95% CI: 0.4-1.0, p<0.0001). Peroneal reaction time was not affected. Sensorimotor deficits occur for joint position sense and postural control in subjects with FAI. Deficits in peroneal muscle reaction time following perturbation are not evident. PMID- 19442582 TI - Throwing velocity and jump height in female water polo players: performance predictors. AB - Throwing velocity and vertical jumping ability are essential components for shooting and passing in water polo. The purpose of this study was to determine whether there is a relationship between throwing velocity and water jump height in highly skilled female water polo players. Throwing velocity and head height at ball release were measured in twenty-two female players (age 20.41 years (6.16); weight 68.28 kg (8.87)) with two 50 frames per second cameras while shooting at goal. Water jump height was also measured with a modified Yardstick device. Multiple regression analyses showed that peak lower limb power was the most significant predictor of maximal velocity. Power alone accounted for 62% of the variance in maximum velocity (p<0.001). Once power was entered into the model none of the other physical characteristics (lean mass, fat mass, land jump height and anthropometry) made a significant contribution to throwing velocity. After controlling for the effect of power, head height at ball release accounted for an additional significant proportion of the variance in maximal velocity (R(2) change 7%; p=0.049). Lower body power was a significant predictor of higher throwing velocity in highly skilled female water polo players. Players with relatively higher underlying levels of lower limb power who are able to generate greater elevation out of the water are able to throw the ball faster. PMID- 19442583 TI - Novel pharmacological approaches to airway and pulmonary vascular disease. PMID- 19442584 TI - The role of the Maurer's clefts in protein transport in Plasmodium falciparum. AB - Maurer's clefts (MCs) are membranous structures that are formed by Plasmodium falciparum and used by the parasite for protein sorting and protein export. Virulence proteins, as well as other proteins used to remodel the erythrocyte, are exported. Discontinuity between major membrane compartments within the infected erythrocyte cytoplasm suggests multiple traffic routes for exported proteins. The sequences of the conserved Plasmodium export element seem insufficient for export of all parasite proteins. The parasite displays remarkable versatility in the types of proteins exported to the MCs and in the functions of the proteins within the MCs. In this Review, protein export to the MCs and the role of the MCs in the transport of proteins to the erythrocyte membrane are summarized. PMID- 19442585 TI - Preceptorship and practical wisdom: A process of engaging in authentic nursing practice. AB - Preceptorship is a teaching/learning approach, in which learners are individually assigned to staff nurses in the practice setting. Practical wisdom is a discerning process of evaluating and applying ideals or principles often in a moral context. The nurse who is practically wise recognizes that actions are always constrained to some extent by chance or context and yet precisely under such circumstances, acts to preserve and enhance the wellbeing of the patient. The purpose of this study was to examine the process used in the preceptorship experience to nurture practical wisdom. A grounded theory study was conducted with fourth year undergraduate nursing students and their preceptors in an acute/tertiary care setting. Data collection comprised a series of semi structured interviews, documentation of field notes and journaling. Findings reveal that preceptors who nurture practical wisdom in the practice setting do so by engaging in a process of authentic nursing practice. PMID- 19442586 TI - Occult dural arteriovenous fistula causing rapidly progressive conus medullaris syndrome and paraplegia after lumbar microdiscectomy. AB - BACKGROUND CONTEXT: A spinal dural arteriovenous fistula (DAVF) is a known cause of venous congestive myelopathy. These lesions are thought to be acquired. There exist two prior reports that describe DAVF presenting with slowly progressive myelopathy years after lumbar disc surgery. PURPOSE: We report the first case of a preexistent, asymptomatic DAVF that became acutely symptomatic after lumbar microdiscectomy causing rapidly progressive conus medullaris syndrome and paraplegia. STUDY DESIGN: Case report. METHODS: A 53-year-old Caucasian male presented with urinary retention, fecal incontinence, and progressive loss of function in bilateral lower extremities less than 3 months after a lumbar discectomy at an outside facility. The patient underwent microdiscectomy at L4/L5 and L5/S1 for left-sided radicular symptoms and evidence of herniated discs on magnetic resonance imaging (MRI). The patient's preoperative pain improved after the discectomy, but his bowel, bladder, and lower extremity function deteriorated steadily after discharge. Postoperative MRI showed salient serpentine vessels in the region of L1 and L2 with an enlarged T2 bright conus medullaris. Retrospective review of preoperative MRI revealed the presence of similar but less pronounced findings. A spinal arteriogram confirmed concerns of an arteriovenous malformation. The patient was transferred to our facility for definitive management of his DAVF via catheter embolization. RESULTS: Complete fistula obliteration was confirmed at the time of embolization and at 8 weeks follow-up with selective spinal angiography. The appearance of the conus medullaris normalized on follow-up MRI. The patient made a slow but significant recovery in rehabilitation. He regained the ability to independently ambulate but remains significantly disabled secondary to residual lower extremity weakness and spasticity. He continues self-catheterization for persistent neurogenic bladder dysfunction. CONCLUSIONS: This represents the first case of an occult spinal DAVF becoming acutely symptomatic after lumbar disc surgery. Although the etiology of the lesion and its symptomatic progression remains unknown, an alteration of blood flow through the DAVF as a result of surgery may have resulted in progressive venous congestive myelopathy. The present case highlights the importance of considering a spinal DAVF in the differential diagnosis of any patient with signs of myelopathy or conus medullaris syndrome after lumbar discectomy. In addition, this case underscores the gravity of recognizing subtle features that suggest the presence of an occult vascular malformation on preoperative imaging, as symptomatic progression of these lesions carries significant potential morbidity. PMID- 19442587 TI - Critical evaluation of interventional pain management literature provides inaccurate conclusions. PMID- 19442588 TI - Reactive oxygen species modulate neuronal excitability in rat intrinsic cardiac ganglia. AB - Reactive oxygen species (ROS) are produced as by-products of oxidative metabolism and occur in the heart during ischemia and coronary artery reperfusion. The effects of ROS on the electrophysiological properties of intracardiac neurons were investigated in the intracardiac ganglion (ICG) plexus in situ and in dissociated neurons from neonatal and adult rat hearts using the whole-cell patch clamp recording configuration. Bath application of ROS donors, hydrogen peroxide (H(2)O(2)) and tert-butyl hydroperoxide (t-BHP) hyperpolarized, and increased the action potential duration of both neonatal and adult ICG neurons. This action was also recorded in ICG neurons in an adult in situ ganglion preparation. H(2)O(2) and t-BHP also inhibited voltage-gated calcium channel (VGCC) currents and shifted the current-voltage (I-V) relationship to more hyperpolarized potentials. In contrast, H(2)O(2) increased the amplitude of the delayed rectifier K(+) current in neonatal ICG neurons. In neonatal ICG neurons, bath application of either superoxide dismutase (SOD) or catalase, scavengers of ROS, prior to H(2)O(2) attenuated the hyperpolarizing shift but not the inhibition of VGCC by H(2)O(2). In contrast, in adult ICG neurons, application of SOD alone had no effect upon either VGCC current amplitude or the I-V relationship, whereas application of SOD prior to H(2)O(2) exposure abolished both the H(2)O(2) mediated hyperpolarizing shift and inhibition. These data indicate that ROS alter depolarization-activated Ca(2+) and K(+) conductances which underlie neuronal excitability of ICG neurons. This affects action potential duration and therefore probably modifies autonomic control of the heart during ischemia/reperfusion. PMID- 19442589 TI - Rapidly evolving genes in pathogens: methods for detecting positive selection and examples among fungi, bacteria, viruses and protists. AB - The ongoing coevolutionary struggle between hosts and pathogens, with hosts evolving to escape pathogen infection and pathogens evolving to escape host defences, can generate an 'arms race', i.e., the occurrence of recurrent selective sweeps that each favours a novel resistance or virulence allele that goes to fixation. Host-pathogen coevolution can alternatively lead to a 'trench warfare', i.e., balancing selection, maintaining certain alleles at loci involved in host-pathogen recognition over long time scales. Recently, technological and methodological progress has enabled detection of footprints of selection directly on genes, which can provide useful insights into the processes of coevolution. This knowledge can also have practical applications, for instance development of vaccines or drugs. Here we review the methods for detecting genes under positive selection using divergence data (i.e., the ratio of nonsynonymous to synonymous substitution rates, d(N)/d(S)). We also review methods for detecting selection using polymorphisms, such as methods based on F(ST) measures, frequency spectrum, linkage disequilibrium and haplotype structure. In the second part, we review examples where targets of selection have been identified in pathogens using these tests. Genes under positive selection in pathogens have mostly been sought among viruses, bacteria and protists, because of their paramount importance for human health. Another focus is on fungal pathogens owing to their agronomic importance. We finally discuss promising directions in pathogen studies, such as detecting selection in non-coding regions. PMID- 19442590 TI - Extracts of proliferating and non-proliferating human cells display different base excision pathways and repair fidelity. AB - Base excision repair (BER) of damaged or inappropriate bases in DNA has been reported to take place by single nucleotide insertion or through incorporation of several nucleotides, termed short-patch and long-patch repair, respectively. We found that extracts from proliferating and non-proliferating cells both had capacity for single- and two-nucleotide insertion BER activity. However, patch size longer than two nucleotides was only detected in extracts from proliferating cells. Relative to extracts from proliferating cells, extracts from non proliferating cells had approximately two-fold higher concentration of POLbeta, which contributed to most of two-nucleotide insertion BER. In contrast, two nucleotide insertion in extracts from proliferating cells was not dependent on POLbeta. BER fidelity was two- to three-fold lower in extracts from the non proliferating compared with extracts of proliferating cells. Furthermore, although one-nucleotide deletion was the predominant type of repair error in both extracts, the pattern of repair errors was somewhat different. These results establish two-nucleotide patch BER as a distinct POLbeta-dependent mechanism in non-proliferating cells and demonstrate that BER fidelity is lower in extracts from non-proliferating as compared with proliferating cells. PMID- 19442591 TI - Venous gas emboli and exhaled nitric oxide with simulated and actual extravehicular activity. AB - The decompression experienced due to the change in pressure from a space vehicle (1013hPa) to that in a suit for extravehicular activity (EVA) (386hPa) was simulated using a hypobaric chamber. Previous ground-based research has indicated around a 50% occurrence of both venous gas emboli (VGE) and symptoms of decompression illness (DCI) after similar decompressions. In contrast, no DCI symptoms have been reported from past or current space activities. Twenty subjects were studied using Doppler ultrasound to detect any VGE during decompression to 386hPa, where they remained for up to 6h. Subjects were supine to simulate weightlessness. A large number of VGE were found in one subject at rest, who had a recent arm fracture; a small number of VGE were found in another subject during provocation with calf contractions. No changes in exhaled nitric oxide were found that can be related to either simulated EVA or actual EVA (studied in a parallel study on four cosmonauts). We conclude that weightlessness appears to be protective against DCI and that exhaled NO is not likely to be useful to monitor VGE. PMID- 19442592 TI - Home exercise training with non-invasive ventilation in thoracic restrictive respiratory disorders: a randomised study. AB - We assessed the effects of exercise training and non-invasive ventilation (NIV) during exercise in patients with restrictive disorders. Sixteen patients underwent an 8-week home-based cycle exercise program. Nine patients exercised with and seven without NIV. Before and after training, evaluations included incremental and constant-load cycling tests, a 6-min walking test and the Chronic Respiratory Questionnaire (CRQ). For the whole group, training increased walking distance (+22+/-35 m), maximal cycling power output (+5+/-9 W), cycling endurance (+75+/-94%) and CRQ score (+10+/-13 pts). These changes did not differ between patients training with or without NIV. However, in acute NIV responders [Borel, J.C., Wuyam, B., Chouri-Pontarollo, N., Deschaux, C., Levy, P., Pepin, J.L., 2008. During exercise non-invasive ventilation in chronic restrictive respiratory failure. Respir. Med. 102, 711-719], training with NIV induced greater improvement in walking distance and CRQ score. We concluded that in patients with restrictive disorders (i) exercise training including NIV is feasible at home, (ii) whatever the modalities, exercise training induces significant benefits in exercise tolerance and quality of life, and (iii) in acute NIV responders, chronic use of NIV during exercise may lead to synergetic effects compared to traditional training. PMID- 19442593 TI - Molecular and nanoparticle postcolumn reagents for assay of low-molecular-mass biothiols using high-performance liquid chromatography. AB - Determination of low-molecular-mass (LMM) biothiols in biological matrixes is of importance in the studies of their related bio-processes and for the clinical diagnostics of a variety of diseases. Standard method for the assay of the small biothiols is in demand. Postcolumn techniques used in high-performance liquid chromatography (HPLC) allow automation of the derivatization step and, therefore, are suitable for standardization of HPLC analysis. This paper gives an overview of the existing reaction systems useful for the postcolumn assay of the LMM biothiol molecules in conjunction with HPLC. The postcolumn reagents are classified by the types of their reactions with thiol-containing compounds. The chemical reactivity and selectivity as well as the spectroscopic characteristics of the postcolumn reagents have been addressed. The emerging strategies of using nanoparticles as thiol-reactive reagents and their applications in postcolumn detection of the LMM biothiols have also been discussed in detail. PMID- 19442595 TI - Natural antibodies and cancer. AB - The innate or natural immunity is the basis and key for all immune processes. Specific receptors on macrophages, dendrites, NK cells and natural antibodies producing B cells act as a first line defense and remove all 'foreign' and potentially harmful substances, that is, bacteria, viruses, cellular waste, modified molecules and, most importantly, cancer cells. Recognition and removal of transformed cells is a lifelong task of immune surveillance processes. Antibodies are hallmark components of this anti-cancer activity. To investigate their nature, specificity, and function, we used the human hybridoma technology for isolating antibodies from cancer patients. These were then tested with a panel of assays against cancer cell lines in vitro and in vivo. Interestingly, all the tumor-specific antibodies we found were germ-line coded and belonged nearly exclusively to the IgM class. Furthermore, they all bound to new carbohydrates on post-translationally modified cell surface receptors on malignant cells. So far no affinity maturated immunoglobulins detecting tumor specific peptides were found. However, only the presentation of peptide motifs can create an immunological memory. In general malignant cells are detected at very early precursor stages and manifest tumors can be considered as exceptional events. In addition, malignant cells are neither infectious nor hide intracellularly like viruses and some bacteria. Therefore, it makes sense that anti-tumor immunity seems to be solely a part of the natural immunity and a memory is not needed and therefore not induced. This indicates that the tumor immunity seems to be restricted to innate immune mechanisms and the instruments used by nature, like natural antibodies, are obviously excellent therapeutics. PMID- 19442594 TI - Determination of metoclopramide in human plasma using hydrophilic interaction chromatography with tandem mass spectrometry. AB - For the rapid, selective and sensitive analysis of metoclopramide in human plasma, hydrophilic interaction chromatography with electrospray ionization tandem mass spectrometric (HILIC/MS/MS) method was developed. This method involved liquid-liquid extraction with dichloromethane followed by separation on an Atlantis HILIC silica column using the mobile phase of acetonitrile-ammonium formate (100 mM, pH 6.5) (85:15, v/v). Analytes were quantified using electrospray ionization mass spectrometry in the selected reaction monitoring mode. The standard curve was linear (r(2)- 0.998) over the concentration range of 2.00 - 150 ng/mL using 50 microL of plasma sample. The coefficient of variation and relative error for intra- and inter-assay at four QC levels were 1.8 - 7.7% and -7.5 to 3.6%, respectively. The matrix effect for metoclopramide and levosulpiride (internal standard) was practically absent. The present method was successfully applied to the pharmacokinetic study of metoclopramide after oral dose of metoclopramide hydrochloride (10mg) to male healthy volunteers. PMID- 19442596 TI - Total knee arthroplasty with limitations of flexion. AB - Does total knee arthroplasty (TKA) increase mobility in stiff knees, where flexion is restricted due to degenerative changes associated with osteoarthritis, inflammatory disease, hemophilia, or post-traumatic sequelae also affecting soft tissue? The results of one hundred twenty eight TKA from five specialized centers were retrospectively reviewed. Only knees with pre-operative flexion less than 90 degrees were included. Forty six of these also had severe flexion contracture (>20 degrees). As a result of the arthroplasty, the flexion increased by 23+/-17 degrees in group 1 (stiff flexion only, 82 cases), and by 17+/-15 degrees in group 2 (combined stiffness), in which the total range of motion (ROM) increased by 39+/-21 degrees. Improvements in mobility were greater in the cases with severe pre-operative stiffness. One-year functional results did not correlate with final flexion. Flexion at last follow-up did not depend on pre-operative flexion; however, in group 2, final postoperative ROM did correlate with pre operative ROM. Complications concerned mainly those cases with severe stiffness, in which extensive quadriceps release was performed (two cases of skin necrosis, one infection and one rupture of the patellar tendon), or the patients of group 2 (one skin necrosis, two femoral fractures, one infection and one sciatic nerve palsy). Hemophilia was a factor of poor prognosis. Overall, TKA provided significant flexion gain. It often required tibial tuberosity osteotomy, to improve exposure and prevent injury to the extensor mechanism. Extensive quadriceps release should be reserved to post-traumatic cases with intact skin and no recent infection. TYPE OF STUDY: level 4 retrospective. PMID- 19442597 TI - Mobile-bearing insert translational and rotational kinematics in a PCL-retaining total knee arthroplasty. AB - INTRODUCTION: Total knee prostheses with a mobile-bearing insert were developed to provide nonconstrained joint range of motion while reducing friction forces. The purpose of this study was, based on weightbearing X-rays, to evaluate the mobility of the polyethylene tibial insert in relation to the femoral and tibial components. We studied the results of a cementless total knee arthroplasty (TKA) retaining the posterior cruciate ligament (PCL), with a mobile-bearing platform in rotation and anteroposterior translation (Innex Anterior-Posterior Glide, Zimmer) with a mean 23-month follow-up duration after surgery. HYPOTHESIS: Both anterior-posterior tibiofemoral translation and intraprosthetic axial rotation occur between the mobile polyethylene insert and the tibial endplate. MATERIAL AND METHOD: In a series of 51 primary TKA, the three-dimensional (3D) kinematics of the femoral, tibial, and mobile insert components were determined using a computerized matching system between the prosthetic 3D models and the radiographic images of the implants on three lateral follow-up weightbearing knee X-rays: films were taken in full extension, at 45 degrees flexion, and at maximum flexion. RESULTS: There was a statistically significant increase in the internal rotation of the mobile tray with flexion, (up to a mean -3+/-3 degrees between the femoral box and the mobile tray [p<0.0001] and up to a mean -5+/-7 degrees between the tibial tray and the mobile tray [p<0.0001]). The mobile tray did not translate in relation to the tibial endplate from extension to 45 degrees flexion (0+/-2 mm [range: -5 to 6 mm]). However, from 45 degrees to maximum flexion, a statistically significant mean 1+/-2 mm (range: -2 to 9 mm) of anterior translation (p<0.0001) was found. DISCUSSION: The extent of insert mobility varies from one study to another. Some have reported relatively limited mobility stemming from a superior surface that is not highly congruent, (thus allowing anterior-posterior and mediolateral translation through gliding of the femur in contact with the insert). Other studies have reported mobile-bearing tray mobility in relation to the tibial endplate and minimal rotation at the femoral component level. In this series of PCL retaining TKA with a mobile-bearing platform, the mobile-bearing platform showed a progressive increase in internal rotation during flexion. Most of this rotational mobility occurred between the mobile platform and the tibial endplate, confirming our hypothesis. However, with flexion, the femoral component increased its mobility relatively to the platform. During flexion, an anterior-posterior translation occurred between the femoral implant and the tibial insert, and between the tibial insert and the tibial endplate, but the direction of the mobile tibial insert translation remained unpredictable with this nonconstrained implant design used. LEVEL OF EVIDENCE: Level IV. Prospective non-controlled therapeutic study. PMID- 19442598 TI - Total knee arthroplasty in patients with greater than 20 degrees flexion contracture. AB - Does total knee arthroplasty (TKA) correct the flexion contracture in knee stiffness associated with osteoarthritis, inflammatory disease, hemophilia or post-traumatic sequelae? The results of 107 TKAs from five specialized centers were retrospectively reviewed. Only knees with greater than or equal to 20 degrees flexion contracture on extension were included, 46 of which also had less than 90 degrees flexion. As a result of the arthroplasty, extension increased by 20+/-6 degrees in group 1 (flexion contracture only, n=61), and by 22+/-11 degrees in group 2 (combined stiffness, n=46), in which the total range of motion increased of 39+/-21 degrees. Overall, mean residual flexion contracture was 7+/ 7 degrees. Improvements in mobility were greater in the cases with severe preoperative stiffness. One-year functional results correlated with final residual flexion contracture. Mobility at last follow-up did not depend on preoperative mobility, except in group 2, in which the final postoperative range of motion (ROM) correlated with preoperative ROM. Hemophilia was a factor of poor prognosis. Recovering full extension at end of surgery is mandatory, by first releasing the posterior capsule and the collateral ligaments from their osteophytes, and secondly by extending the distal femoral cut where necessary. TYPE OF STUDY: Level 4 retrospective. PMID- 19442599 TI - Management of massive traumatic compound defects of the foot. AB - The management of high-energy trauma to the foot often requires multiple tissues reconstructive procedures with various technical options. The authors report the case of a patient presenting an extensive defect of the medioplantar region of the right foot involving an almost complete (90%) medial cuneiform bone loss. A deferred operation with saphenous cross-leg flap and interposition of a cement spacer was first performed. Reconstruction of the bone defect with corticocancellous iliac bone graft was subsequently carried out at two months post-trauma. At four months follow-up, the bone and soft tissues healing were good. At 24 months follow-up, the patient could return to normal professional and sports activities. The saphenous cross-leg flap has proven to be a reliable reconstructive procedure. The use of the modified Masquelet technique ensured an anatomical reconstruction and a satisfying final functional outcome. PMID- 19442600 TI - Friction couples in total hip replacement. AB - The problem of friction couples remains unresolved to this day. Improvements in femoral and acetabulum implant anchorage over the last 20 years have significantly extended total hip replacement (THR) implant lifespan; the formation of wear debris, however, leads to resorption and osteolysis, considerably shortening implant lifespan in active patients. Alumina-alumina friction couples provide an excellent friction coefficient, with wear particles that do not cause any osteolysis. There is, however, a problem of acetabulum anchorage of solid alumina, and the risk of fracture persists with ceramic implants despite improvements in their mechanical properties. Metal-metal couples also display very good tribological behavior, but at the cost of the formation of Co and Cr ions impacting surrounding bone tissue and accumulating in remote organs. The behavior of such "hard-hard" couples greatly depends on implant component positioning and on the consequences of repeated neck-insert contact. Very highly crosslinked polyethylene (PE) shows very significant improvement in terms of wear at five years' follow-up compared to conventional PE, but the behavior of this new concept will need to be monitored in the clinical situation if the disappointments experienced with previous hylamer-type improved PE are to be avoided. All these friction couples need to be validated by prospective clinical studies conducted over more than five years, to provide orthopedic surgeons with an eclectic choice of friction couples adapted to the patient's activity. PMID- 19442602 TI - Silicon and bone. PMID- 19442605 TI - Effect of 1,25-dihydroxy vitamin D3 on fracture healing and bone remodeling in ovariectomized rat femora. AB - Osteoporosis is a major health problem characterized by compromised bone strength that predisposes patients to an increased risk of fracture, more and more investigations are focusing on the treatment of osteoporotic fracture healing. However, there are few studies elucidating the efficacy of vitamin D, 1,25 dihydroxy vitamin D(3) (1,25(OH)(2)D(3)), on osteoporotic fracture healing. In the present study we have established an osteoporotic fracture rat model to evaluate the effects of 1,25(OH)(2)D(3) on fracture healing. Female SD rats of six-month-old (n=40) allocated randomly into two groups were given ovariectomy. Bilateral midshaft femoral osteotomy was performed 12 weeks post-ovariectomy. Then treatment was begun at the second day after osteotomy and continued until sacrifice at 6 and 16 weeks post-fracture with middle chain triglyceride (MCT) vehicle and 1,25(OH)(2)D(3) at 0.1 microg/kg/day by oral gavage. Fracture callus was evaluated by soft X-ray radiography, micro-computed tomography (micro-CT), biomechanical testing and histology. Soft X-ray radiography, at 6 weeks post fracture, showed a less distinct fracture line in the 1,25(OH)(2)D(3) group compared with the MCT-vehicle group, however, the fracture line was invisible in both groups at 16 weeks post-fracture. Micro-CT based histomorphometric data, at 6 weeks post-fracture, showed that the total volume of callus (TV) was approximately 23% higher in the 1,25(OH)(2)D(3) group than that in the MCT vehicle group (P<0.001), and the new bone volume (BV), BV/TV, the trabecular number (Tb.N), and density of TV also showed the same trend. At 16 weeks post fracture, the increment still existed as shown by Tb.Th and density of TV (P<0.001, vs control). Biomechanical testing data, at 6 weeks post-fracture, showed that the ultimate load at failure and energy absorption of the 1,25(OH)(2)D(3) group were nearly one fold higher than that of the MCT-vehicle group (P<0.001). At 16 weeks post-fracture, the ultimate load and energy absorption were also higher with the treatment of 1,25(OH)(2)D(3) (P<0.01 vs control). Histology showed that the fracture callus in the 1,25(OH)(2)D(3) group was remodeled better compared to the control group. In conclusion, 1,25(OH)(2)D(3) could promote fracture healing by improving the histomorphometric parameters, mechanical strength and tendency to increase transformation of woven bone into lamellar bone in an ovariectomized rat model. PMID- 19442604 TI - Collagenase expression and activity in the stromal cells from giant cell tumour of bone. AB - The characteristic bone destruction in giant cell tumour of bone (GCT) is largely attributed to the osteoclast-like giant cells. However, experimental analyses of bone resorption by cells from GCT often fail to exclude the neoplastic spindle like stromal cells, and several studies have demonstrated that bone resorption by GCT cells is increased in the presence of stromal cells. The spindle-like stromal cells from GCT may therefore actively contribute to the bone resorption observed in the tumour. Type I collagen, a major organic constituent of bone, is effectively degraded by three matrix metalloproteinases (MMPs) known as the collagenases: MMP-1, MMP-8 and MMP-13. We established primary cell cultures from nine patients with GCT and the stromal cell populations were isolated in culture. The production of collagenases by primary cultures of GCT stromal cells was determined through real-time PCR, western blot analysis and a multiplex assay system. Results show that the cells produce MMP-1 and MMP-13 but not MMP-8. Immunohistochemistry confirmed the presence of MMP-1 and MMP-13 in paraffin embedded GCT tissue samples. Medium conditioned by the stromal cell cultures was capable of proteolytic activity as determined by MMP-1 and MMP-13-specific standardized enzyme activity assays. The spindle-like stromal cells from GCT may therefore actively participate in the bone destruction that is characteristic of the tumour. PMID- 19442606 TI - Potential roles of growth factor PDGF-BB in the bony repair of injured growth plate. AB - Injured growth plate cartilage is often repaired by bony tissue resulting in impaired bone growth in children. Using a rat injury model, our previous studies show that following the injury-induced initial inflammatory response, an influx of mesenchymal-like cells occurs within the growth plate injury site prior to formation of bony tissue. As platelet-derived growth factor (PDGF-BB) is a potent chemotactic factor of mesenchymal cells during skeletal tissue repair, we examined its role during the early fibrogenic response and the subsequent bony repair of injured growth plate. Following growth plate injury, rats received daily injection of the PDGF receptor (PDGFR) inhibitor, Imatinib, for 7 days. Immunohistochemical analysis of injured growth plate at day 1 showed the presence of PDGF-BB expression in some inflammatory cells, while at day 4 PDGFR was expressed by a proportion of the infiltrating mesenchymal cells at the injury site. By day 4, PDGFR inhibition reduced mesenchymal infiltrate (P<0.05); by day 14, Imatinib-treated rats exhibited less bony trabeculae and cartilaginous repair tissues, fewer osteoclasts and less bone marrow (BM) at the injury site, compared to vehicle controls (P<0.01). In vitro "scratch" migration assays with rat BM mesenchymal cells revealed that recombinant PDGF-BB increased cell migration into the "wound" (P<0.05), while Imatinib inhibited this chemotactic response. Quantitative RT-PCR analysis showed that Imatinib treatment decreased expression of the cartilage and bone related genes, Col2a1 and osteocalcin, respectively. These results suggest that PDGF-BB contributes to growth plate injury repair by promoting mesenchymal progenitor cell infiltration, the chondrogenic and osteogenic responses, and remodelling of the repair tissues. PMID- 19442607 TI - An effective histological staining process to visualize bone interstitial fluid space using confocal microscopy. AB - Bone is a composite porous material with two functional levels of porosity: the vascular porosity that surrounds blood vessels and the lacunar-canalicular porosity that surrounds the osteocytes. Both the vascular porosity and lacunar canalicular porosity are directly involved in interstitial fluid flow, thought to play an important role in bone's maintenance. Because of the small dimensions of the lacunar-canalicular porosity, interstitial fluid space has been difficult to visualize and quantify. We report a new staining protocol that is reliable and easily reproducible, using fluorescein isothiocyanate (FITC) as a probe visualized by confocal microscopy. Reconstructed FITC-stained cross sections enable effective visualization of bone microstructure and microporosities. This new staining process can be used to analyze interstitial fluid space, providing high-resolution quantification of the vascular pores and the lacunar-canalicular network of cortical and cancellous bone. PMID- 19442608 TI - Novel and unexpected functions of zebrafish CCAAT box binding transcription factor (NF-Y) B subunit during cartilages development. AB - We used zebrafish as a model to study the biological functions of NF-YB during early development. Both RT-PCR and whole-mount in situ hybridization experiments revealed that nf-yb was a maternally inherited gene. Later, its expression was restricted in the future head cartilages as well as in the developing notochord. Embryos after injection with nf-yb-morpholino displayed reduced-head phenotypes, including smaller head (WT, length of head, L: 0.515+/-0.019 mm, width of head, W: 0.323+/-0.077 mm; nf-yb-morphant, L: 0.347+/-0.037 mm; W: 0.266+/-0.018 mm), sharpen Meckel's cartilage, loss of ceratobranchial, and enlarged angles of ceratohyal (WT: 72.6+/-9.4 degrees ; nf-yb-morphant: 110.0+/-32.5 degrees ). Subsequently, those abnormalities can be rescued after injection with capped nf yb mRNA. TUNEL assay suggested that large amounts of cell apoptosis appeared in the head region of nf-yb-morphants. Staining with digoxigenin-labeled dlx2a, sox9a, runx2b and col2a1 riboprobes showed that nf-yb-morphants displayed reduced amounts of cranial neural crest cells which are required for mandibular and branchial arches formation. These observations clearly indicate that knockdown of nf-yb translation induced parts of cranial neural crest cells apoptosis, affected cartilages formation and consequently caused reduced-head phenotypes. These findings uncover a novel and unexpected role for NF-YB as a critical modulator of neural crest cell's gene expression governing embryonic cartilage growth. PMID- 19442610 TI - Assessment of trabecular bone structure of the calcaneus using multi-detector CT: correlation with microCT and biomechanical testing. AB - The prediction of bone strength can be improved when determining bone mineral density (BMD) in combination with measures of trabecular microarchitecture. The goal of this study was to assess parameters of trabecular bone structure and texture of the calcaneus by clinical multi-detector row computed tomography (MDCT) in an experimental in situ setup and to correlate these parameters with microCT (microCT) and biomechanical testing. Thirty calcanei in 15 intact cadavers were scanned using three different protocols on a 64-slice MDCT scanner with an in-plane pixel size of 208 microm and 500 microm slice thickness. Bone cores were harvested from each specimen and microCT images with a voxel size of 16 microm were obtained. After image coregistration, trabecular bone structure and texture were evaluated in identical regions on the MDCT images. After data acquisition, uniaxial compression testing was performed. Significant correlations between MDCT- and microCT-derived measures of bone volume fraction (BV/TV), trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp) were found (range, R(2)=0.19-0.65, p<0.01 or 0.05). The MDCT-derived parameters of volumetric BMD, app. BV/TV, app. Tb.Th and app. Tb.Sp were capable of predicting 60%, 63%, 53% and 25% of the variation in bone strength (p<0.01). When combining those measures with one additional texture index (either GLCM, TOGLCM or MF.euler), prediction of mechanical competence was significantly improved to 86%, 85%, 71% and 63% (p<0.01). In conclusion, this study showed the feasibility of trabecular microarchitecture assessment using MDCT in an experimental setup simulating the clinical situation. Multivariate models of BMD or structural parameters combined with texture indices improved prediction of bone strength significantly and might provide more reliable estimates of fracture risk in patients. PMID- 19442611 TI - Parathyroid hormone enhances bone morphogenetic protein activity by increasing intracellular 3', 5'-cyclic adenosine monophosphate accumulation in osteoblastic MC3T3-E1 cells. AB - Intermittent subcutaneous injections of parathyroid hormone (PTH) increase bone mass in a variety of animal models and humans. The anabolic actions of PTH on osteogenic cells are mainly mediated through the protein kinase A (PKA) signaling pathway via PTH receptor 1 (PTHR1). We have already reported 3', 5'-cyclic adenosine monophosphate (cAMP)/PKA-mediated enhancement of bone morphogenetic protein (BMP) signaling. Herein, we focused on the involvement of PTH in BMP signaling pathways in the MC3T3-E1 mouse osteoblastic cell line, to elucidate a potential mechanism of the anabolic actions of PTH on bone formation. Elevation of intracellular cAMP level in MC3T3-E1 cells by addition of PTH (10(-7) M) to culture media was transient without significant effect on biological actions of BMP. Cyclic addition of PTH (10 cyclic additions of 10(-8) M PTH at 3-min intervals) maintained a high intracellular cAMP level for about 2 h and mRNA expression and enzymatic activity of alkaline phosphatase (ALP) by BMP was enhanced by this addition. Relative luciferase expression assay in MC3T3-E1 cells using the Id1 promoter, an early response gene to BMPs, enhanced elevation of transcriptional activity in response to recombinant human BMP-2 by concomitant addition of PTH and BMP. Furthermore, cyclic PTH treatment significantly further suppressed BMP-induced inhibitory Smad6 expression. H89 (PKA inhibitor) almost completely abolished PTH actions on BMP signaling. IBMX (phosphodiesterase inhibitor) enhanced PTH actions. These results suggest that PTH enhances BMP signaling when PTH-induced intracellular cAMP level is maintained for a few hours, accelerating BMP actions to promote osteoblastic function and anabolic actions of new bone formation. PMID- 19442613 TI - Bisphosphonate dose and incidence of fractures in postmenopausal osteoporosis. AB - INTRODUCTION: The specific pharmacological properties of bisphosphonates have raised concerns about their long-term effects on skeletal fragility that may be related to the total dose of bisphosphonate given. However, the effect of different doses on the incidence of osteoporotic fractures has not been adequately studied. METHODS: In this retrospective analysis, we investigated the effect of different doses of intravenous pamidronate given at 3-monthly intervals on the incidence of fractures in 92 women with severe postmenopausal osteoporosis. RESULTS: The risk of sustaining a new vertebral fracture on treatment was significantly increased by 32% for every prevalent vertebral fracture (OR: 1.32, CI: 1.05, 1.66; p=0.02). Patients with nonvertebral fractures received a significantly lower dose of pamidronate and their risk for these fractures increased by 25% for every prevalent vertebral fracture at baseline (OR: 1.25, CI: 1.01, 1.53; p=0.03). Patients who had received oral bisphosphonate before intravenous pamidronate had a significantly higher incidence of nonvertebral fractures which, however, did not hold true after adjustment for baseline BMD and prevalent fractures. CONCLUSIONS: In patients with established osteoporosis bone fragility during treatment with intravenous pamidronate is mainly determined by the severity of the disease, assessed by the presence and numbers of prevalent fractures, rather than the dose of the bisphosphonate or the rate of bone turnover. PMID- 19442614 TI - Multiple osteoporosis susceptibility genes on chromosome 1p36 in Chinese. AB - INTRODUCTION: Chromosome 1p36 is a region that has previously shown good evidence of linkage to bone mineral density (BMD) in multiple studies, but the genes that are responsible for the linkage signals are unknown. MATERIALS AND METHODS: We performed a gene-wide and tag SNP-based association study of four positional and functional candidate genes (TNFRSF1B, PLOD, CNR2, and MTHFR) at 1p36 in 1, 243 case-control Chinese subjects. Twenty-three tag SNPs were selected and genotyped using the high-throughput Sequenom genotyping platform. Binary logistic regression analyses were performed to test for genotype associations between each SNP and BMD. Allelic and haplotype association analyses were conducted by Haploview. Gene-gene interactions were investigated using multifactor dimensionality reduction method. RESULTS: The PLOD rs7529452 (C385T; F98F) and MTHFR rs1801133 (C677T; A429E) showed significant genotypic/allelic associations with BMDs at all sites measured (P=0.08-0.001), and a promising two-locus gene gene interaction for femoral neck BMD. The CNR2 rs2501431 (A592G; G155G) showed nominally significant allelic associations with trochanter and hip BMD. The TNFRSF1B rs976881 showed genotypic associations with BMDs (P=0.08-0.04). CONCLUSIONS: Our results suggest that multiple genes at 1p36, individually or in different combinations, contribute to osteoporosis susceptibility in Chinese. PMID- 19442615 TI - COMP-Angiopoietin-1 ameliorates surgery-induced ischemic necrosis of the femoral head in rats. AB - INTRODUCTION: Ischemic necrosis of the femoral head (INFH) can lead to loss of femoral head architecture and deformity. Moreover, the process of bone healing is intimately associated with angiogenesis. We considered that COMP-Ang1 (an angiogenic factor) might preserve femoral head structure and facilitate bone repair. METHODS: INFH was induced in the femoral head of rats by dissecting the cervical periosteum and placing a ligature tightly around the femoral neck. Two weeks later, COMP-Ang1 was injected directly into infarcted areas. Rats were divided into the following groups; 1) the sham-operated group (the sham group), 2) the bovine serum albumin-injected group (the BSA group), and 3) the COMP-Ang1 injected group (the COMP-Ang1 group) (n=20/group). At 8 weeks post-surgery animals were sacrificed and radiologic and histomorphometric assessments were performed. RESULTS: Radiographs obtained at 8 weeks post-surgery showed better preservation of femoral head architecture in the COMP-Ang1 group than in the BSA group. Histological findings and immunostainings of endothelial cells for factor VIII revealed that COMP-Ang1 group animals showed higher levels of vascularity in the secondary ossification center of infarcted femoral heads. CONCLUSIONS: When INFH was surgically induced in rats, an intraosseous injection of COMP-Ang1 preserved the trabecular framework of the osseous epiphysis and prevented femoral head deformities by promoting angiogenesis and bone remodeling. PMID- 19442616 TI - Joint loading-driven bone formation and signaling pathways predicted from genome wide expression profiles. AB - Joint loading is a recently developed loading modality that induces anabolic responses by lateral loads applied to a synovial joint such as an elbow and a knee. The present study extended this loading modality to an ankle and addressed a question: does ankle loading promote bone formation in the tibia? If so, what signaling pathways are involved in the anabolic responses? Using C57BL/6 female mice as a model system, lateral loads of 0.5 N were applied to the ankle at 5 Hz for 3 min/day for 3 consecutive days and load-driven bone formation was evaluated at three tibial cross-sections (the proximal, middle, and distal diaphysis). Furthermore, total RNA was isolated for 3 pairs of microarray experiments as well as quantitative real-time PCR analyses. The histomorphometric results revealed that in all cross-sections ankle loading elevated the cortical area and thickness as well as the calcein-labeled surface. Signaling pathway analysis from microarray-derived whole-genome mRNA expression profiles and quantitative real time PCR predicted that molecules in phosphoinositide 3-kinase (PI3K), ECM receptor interactions, TGFbeta signaling, and Wnt signaling were involved in the joint-loading driven responses. Since ankle loading stimulates bone formation throughout the tibia both in the endosteum and the periosteum, it may provide a non-pharmacological approach to effectively activate molecular signaling necessary for preventing bone loss. PMID- 19442617 TI - Galectin-9 accelerates transforming growth factor beta3-induced differentiation of human mesenchymal stem cells to chondrocytes. AB - Galectin-9 (Gal-9), a beta-galactoside binding lectin, plays a crucial role in innate and adaptive immunity. In the rat collagen-induced arthritis model, administration of Gal-9 induced repair of existing cartilage injury even when joints were already swollen with cartilage destruction. We thus attempted to explore the role of Gal-9 in chondrocyte differentiation utilizing human mesenchymal stem cell (MSC) pellet cultures. During chondrogenesis induced by transforming growth factor beta3 (TGFbeta3), MSCs strongly expressed endogenous Gal-9. Expression of Gal-9 peaked on day 14 and the neutralization of endogenous Gal-9 resulted in the reduced chondrogenesis, indicating possible involvement of Gal-9 in TGFbeta-mediated chondrogenesis. In pellets, addition of Gal-9 significantly enhanced TGFbeta3-induced chondrogenesis, as evidenced by increasing proteoglycan content, but not cell proliferation. In the absence of Gal-9, collagen expression by MSCs switched from type I to type II on 28 days after stimulation with TGFbeta3. When MSCs were co-stimulated with Gal-9, the class switch occurred on day 21. In addition, Gal-9 synergistically enhanced TGFbeta3-induced phosphorylation of Smad2, though Gal-9 did not itself induce detectable Smad2 phosphorylation. These results suggest that Gal-9 has a beneficial effect on cartilage repair in injured joints by induction of differentiation of MSCs into chondrocytes. PMID- 19442618 TI - Pulse treatment with zoledronic acid causes sustained commitment of bone marrow derived mesenchymal stem cells for osteogenic differentiation. AB - The aminobisphosphonate zoledronic acid (ZA) is a bone seeking specific inhibitor of protein farnesylation and geranylgeranylation, which causes inhibition of osteoclast function and apoptosis. It is widely used as an osteoclast targeted antiresorptive treatment of metastatic bone disease, Paget's disease and osteoporosis. Mesenchymal stem cells (MSC) and osteoblast precursors can also be targets of bisphosphonates, but the clinical relevance of these effects is under debate. We show here that ZA in vitro causes inhibition of proliferation and induction of apoptosis in hMSC, when applied in concentrations of 20 and 50 microM for more than 24 h which can be rescued by treatment with 10 microM geranylgeranyl pyrophosphate (GGPP). However, pulse stimulation for 3 and 6 h with these concentrations and subsequent culture for up to 2 weeks under osteogenic conditions exerts sustained regulation of osteogenic marker genes in hMSC. The effect on gene regulation translates into marked enhancement of mineralization, as shown by alizarin red and alkaline phosphatase staining after 4 weeks of osteogenic culture. ZA, when applied as a pulse stimulus, might therefore also stimulate osteogenic differentiation in vivo, since muM plasma concentrations can be achieved by intravenous application of 5 mg in patients. These data set the stage for the future dissection of the effects of ZA and other aminobisphosphonates on cells beyond osteoclasts, with respect to cell differentiation in benign metabolic and to antitumor efficacy in metastatic bone diseases, as well as adverse events due to putative substance accumulation in bone during long-term treatment. PMID- 19442619 TI - Vitamin D and vascular calcification in chronic kidney disease. AB - Vascular calcification is frequently observed and is closely associated with cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular calcification is largely divided into two types. One is atherosclerotic intimal layer calcification and the other is medial layer calcification (Monckeberg's calcification). The latter is more common in patients with CKD than in general population. Evidence is growing that vascular calcification is a regulated active process as well as a passive process resulting from elevated serum phosphate (P) and an increase in the calcium phosphate (Ca x P) product leading to oversaturated plasma. Proving the active process, in vitro studies have demonstrated that the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells is a crucial mechanism in the progression of vascular calcification. Reduction of the activity of systemic and local inhibitors has also been recognized to be important. The link between vitamin D and vascular calcification is complex. Experimental and clinical researches have revealed that both vitamin D excess and vitamin D deficiency have been shown to be associated with vascular calcification in uremic milieu. On the other hand, although there are some biases, recent large observational studies have demonstrated that vitamin D has beneficial effects on the mortality of patients with CKD independent of serum Ca, P, and parathyroid hormone levels, likely due to its activation of the vitamin D receptor in vasculature and cardiac myocytes. Further prospective studies are necessary to evaluate the direct effect of vitamin D on vascular calcification in order to improve the cardiovascular health of patients with CKD. PMID- 19442621 TI - Oral phosphate binders: history and prospects. AB - The use of an oral phosphate binder is a promising and most practical strategy for the prevention of vascular calcification in patients with chronic kidney disease (CKD). To secure the safety: 1) the oral phosphate binder must not cause adverse effects in the gastrointestinal tract; 2) the oral phosphate binder should be non-absorbable or barely absorbable through the gastrointestinal tract, or 3) if partially absorbed through the gastrointestinal tract, it must be eliminated from circulation through a pathway other than urinary excretion, and 4) even if it accumulates in the body, it should not cause organ dysfunctions. Metal salt type oral phosphate binder is the most classical type of oral phosphate binders that includes aluminum hydroxide gel and lanthanum carbonate. These oral phosphate binders effectively adsorb phosphate ions, however, have a potential risk for accumulation and intoxication. Calcium salt type oral phosphate binder was the most widely prescribed oral phosphate binder in the last decade but is now believed to exert potential harm, favoring progression of vascular calcification through excessive intestinal calcium load. However, recent studies failed to detect an inferiority of calcium salt type oral phosphate binders as compared to non-calcium salt type oral phosphate binders in terms of mortality and/or morbidity of hemodialysis patients. Polymerized resin type is a safe and relatively effective oral phosphate binder, which is supported by many clinical evidences. However, it sometimes causes severe constipation, especially in Japanese patients. Among metal compound type oral phosphate binder, other promising compounds include boehmite-type aluminum and hydrotalcite-like compounds but they are not yet available in the clinical setting. PMID- 19442620 TI - The bisphosphonate zoledronic acid decreases tumor growth in bone in mice with defective osteoclasts. AB - Bisphosphonates (BPs), bone targeted drugs that disrupt osteoclast function, are routinely used to treat complications of bone metastasis. Studies in preclinical models of cancer have shown that BPs reduce skeletal tumor burden and increase survival. Similarly, we observed in the present study that administration of the Nitrogen-containing BP (N-BP), zoledronic acid (ZA) to osteolytic tumor-bearing Tax+ mice beginning at 6 months of age led to resolution of radiographic skeletal lesions. N-BPs inhibit farnesyl diphosphate (FPP) synthase, thereby inhibiting protein prenylation and causing cellular toxicity. We found that ZA decreased Tax+ tumor and B16 melanoma viability and caused the accumulation of unprenylated Rap1a proteins in vitro. However, it is presently unclear whether N-BPs exert anti-tumor effects in bone independent of inhibition of osteoclast (OC) function in vivo. Therefore, we evaluated the impact of treatment with ZA on B16 melanoma bone tumor burden in irradiated mice transplanted with splenic cells from src(-/ ) mice, which have non-functioning OCs. OC-defective mice treated with ZA demonstrated a significant 88% decrease in tumor growth in bone compared to vehicle-treated OC-defective mice. These data support an osteoclast-independent role for N-BP therapy in bone metastasis. PMID- 19442622 TI - Ethnic differences in bone geometry and strength are apparent in childhood. AB - PURPOSE: Ethnic differences in bone strength and structure likely contribute to the disparity in fracture rates, however few studies have assessed bone structure in multiethnic cohorts of children. The purpose of this study was to investigate ethnic differences in bone strength in childhood and to characterize the structural bases for these differences. METHODS: Peripheral quantitative computed tomography (pQCT 3000, Orthometrix) was used to assess bone parameters at the radius and tibia in Caucasian (CA, n=21), African American (AA, n=23), and Hispanic (HI, n=29) children (10.9+/-0.1 yrs). At the distal site (8%), we measured compressive bone strength (BSI), trabecular and total bone density, and total bone area. Polar strength-strain index, total and cortical bone area, and cortical density were assessed at the midshaft (50%). Muscle cross-sectional area (CSA) and fat CSA were measured at the tibia (66%) and the radius (50%). Physical activity and calcium intake were assessed by questionnaire. Analysis of covariance was used to compare bone outcomes among ethnic groups adjusting for age, sex, limb length and muscle CSA. RESULTS: Age, BMI, and body composition were similar among the 3 groups, however AA children were taller and had longer bone length. At all sites, AA and HI children had higher bone strength (SSIp and BSI +10-37%) than CA children due mainly to greater bone tissue density (2 18%>CA) at the distal sites of the radius and tibia. The greater bone strength at the midshaft was due to both a higher bone density (2-5%) and greater bone area than CA (7-18%). CONCLUSION: AA and HI children have significantly higher bone strength than CA children, due to greater bone volumetric density and greater cortical area. AA and HI children also have higher bone strength relative to load. These observations suggest that ethnic differences in bone strength manifest in childhood. PMID- 19442623 TI - Optimal increase in bone mass by continuous local infusion of alendronate during distraction osteogenesis in rabbits. AB - Several methods have been used to increase bone mass in distraction osteogenesis. Since bone resorption as well as regeneration is stimulated in the distracted segment, bisphosphonate can be a beneficial agent for distraction osteogenesis. Here, we examined the effects of bisphosphonate injected continuously into the regenerate on bone volume, and architectural and mechanical properties of distraction osteogenesis. The left tibia of Japanese White rabbits (n=66) was subjected to slow distraction using an external fixator. At the beginning of the consolidation phase, alendronate (7 microg/kg/day) was infused directly into the lengthened segment for 14 days using an osmotic pump. Control rabbits were infused with phosphate buffered saline (PBS). The tibiae were monitored weekly by soft X-ray and dual-energy X-ray absorptiometry (DXA). The animals were sacrificed at 4, 6, and 8 weeks after operation to examine bone mineral density (BMD) and cortical bone thickness (CBT) by peripheral quantitative computerized tomography (pQCT), while the mechanical property of the lengthened tibia was measured by three-point bending test. In PBS-infused control animals, bone mineral content around the lengthened segment began to decrease after the first week of consolidation phase, forming a tubular bone structure with thin cortex. Infusion of alendronate increased peak bone mineral content around the lengthened segment. At the end of the experiment, volumetric BMD, CBT and mechanical strength of the lengthened segment of the treatment group were approximately twice those of the control animals. Alendronate infused in this manner significantly prevented the osteopenia that critically began early in the consolidation phase, though the dose used in this study was relatively low and no adverse events were noted. PMID- 19442624 TI - Osteocyte-derived HB-GAM (pleiotrophin) is associated with bone formation and mechanical loading. AB - HB-GAM (also known as pleiotrophin) is a cell matrix-associated protein that is highly expressed in bone. It affects osteoblast function, and might therefore play a role in bone development and remodeling. We aimed to investigate the role of HB-GAM in bone in vivo and in vitro. The bones of HB-GAM deficient mice with an inbred mouse background were studied by histological, histomorphometrical, radiological, biomechanical and mu-CT analyses and the effect of immobilization was evaluated. HB-GAM localization in vivo was studied. MLO-Y4 osteocytes were subjected to fluid shear stress in vitro, and gene and protein expression were studied by subtractive hybridization, quantitative PCR and Western blot. Human osteoclasts were cultured in the presence of rhHB-GAM and their formation and resorption activities were assayed. In agreement with previous reports, the skeletal structure of the HB-GAM knockout mice developed normally. However, a growth retardation of the weight-bearing bones was observed by 2 months of age, suggesting a link to physical activity. Adult HB-GAM deficient mice were characterized by low bone formation and osteopenia, as well as resistance to immobilization-dependent bone remodeling. HB-GAM was localized around osteocytes and their processes in vivo and furthermore, osteocytic HB-GAM expression was upregulated by mechanical loading in vitro. HB-GAM did not affect on human osteoclast formation or resorption in vitro. Taken together, our results suggest that HB-GAM is an osteocyte-derived factor that could participate in mediating the osteogenic effects of mechanical loading on bone. PMID- 19442625 TI - Thrombin-stimulated growth factor and cytokine expression in osteoblasts is mediated by protease-activated receptor-1 and prostanoids. AB - Thrombin exerts multiple effects upon osteoblasts including stimulating proliferation, and inhibiting osteoblast differentiation and apoptosis. Some of these effects are believed to be mediated by the synthesis and secretion of autocrine factors such as growth factors and cytokines. Many but not all cellular responses to thrombin are mediated by members of the protease-activated receptor (PAR) family of G protein-coupled receptors. The current study was undertaken to investigate the nature of thrombin's induction of autocrine factors by analysing the expression of twelve candidate genes in thrombin-stimulated primary mouse osteoblasts. Analysis by quantitative reverse transcription polymerase chain reaction (qRT-PCR) demonstrated that thrombin induced transforming growth factor beta, cyclooxygenase-2, tenascin C, fibroblast growth factor-1 and -2, connective tissue growth factor and interleukin-6 expression in wild type osteoblasts, but not PAR-1 null mouse osteoblasts. Induction of all the thrombin-responsive genes was blocked by the presence of the non-selective cyclooxygenase inhibitor indomethacin. Further studies were conducted on interleukin-6, which was the gene that showed the greatest increase in expression following stimulation of osteoblast-like cells with thrombin. A PAR-1-specific activating peptide, but neither a PAR-4-activating peptide nor catalytically inactive thrombin induced release of interleukin-6 by osteoblasts. Furthermore, in the presence of the selective cyclooxygenase-1 and -2 inhibitors SC-560 and NS-398 thrombin-induced interleukin-6 release was prevented. Levels of both prostaglandin E(2) and interleukin-6 in medium conditioned by thrombin-stimulated osteoblast-like cells were found to be significantly increased compared to medium conditioned by non stimulated cells, however release of prostaglandin E(2) was found to precede release of interleukin-6. Treatment of isolated osteoblast-like cells with a number of synthetic prostanoids stimulated secretion of interleukin-6 with differing potencies. These studies suggest that activation of PAR-1 on osteoblasts by thrombin induces cyclooxygenase activity, which in turn results in the increased expression of multiple secreted factors. The induction of these secreted factors may act in an autocrine fashion to alter osteoblast function, allowing these cells to participate in the earliest stages of bone healing by both autocrine and paracrine mechanisms. PMID- 19442626 TI - The mouse fibula as a suitable bone for the study of functional adaptation to mechanical loading. AB - Bones' functionally adaptive responses to mechanical loading can usefully be studied in the tibia by the application of loads between the knee and ankle in normal and genetically modified mice. Such loading also deforms the fibula. Our present study was designed to ascertain whether the fibula adapts to loading in a similar way to the tibia and could thus provide an additional bone in which to study functional adaptation. The right tibiae/fibulae in C57BL/6 mice were subjected to a single period of axial loading (40 cycles at 10 Hz with 10-second intervals between each cycle; approximately 7 min/day, 3 alternate days/week, 2 weeks). The left tibiae/fibulae were used as non-loaded, internal controls. Both left and right fibulae and tibiae were analyzed by micro-computed tomography at the levels of the mid-shaft of the fibula and 25% from its proximal and distal ends. We also investigated the effects of intermittent parathyroid hormone (iPTH) on the (re)modelling response to 2-weeks of loading and the effect of 2 consecutive days of loading on osteocytes' sclerostin expression. These in vivo experiments confirmed that the fibula showed similar loading-related (re)modelling responses to those previously documented in the tibia and similar synergistic increases in osteogenesis between loading and iPTH. The numbers of sclerostin-positive osteocytes at the proximal and middle fibulae were markedly decreased by loading. Collectively, these data suggest that the mouse fibula, as well as the tibia and ulna, is a useful bone in which to assess bone cells' early responses to mechanical loading and the adaptive (re)modelling that this engenders. PMID- 19442628 TI - Density and architecture have greater effects on the toughness of trabecular bone than damage. AB - Bone damage has been cited as an important aspect of bone quality. As such, understanding the effects of damage on the toughness of trabecular bone should provide insight into trabecular bone behavior during energy-limiting cases, such as falls. The effects of damage on the toughness of 35 bovine trabecular bone specimens were studied. Damage was induced by compressing the on-axis specimens to either 1.5% or 2.5% strain, followed by compression to 7.5% strain. The overloads resulted in significant decreases in both modulus and elastic toughness, with significantly greater decreases for the high-damage group than the low-damage group. Following damage, the elastic toughness of the high-damage group was also lower than the undamaged elastic toughness of the control group. In contrast, there was no detectable effect of damage level on toughness measured to 7.5% strain. Toughness increased linearly with BMD (R(2)=0.50) and by a power law relationship with volume fraction (BV/TV) (R(2)=0.65). Microarchitectural parameters also predicted the toughness in the absence of BV/TV or BMD. Toughness decreased with increasing slenderness ratio (Tb.Sp/Tb.Th) and structure model index (SMI) (R(2)=0.68, multiple regression), again independent of damage level, suggesting that failure is influenced by trabecular buckling. Taken together, the results show that normal variations in toughness due to density and architecture dominate the changes due to damage at the levels induced in this study. Moreover, measuring toughness is sensitive to the final strain, as differences found in the elastic and initial plastic regions were undetectable at higher strains. The self limiting nature of microcracks in trabecular bone, or the trabecular architecture itself, may inhibit microcracks from propagating to macroscopic trabecular fractures, thereby limiting the effect of damage on toughness and making it difficult to detect in comparison to normal population variability. PMID- 19442629 TI - Prevalence and risk factors of osteoporosis and vertebral fractures in patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is characterized by inflammation of the entheses and paravertebral structures, leading in time to bone formation at those sites. As well, vertebral bone loss is also a recognized feature of AS Objective: To calculate the prevalence and risk factors of osteoporosis and vertebral fractures in patients with AS. METHODS: Eighty patients with AS were enrolled in the study. Clinical, biological and radiological status was assessed by the Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), ESR and C-reactive protein (CRP), Bath AS Radiology Index (BASRI) and modified stoke AS spine score (mSASSS). BMD of the hip and spine was measured and vertebral fractures were defined using a combination of Genant semiquantitative (SQ) approach and morphometry by VFA (fracture vertebral assessment). RESULTS: The years+/-11.8. The mean BMI was 22.8 kg/m(2)+/-4.1 and the mean disease duration was 10.8 years+/-6.6. Prevalence of osteoporosis was 25%. 18.8% of patients had a vertebral fracture (grades 2 and 3). Factors associated with osteoporosis were low weight and BMI and longer disease duration, higher ESR, CRP, BASFI and BASDAI. Vertebral fractures were associated with advanced age, longer disease duration, higher BASFI, BASRI and mSASSS and reduced BMD and T-score at the hip site, presence of osteoporosis at any site. Multiple logistic regression analysis (Table 4) revealed that parameters significantly associated with osteoporosis were BASDAI (OR=1.05, 95% confidence interval [CI]: 1.03-1.09); disease duration (OR=1.13, 95%CI: 1.03-1.25); and BMI (OR=0.82, 95%CI: 0.69-0.93). The presence of VFs (grades 2 and 3) were independently associated with disease duration (OR=1.50, 95%CI: 1.07-2.10); and mSASSS (OR=1.17, 95%CI: 1.05-1.30). CONCLUSION: Osteoporosis is common in patients with AS and seems to be related to disease activity while vertebral fractures appear to be related to the duration and structural severity of the disease rather than BMD. PMID- 19442627 TI - Glutaredoxin 5 regulates osteoblast apoptosis by protecting against oxidative stress. AB - There is now increasing evidence which suggests an important role for reactive oxygen species (ROS) in the pathogenesis of osteoporosis. However, little is known on the molecular components of the oxidative stress pathway or their functions in bone. In this study, we evaluated the role and mechanism of action of glutaredoxin (Grx) 5, a protein that is highly expressed in bone. Osteoblasts were transfected with Grx5 siRNA and treated with hydrogen peroxide (H(2)O(2)). Grx5 siRNA treatment increased apoptosis while Grx5 overexpression protected MC3T3-E1 cells against H(2)O(2) induced apoptosis and ROS formation. Grx5 deficiency results in impaired biogenesis of Fe-S cluster in yeast. Accordingly, activity of mitochondrial aconitase, whose activity is dependent on Fe-S cluster, decreased in Grx5 siRNA treated cells. Since reduced formation of Fe-S cluster would lead to increased level of free iron, a competitive inhibitor of manganese superoxide dismutase (MnSOD), we measured MnSOD activity in Grx5 deficient osteoblasts and found MnSOD activity was significantly reduced. The consequence of long term inhibition of Grx5 on osteoblast apoptosis was evaluated using lentiviral shRNA technology. Grx5 shRNA cells exhibited higher caspase activity and cardiolipin oxidation in the presence of H(2)O(2). MnSOD activity was rescued by the addition of MnCl(2) to Grx5 shRNA osteoblasts in the presence of H(2)O(2). Our findings are consistent with the hypothesis that Grx5 is an important determinant of osteoblast apoptosis and acts via a molecular pathway that involves regulation of ROS production, cardiolipin oxidation, caspase activity, Fe-S cluster formation, and MnSOD activity. PMID- 19442630 TI - Use of rapidly mineralising osteoblasts and short periods of mechanical loading to accelerate matrix maturation in 3D scaffolds. AB - MLO-A5 cells are a fully differentiated osteoblastic cell line with the ability to rapidly synthesise mineralised extracellular matrix (ECM). We used MLO-A5 cells to develop a system for studying the mechanical modulation of bone matrix formation in 3D using a cyclic compressive loading stimulus. Polyurethane (PU) open cell foam scaffolds were seeded with MLO-A5 cells under static conditions and loaded in compression at 1 Hz, 5% strain in a sterile fluid-filled chamber. Loading was applied for only 2 h per day on days 5, 10 and 15 of culture and cell seeded scaffolds were assayed on days 10, 15 and 20 of culture. Collagen content as assayed by Sirius red was significantly (2 fold) higher at days 15 and 20 in loaded samples compared with static controls. Calcium content as assayed by alizarin red was significantly (4 fold) higher by day 20. The number of viable cells as assayed by MTS was higher in loaded samples at day 10 but there was no difference by days 15 and 20. Loaded samples also had higher stiffness in compression by the end of the experiment. The mRNA expression of type I collagen, osteopontin and osteocalcin was higher, after a single bout of loading, in loaded than in non-loaded samples as assayed by RT-PCR. In conclusion, mineralisation by fully differentiated osteoblasts, MLO-A5s, was shown to be highly sensitive to mechanical loading, with short bouts of mechanical loading having a strong effect on mineralised matrix production. The 3D system developed will be useful for systematic investigation of the modulators of in vitro matrix mineralisation by osteoblasts in mechanobiology and tissue engineering studies. PMID- 19442632 TI - 5S rRNA-derived and tRNA-derived SINEs in fruit bats. AB - Most short retroposons (SINEs) descend from cellular tRNA of 7SL RNA. Here, four new SINEs were found in megabats (Megachiroptera) but neither in microbats nor in other mammals. Two of them, MEG-RS and MEG-RL, descend from another cellular RNA, 5S rRNA; one (MEG-T2) is a tRNA-derived SINE; and MEG-TR is a hybrid tRNA/5S rRNA SINE. Insertion locus analysis suggests that these SINEs were active in the recent fruit bat evolution. Analysis of MEG-RS and MEG-RL in comparison with other few 5S rRNA-derived SINEs demonstrates that the internal RNA polymerase III promoter is their most invariant region, while the secondary structure is more variable. The mechanisms underlying the modular structure of these and other SINEs as well as their variation are discussed. The scenario of evolution of MEG SINEs is proposed. PMID- 19442633 TI - Estimation of bacterial species phylogeny through oligonucleotide frequency distances. AB - Classification of bacteria is mainly based on sequence comparisons of certain homologous genes such as 16S rRNA. Recently there are challenges to classify bacteria using oligonucleotide frequency pattern of nonhomologous sequences. However, the evolutionary significance of oligonucleotides longer than tetra nucleotide is not studied well. We performed phylogenetic analysis by using the Euclidean distances calculated from the di to deca-nucleotide frequencies in bacterial genomes, and compared these oligonucleotide frequency-based tree topologies with those for 16S rRNA gene and concatenated seven genes. When oligonucleotide frequency-based trees were constructed for bacterial species with similar GC content, their topologies at genus and family level were congruent with those based on homologous genes. Our results suggest that oligonucleotide frequency is useful not only for classification of bacteria, but also for estimation of their phylogenetic relationships for closely related species. PMID- 19442631 TI - Wnt signaling inhibits cementoblast differentiation and promotes proliferation. AB - Cementoblasts, tooth root lining cells, are responsible for laying down cementum on the root surface, a process that is indispensable for establishing a functional periodontal ligament. Cementoblasts share phenotypical features with osteoblasts. Wnt signaling has been implicated in increased bone formation by controlling mesenchymal stem cell or osteoblastic cell functions; however the role of Wnt signaling on cementogenesis has not been examined. In this study, we have identified a consistent expression profile of Wnt signaling molecules in cementoblasts, in vitro by RT-PCR. Exposure of cells to LiCl, which promotes canonical Wnt signaling by inhibiting GSK-3beta, increased beta-catenin nuclear translocation and up-regulated the transcriptional activity of a canonical Wnt responsive promoters, suggesting that an endogenous canonical Wnt pathway functions in cementoblasts. Activation of endogenous canonical Wnt signaling with LiCl suppressed alkaline phosphatase (ALP) activity and expression of genes associated with cementum function; ALP, bone sialoprotein (BSP), and osteocalcin (OCN). Exposure to Wnt3a, as a representative canonical Wnt member, also inhibited the expression of ALP, BSP, and OCN gene. This effect was accompanied by decreased gene expression of Runx2 and Osterix and by increased gene expression of lymphoid enhancer factor-1. Pretreatment with Dickkopf (Dkk)-1, a potent canonical Wnt antagonist, which binds to a low-density lipoprotein receptor-related protein (LRP)-5/6 co-receptor, attenuated the suppressive effects of Wnt3a on mRNA expression of Runx2 and OCN on cementoblasts. These findings suggest that canonical Wnt signaling inhibits cementoblast differentiation via regulation of expression of selective transcription factors. Wnt3a also increased the expression of cyclin D1, known as a cell cycle regulator, as well as cell proliferation. In conclusion, these observations suggest that Wnt signaling inhibits cementoblast differentiation and promotes cell proliferation. Elucidating the role of Wnt in controlling cementoblast function will provide new tools needed to improve on existing periodontal regeneration therapies. PMID- 19442634 TI - Systematic analysis of alternative promoters correlated with alternative splicing in human genes. AB - Interactions between various events are essential for complex and delicate transcriptional regulation. To delineate the features and potential roles of alternative promoters (APs) correlated with alternative splicing (AS), we have systematically analyzed 9908 putative alternative promoters (PAPs) from 3797 human genes. Our results showed that approximately 65% of AS events are associated with PAPs. Intriguingly, PAPs per human AS gene only averaged 2.6 for our dataset, which was significantly lower than previously reported. This seems to imply that the human genome contains a small pool of appropriable PAPs for AS genes. Exploration of the characteristics of PAPs such as CpG islands, TATA boxes, GC-content, transcription factor binding sites (TFBSs) and repetitive elements suggested that, respectively, 87% and 90% of PAPs of human AS genes are CpG- and TATA box-poor. The GC-content is significantly higher in the downstream of transcription start sites (TSSs) than upstream (58% vs. 53%), and there is a strong negative correlation between the GC-content and the number of PAPs. These suggested that GC-content around the TSSs plays an important role in the regulation of AS. Moreover, different APs contain distinct densities of repetitive elements and TFBSs, indicating that such sequences have an intrinsic role in the divergent regulation of PAPs and AS. Substantial difference was also found between human AS genes in terms of PAP numbers. A close connection between PAPs and AS may play a critical role in the choice of APs and regulation of AS genes. Furthermore, the distribution of AS genes on different human chromosomes also influences the numbers of PAPs and isoforms of AS genes. Our results may provide important clues for further studies on regulatory network of transcription-related events. PMID- 19442635 TI - Genome-wide analysis reveals increased levels of transcripts related with infectivity in peanut lectin non-agglutinated promastigotes of Leishmania infantum. AB - Metacyclic promastigotes are transmitted during bloodmeals after development inside the gut of the sandfly vector. The isolation from axenic cultures of procyclic and metacyclic promastigotes by peanut lectin agglutination followed by differential centrifugation is controversial in Leishmania infantum. The purpose of this study has been to isolate both fractions simultaneously from the same population in stationary phase of axenic culture and compare their expression profiles by whole-genome shotgun DNA microarrays. The 317 genes found with meaningful values of stage-specific regulation demonstrate that negative selection of metacyclic promastigotes by PNA agglutination is feasible in L. infantum and both fractions can be isolated. This subpopulation up-regulates a cysteine peptidase A and several genes involved in lipophosphoglycan, proteophosphoglycan and glycoprotein biosynthesis, all related with infectivity. In fact, we have confirmed the increased infection rate of PNA(-) promastigotes by U937 human cell line infection experiments. These data support that metacyclic promastigotes are related with infectivity and the lack of agglutination with PNA is a phenotypic marker for this subpopulation. PMID- 19442636 TI - Inference of active transcriptional networks by integration of gene expression kinetics modeling and multisource data. AB - Inference of gene expression networks has become one of the primary challenges in computational biology. Analysis of microarray experiments using appropriate mathematical models can reveal interactions among protein regulators and target genes. This paper presents a combined approach to the inference of gene expression networks from time series measurements, ChIP-on-chip experiments, analyses of promoter sequences, and protein-protein interaction data. A recursive model of gene expression allowing for identification of active gene expression control networks with up to two regulators of one target gene is presented. The model was used to inspect all possible regulator-target gene combinations and predict those that are active during the underlying biological process. The procedure was applied to the inference of part of a regulatory network of the S. cerevisiae cell cycle, formed by 37 target genes and 128 transcription factors. A set of the most probable networks was suggested and analyzed. PMID- 19442637 TI - Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese. AB - The epsilon4 allele of APOE is a well-characterized genetic risk factor for late onset Alzheimer disease (LOAD). Nevertheless, using high-density single nucleotide polymorphisms (SNPs), there have only been a few studies involving genetic association and linkage disequilibrium (LD) analyses of in and around the APOE. Here, we report fine mapping of a genomic region (about 200 kb) including the APOE in Japanese using 260 SNPs (mean intermaker distance, 0.77 kb). A case control study demonstrated that 36 of these SNPs exhibited significance after adjustment for multiple testing. These SNPs are located in a genomic region including four genes, PVRL2, TOMM40, APOE and APOC1. Recombination rate estimation revealed that the associated region is firmly sandwiched between two recombination hotspots. Strong LD between these SNPs was observed (mean |D'|=0.914). These data suggest that the three genes other than APOE, i.e. PVRL2, TOMM40 and APOC1, could also yield a predisposition to LOAD. PMID- 19442638 TI - SNP-based prediction of the human germ cell methylation landscape. AB - Base substitution occurs at a high rate at CpG dinucleotides due to the frequent methylation of CpG and the deamination of methylated cytosine to thymine. If these substitutions occur in germ cells, they constitute a heritable mutation that may eventually rise to polymorphic frequencies, hence resulting in a SNP that is methylation associated. In this study, we sought to identify clusters of methylation associated SNPs as a basis for prediction of methylation landscapes of germ cell genomes. Genomic regions enriched with methylation associated SNPs, namely "methylation associated SNP clusters", were identified with an agglomerative hierarchical clustering algorithm. Repetitive elements, segmental duplications, and syntenic tandem DNA repeats were enriched in methylation associated SNP clusters. The frequency of methylation associated SNPs in Alu Y/S elements exhibited a gradient pattern suggestive of linear spreading, being higher in proximity to methylation associated SNP clusters and lower closer to CpG islands. Interestingly, methylation associated SNP clusters were over represented near the transcriptional initiation sites of immune response genes. We propose a de novo DNA methylation model during germ cell development whereby a pattern is established by long-range chromatic interactions through syntenic repeats combined with regional methylation spreading from methylation associated SNP clusters. PMID- 19442639 TI - Identification of microRNA in the protist Trichomonas vaginalis. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. However, miRNA has never been identified experimentally in protist. Direct cloning of 438 expressed miRNA tags by microRNA serial analysis of gene expression from the parasitic protist Trichomonas vaginalis identified nine candidate miRNAs. Bioinformatics analysis of the corresponding genomic region revealed that these miRNA candidates contain a classical stem-loop-stem structure of pre-microRNAs. Analysis of the 20 nt long mature tva-miR-001 showed that it is an intergenic miRNA located at the scaffold DS113596. Tva-miR-001 was differentially expressed in the trophozoite, pseudocyst and amoeboid stages. Based on the experimental results of the present study, we provided solid evidence that protist possesses a miRNA regulating network comparable with multicellular organisms for the first time. PMID- 19442640 TI - Genome-wide identification of lineage-specific genes in Arabidopsis, Oryza and Populus. AB - Protein sequences were compared among Arabidopsis, Oryza and Populus to identify differential gene (DG) sets that are in one but not the other two genomes. The DG sets were screened against a plant transcript database, the NR protein database and six newly-sequenced genomes (Carica, Glycine, Medicago, Sorghum, Vitis and Zea) to identify a set of species-specific genes (SS). Gene expression, protein motif and intron number were examined. 165, 638 and 109 SS genes were identified in Arabidopsis, Oryza and Populus, respectively. Some SS genes were preferentially expressed in flowers, roots, xylem and cambium or up-regulated by stress. Six conserved motifs in Arabidopsis and OryzaSS proteins were found in other distant lineages. The SS gene sets were enriched with intronless genes. The results reflect functional and/or anatomical differences between monocots and eudicots or between herbaceous and woody plants. The Populus-specific genes are candidates for carbon sequestration and biofuel research. PMID- 19442641 TI - Incrimination of Eratyrus cuspidatus (Stal) in the transmission of Chagas' disease by molecular epidemiology analysis of Trypanosoma cruzi isolates from a geographically restricted area in the north of Colombia. AB - Following the report of two cases of acute Chagas' disease and the appearance of several triatomine species in human dwellings in an area considered non-endemic for domestic transmission of Trypanosoma cruzi; a epidemiological, entomological and T. cruzi molecular epidemiology analysis was performed in order to establish the transmission dynamic of the parasite in the studied area. 2 T. cruzi isolates from human patients, 5 from Eratyrus cuspidatus, 4 from Rhodnius pallescens, 4 from Panstrongylus geniculatus and 7 reference stocks were analyzed by mini-exon gene, random amplified polymorphic DNA (RAPD) and multilocus enzyme electrophoresis (MLEE). All isolates from vectors and human resulted T. cruzi group I by mini-exon, RAPD and MLEE. While mini-exon and MLEE did not showed any differences between the studied isolates, RAPD analysis identified a common T. cruzi genotype for the E. cuspidatus isolates and human isolates and distinguished different strains from R. pallescens and P. geniculatus isolates. The presence of the same T. cruzi genotype in isolates from patients and E. cuspidatus suggests that this species can be responsible for the transmission of Chagas' disease in the study area. RAPD analysis showed better resolution and discrimination of T. cruzi strains than mini-exon and MLEE and can be considered a useful tool for molecular epidemiology studies. Incrimination of sylvatic triatomine species in the transmission of Chagas' disease indicates that more knowledge about the ecology of these vectors is necessary to improve control strategies. PMID- 19442642 TI - A silver staining procedure for nucleic acids in polyacrylamide gels without fixation and pretreatment. AB - Silver staining of nucleic acid has been widely used in molecular marker analysis such as simple sequence repeat (SSR), single-strand conformation polymorphism (SSCP), and amplified fragment-length polymorphism (AFLP). Many alternatives to silver staining methods have been described, but these methods are not efficient or cost-effective. Here we report a silver staining method that requires less than 10min for one gel and can save chemicals as well. It has a detection limit of approximately 5.6pg of DNA/mm(2) in nondenaturing polyacrylamide gels and 12.8pg/mm(2) in denaturing polyacrylamide gels. PMID- 19442643 TI - Efficiency and specificity of microRNA-primed nucleotide analog incorporation by various DNA polymerases. AB - MicroRNAs (miRNAs) as endogenous regulators of gene expression have spurred a surge of interest for their quantification and expression analysis. High sensitivity and high-specificity miRNA detection techniques, such as real-time polymerase chain reaction and recently introduced bioluminescent miRNA detection, require systematic study of DNA polymerases for use with miRNAs. In this study, a variety of DNA polymerases were studied to assess their capabilities of using miRNA as a primer and incorporating 2'-deoxyadenosine-5'-O-(1-thiotriphosphate) as a dATP alternative during DNA strand extension. Five DNA polymerases were investigated: mesophilic DNA polymerase I large (Klenow) fragment, 3'-->5' exo(-) Klenow DNA polymerase, thermophilic Bst DNA polymerase large fragment, Therminator DNA polymerase, and Taq DNA polymerase. The experimental results show that, except for Taq DNA polymerase, the polymerases can use miRNA as a primer and have both common and divergent properties of the nucleotide analog incorporation and miRNA discrimination. DNA polymerase I large (Klenow) fragment showed no detectable polymerization product with the thio-modified dATP as a substrate. Thermophilic Bst DNA polymerase had the highest specificity for miRNA recognition on a DNA template. The study provides a novel method for miRNA detection without reverse transcription to complementary DNA that is faster, simpler, and less prone to biases and errors. PMID- 19442644 TI - Single-stranded DNA binding protein facilitates specific enrichment of circular DNA molecules using rolling circle amplification. AB - Many techniques in molecular biology require the use of pure nucleic acids in general and circular DNA (plasmid or mitochondrial) in particular. We have developed a method to separate these circular molecules from a mixture containing different species of nucleic acids using rolling circle amplification (RCA). RCA of plasmid or genomic DNA using random hexamers and bacteriophage Phi29 DNA polymerase has become increasingly popular for the amplification of template DNA in DNA sequencing protocols. Recently, we reported that the mutant single stranded DNA binding protein (SSB) from Thermus thermophilus (TthSSB) HB8 eliminates nonspecific DNA products in RCA reactions. We developed this method for separating circular nucleic acids from a mixture having different species of nucleic acids. Use of the mutant TthSSB resulted in an enhancement of plasmid or mitochondrial DNA content in the amplified product by approximately 500x. The use of mutant TthSSB not only promoted the amplification of circular target DNA over the background but also could be used to enhance the amplification of circular targets over linear targets. PMID- 19442645 TI - Quantification of regional DNA methylation by liquid chromatography/tandem mass spectrometry. AB - Promoter hypermethylation-associated tumor suppressor gene (TSG) silencing has been explored as a therapeutic target for hypomethylating agents. Promoter methylation change may serve as a pharmacodynamic endpoint for evaluation of the efficacy of these agents and predict the patient's clinical response. Here a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay has been developed for quantitative regional DNA methylation analysis using the molar ratio of 5-methyl-2'-deoxycytidine (5mdC) to 2'-deoxycytidine (2dC) in the enzymatic hydrolysate of fully methylated bisulfite-converted polymerase chain reaction (PCR) amplicons as the methylation indicator. The assay can differentiate 5% of promoter methylation level with an intraday precision ranging from 3 to 16% using two TSGs: HIN-1 and RASSF1A. This method was applied to characterize decitabine-induced promoter DNA methylation changes of these two TSGs in a breast cancer MCF-7 cell line. Promoter methylation of these TSGs was found to decrease in a dose-dependent manner. Correspondingly, the expression of these TSGs was enhanced. The sensitivity and reproducibility of the method make it a valuable tool for specific gene methylation analysis that could aid characterization of hypomethylating activity on specific genes by hypomethylating agents in a clinical setting. PMID- 19442646 TI - Preparative enzymatic synthesis of polyprenyl-pyrophosphoryl-N-acetylglucosamine, an essential lipid intermediate for the biosynthesis of various bacterial cell envelope polymers. AB - The WecA transferase is an integral membrane protein and a member of the polyprenyl phosphate N-acetylhexosamine-1-phosphate transferase superfamily. It initiates the biosynthesis of various bacterial cell envelope components such as the lipopolysaccharide O-antigen. We report on the first large-scale enzymatic synthesis, purification, and characterization of the undecaprenyl-pyrophosphoryl N-acetylglucosamine product of the WecA transferase. This is an essential lipid intermediate for the biosynthesis of various bacterial cell envelope components. Its availability in a pure form will allow the biochemical and structural characterization of the various enzymes requiring it as a substrate for the synthesis of cell wall polymers. PMID- 19442647 TI - An automated microfluidic-based immunoassay cartridge for allergen screening and other multiplexed assays. AB - A microfluidic cartridge and system for multiplexed immunoassays is described. The passive microfluidic cartridge was composed of three layers of injection molded plastic sealed together using a thermal staking technique. Using this platform technology, a specific immunoglobulin E (IgE) panel assay was constructed. Allergen extract targets, positive and negative controls, and IgE calibration standards were immobilized within the cartridge as a microarray. A computer-controlled solenoid array provided the necessary actuation force for pumping reagents within the cartridge to perform an automated, chemiluminescent indirect immunoassay. A 20-target allergen extract panel was demonstrated on the device with a total analysis time of 27 min. Allergen screening results showed 84% agreement for 3 house dust mites (N=300) compared with a commercial test and 80% agreement overall (N=978). Average coefficients of variation (N=80) were measured as 20.5% for low/medium levels and 20.4% for medium/high levels. The average limit of detection (N=160) was measured at 0.535 AU, and cutoff levels of 1.0 AU were estimated at less than 1 IU/ml (2.4 ng/ml). Such a system has potential applications in decentralized allergen screening as well as in other near-patient diagnostic immunoassays where multiplexed analysis, ease of use, and short analysis time are critical. PMID- 19442648 TI - An automated sample preparation system with mini-reactor to isolate and process submegabase fragments of bacterial DNA. AB - Existing methods for extraction and processing of large fragments of bacterial genomic DNA are manual, time-consuming, and prone to variability in DNA quality and recovery. To solve these problems, we have designed and built an automated fluidic system with a mini-reactor. Balancing flows through and tangential to the ultrafiltration membrane in the reactor, cells and then released DNA can be immobilized and subjected to a series of consecutive processing steps. The steps may include enzymatic reactions, tag hybridization, buffer exchange, and selective removal of cell debris and by-products of the reactions. The system can produce long DNA fragments (up to 0.5 Mb) of bacterial genome restriction digest and perform DNA tagging with fluorescent sequence-specific probes. The DNA obtained is of high purity and floating free in solution, and it can be directly analyzed by pulsed-field gel electrophoresis (PFGE) or used in applications requiring submegabase DNA fragments. PFGE-ready samples of DNA restriction digests can be produced in as little as 2.1 h and require less than 10(8) cells. All fluidic operations are automated except for the injection of the sample and reagents. PMID- 19442649 TI - Identification of proteins interacting with GTP cyclohydrolase I. AB - GTP cyclohydrolase I (GCH-1) is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase and aromatic amino acid hydroxylase. To explore the interactome of GCH-1, we established a HEK 293 cell line stably expressing tetracycline-inducible FLAG-GCH-1. FLAG-GCH-1 and associated proteins were immunoprecipitated and analyzed by liquid chromatography/tandem mass spectrometry. Twenty-nine proteins, derived from different subcellular components such as cytosol, membranes, nucleus and mitochondria were identified to interact with GCH-1. Cell fractionation studies also showed that GCH-1 was present in the cytosol, membranes and nucleus. Gene ontology analysis revealed that GCH-1 interactome was involved in a variety of biological processes such as signal transduction, apoptosis, metabolism, transport and cell organization. To our knowledge, this study is the first to provide a comprehensive analysis of the GCH-1 interactome. Findings expand the number and diversity of proteins that are known to associate with GCH-1. PMID- 19442650 TI - Time-resolved analysis of transcriptional events during SNAI1-triggered epithelial to mesenchymal transition. AB - The transcription regulator SNAI1 triggers a transcriptional program leading to epithelial to mesenchymal transition (EMT), providing epithelial cells with mesenchymal features and invasive properties during embryonic development and tumor progression. To identify early transcriptional changes occurring during SNAI1-induced EMT, we performed a time-resolved genome-scale study using human breast carcinoma cells conditionally expressing SNAI1. The approach we developed for microarray data analysis, allowed identifying three distinct EMT stages and the temporal classification of genes. Importantly, we identified unexpected, biphasic expression profiles of EMT-associated genes, supporting their pivotal role during this process. Finally, we established early EMT gene networks by identifying transcription factors and their potential targets which may orchestrate early events of EMT. Collectively, our work provides a framework for the identification and future systematic analysis of novel genes which contribute to SNAI1-triggered EMT. PMID- 19442651 TI - PROP1 coexists with SOX2 and induces PIT1-commitment cells. AB - Prophet of PIT1 (PROP1) is a pituitary-specific factor and responsive gene for the combined pituitary hormone deficiency in Ames dwarf mice and human patients. Our immunohistochemical studies demonstrated that PROP1 is consistently expressed in SOX2-expressing stem/progenitor cells in the rat pituitary from embryonic (E) to postnatal periods. At E13.5, all the cells in Rathke's pouch, the primordium of the pituitary, express PROP1. Afterward, PROP1-positive cells localize along the marginal cell layer, a putative stem cell niche in the pituitary, and stratify in the parenchyma of the anterior pituitary. In the embryonic period, PROP1 coexists transiently with PIT1, which is the anterior pituitary-specific factor and is a target of PROP1, but not any hormones. Thus, the present results imply a regulatory role of PROP1 not only in pituitary organogenesis but also in conversion of PIT1-lineage cells. PMID- 19442652 TI - Lipopolysaccharide extends the lifespan of mouse primary-cultured microglia. AB - Microglial activation has been implicated in the recognition and phagocytic removal of degenerating neurons; however, this process must be tightly regulated in the central nervous system, because prolonged activation could damage normal neurons. We report that mouse primary-cultured microglia, which are destined to die within a few days under ordinary culture conditions, can live for more than 1 month when kept activated by lipopolysaccharide (LPS) treatment. Primary-cultured microglia treated with sublethal doses of LPS remained viable, without any measurable increase in apoptotic or necrotic cell death. LPS-treated microglia had an arborescent shape, with enlarged somata and thickened cell bodies. Although the amount of intracellular ATP in these microglia was reduced by 2 h after the start of LPS treatment, this had no effect on the viability of the cells. LPS treatment of microglia increased the antiapoptotic factor Bcl-xL protein level at day 1, although the level of the proapoptotic Bcl-associated X protein was unaffected. Furthermore, the level of microtubule-associated light chain 3, a marker protein for autophagy, decreased at 3 h after exposure to LPS. These data show that the optimal dose of LPS suppresses the induction of both apoptosis and autophagy in primary-cultured microglia, allowing the cells to stay alive for more than 1 month. Because long-lived microglia may play critical roles in the exacerbation of neurodegeneration, our findings suggest that inducing a resting stage in active microglia could be a new and promising strategy to inhibit the deterioration of neurodegenerative disease. PMID- 19442653 TI - Intra-accumbens shell injections of SR48692 enhanced cocaine self-administration intake in rats exposed to an environmentally-elicited reinstatement paradigm. AB - Neurotensin (NT) is a neuropeptide involved in cocaine reward, and in learning and memory processes related to drug use within the mesolimbic dopamine (DA) system. Studies have demonstrated that NT receptor antagonists have potential as pharmacotherapeutical tools for cocaine abuse. Therefore, it is important to understand the molecular profile of NT within mesolimbic neurons and the behavioral effects of NT receptor inhibitors on environmentally-elicited cocaine seeking behavior. To address this issue, male Sprague Dawley rats were trained to self-administer cocaine and to discriminate between environmental cues signaling cocaine vs. saline availability. Then, following extinction, these cues were used to induce reinstatement of cocaine seeking behavior. A differential expression profile was observed throughout the experiment. Particularly, a significant increase of NT levels was observed within the nucleus accumbens (NAc) shell subregion during the acquisition phase of training. To further examine the implications of this increase, separate groups of animals received intra NAc shell injections of one of three doses (25, 50, 100 nM) of the NT1 receptor antagonist SR48692 after reaching stable self-administration. Animals were injected prior to placement in the operant conditioning chambers for four consecutive sessions. An increase in lever pressing was observed following antagonist treatment, whereas no major changes in locomotor activity were observed. We propose that the observed increase in lever pressing may be a compensatory response to a decrease in reinforcement, possibly due to decreased DA release, as previous studies show that chronic SR48692 decreases basal DA release in the NAc shell. PMID- 19442654 TI - Proliferative and anti-proliferative effects of thymosin alpha1 on cells are associated with manipulation of cellular ROS levels. AB - Reactive oxygen species (ROS) are constantly generated and eliminated in the biological system and play important roles in a variety of physiological and pathological processes. Previous studies indicate that modulation of cellular ROS affects cell proliferation. Thymosin alpha 1 (Talpha1) is a naturally occurring thymic peptide and has previously been shown to be a potential therapy for some immunodeficiencies, malignancies, and infections. However, few reports have focused on manipulation of cellular ROS level effects of Talpha1. In this study, the Talpha1-treated leukomonocytes, which were isolated from mice spleens, exhibited a higher ROS level and a lower reduced glutathione (GSH) level; however, HepG2 cells treated with Talpha1 exhibited lower ROS level and higher GSH level. In addition, after treatment with Talpha1, the population of leukomonocytes in the G(2) phase increased, resulting in a slight increase in viability. However, in Talpha1-treated HepG2 cells, the cell cycle was delayed in the G(1) phase, thereby inhibiting tumor cell proliferation; in addition, dephosphorylation of the serine/threonine kinase Akt was detected. In conclusion, we show that Talpha1 has potent anti-proliferative activity against malignant human hepatoma cells and proliferative activity against leukomonocytes associated with manipulation of oxidative stress levels which indicates the potential of Talpha1 as an antitumor drug. PMID- 19442655 TI - The role of endoplasmic reticulum in cadmium-induced mesangial cell apoptosis. AB - Cd is an industrial and environmental pollutant that affects many organs in humans and other mammals. However, the molecular mechanisms of Cd-induced nephrotoxicity are unclear. In this study, we show that endoplasmic reticula (ER) played a pivotal role in Cd-induced apoptosis in mesangial cells. Using Fluo-3 AM, the intracellular concentration of calcium ([Ca(2+)](i)) was detected as being elevated as time elapsed after Cd treatment. Co-treatment with BAPTA-AM, a calcium chelator, was able to significantly suppress Cd-induced apoptosis. Calcineurin is a cytosolic phosphatase, which was able to dephosphorylate the inositol-1,4,5-triphosphate receptor (IP(3)R) calcium channel to prevent the release of calcium from ER. Cyclosporine A, a calcineurin inhibitor, increased both [Ca(2+)](i) and the percentage of Cd-induced apoptosis. However, EGTA and the IP(3)R inhibitor, 2-APB, were able to partially modulate Cd cytotoxicity. These results led us to suggest that the extracellular and ER-released calcium plays a crucial role in Cd-induced apoptosis in mesangial cells. Following this line, we further detected the ER stress after Cd treatment since ER is one of the major calcium storage organelles. After Cd exposure, GADD153, a hallmark of ER stress, was upregulated (at 4h of exposure), followed by activation of ER specific caspase-12 and its downstream molecule caspase-3 (at 16h of exposure). The pan caspase inhibitor, Z-VAD, and BAPTA-AM were able to reverse the Cd induced cell death and ER stress, respectively. Furthermore, the mitochondrial membrane potential (DeltaPsi(m)) was depolarized significantly and cytochrome c was released after 24h of exposure to Cd and followed by mild activation of caspase-9 at the 36-h time point, indicating that mitochondria stress is a late event. Therefore, we concluded that ER is the major killer organelle in Cd induced mesangial cell apoptosis and that calcium oscillation plays a pivotal role. PMID- 19442656 TI - Involvement of an aldo-keto reductase (AKR1C3) in redox cycling of 9,10 phenanthrenequinone leading to apoptosis in human endothelial cells. AB - 9,10-Phenanthrenequinone (9,10-PQ), a major quinone found in diesel exhaust particles, is considered to generate reactive oxygen species (ROS) through its redox cycling. Here, we show that 9,10-PQ evokes apoptosis in human aortic endothelial cells (HAECs) and its apoptotic signaling includes ROS generation and caspase activation. The 9,10-PQ-induced cytotoxicity was inhibited by ROS scavengers, indicating that intracellular ROS generation is responsible for the 9,10-PQ-induced apoptosis. Comparison of mRNA expression levels and kinetic constants in the 9,10-PQ reduction among 10 human reductases suggests that aldo keto reductase 1C3 (AKR1C3) is a 9,10-PQ reductase in HAECs. In in vitro 9,10-PQ reduction by AKR1C3, the reduced product 9,10-dihydroxyphenanthrene and superoxide anions were formed, suggesting the enzymatic two-electron reduction of 9,10-PQ that thereby causes oxidative stress through its redox cycling. In addition, the participation of AKR1C3 in 9,10-PQ-redox cycling was confirmed by the data that AKR1C3 overexpression in endothelial cells augmented the ROS generation and cytotoxicity by 9,10-PQ, and the ROS scavengers inhibited the toxic effects. Pretreatment of the overexpressing cells with AKR1C3 inhibitors, flufenamic acid and indomethacin, suppressed the 9,10-PQ-induced GSH depletion. These results suggest that AKR1C3 is a key enzyme in the initial step of 9,10-PQ induced cytotoxicity in HAECs. PMID- 19442657 TI - Evidence for a direct involvement of hMSH5 in promoting ionizing radiation induced apoptosis. AB - Although increasing evidence has suggested that the hMSH5 protein plays an important role in meiotic and mitotic DNA recombinational repair, its precise functions in recombination and DNA damage response are presently elusive. Here we show that the interaction between hMSH5 and c-Abl confers ionizing radiation (IR) induced apoptotic response by promoting c-Abl activation and p73 accumulation, and these effects are greatly enhanced in cells expressing hMSH5(P29S) (i.e. the hMSH5 variant possessing a proline to serine change within the N-terminal (Px)(5) dipeptide repeat). Our current study provides the first evidence that the (Px)(5) dipeptide repeat plays an important role in modulating the interaction between hMSH5 and c-Abl and alteration of this dipeptide repeat in hMSH5(P29S) leads to increased IR sensitivity owing to enhanced caspase-3-mediated apoptosis. In addition, RNAi-mediated hMSH5 silencing leads to the reduction of apoptosis in IR treated cells. In short, this study implicates a role for hMSH5 in DNA damage response involving c-Abl and p73, and suggests that mutations impairing this process could significantly affect normal cellular responses to anti-cancer treatments. PMID- 19442658 TI - Nuclear protein import is reduced in cells expressing nuclear envelopathy-causing lamin A mutants. AB - Lamins, which form the nuclear lamina, not only constitute an important determinant of nuclear architecture, but additionally play essential roles in many nuclear functions. Mutations in A-type lamins cause a wide range of human genetic disorders (laminopathies). The importance of lamin A (LaA) in the spatial arrangement of nuclear pore complexes (NPCs) prompted us to study the role of LaA mutants in nuclear protein transport. Two mutants, causing prenatal skin disease restrictive dermopathy (RD) and the premature aging disease Hutchinson Gilford progeria syndrome, were used for expression in HeLa cells to investigate their impact on the subcellular localization of NPC-associated proteins and nuclear protein import. Furthermore, dynamics of the LaA mutants within the nuclear lamina were studied. We observed affected localization of NPC-associated proteins, diminished lamina dynamics for both LaA mutants and reduced nuclear import of representative cargo molecules. Intriguingly, both LaA mutants displayed similar effects on nuclear morphology and functions, despite their differences in disease severity. Reduced nuclear protein import was also seen in RD fibroblasts and impaired lamina dynamics for the nucleoporin Nup153. Our data thus represent the first study of a direct link between LaA mutant expression and reduced nuclear protein import. PMID- 19442659 TI - Identification of LOXL1 protein and Apolipoprotein E as components of surgically isolated pseudoexfoliation material by direct mass spectrometry. AB - Pseudoexfoliation (PEX) syndrome is the commonest cause of secondary glaucoma. Many extracellular matrix proteins and elastic fibre structure components are present in the pathological PEX deposits in the anterior segment of the eye including the anterior lens capsule. Common coding variants in the lysyl oxidase like 1 (LOXL1) gene, involved in cross-linking elastin, have been reported to be strongly associated with PEX syndrome in various human populations. The mechanism by which the LOXL1 protein contributes to the formation of PEX material is unknown. A comprehensive map of the component proteins of PEX deposits can aid the understanding of disease pathogenesis. The purpose of this study was to identify additional protein constituents of pathological PEX deposits. We employed a novel proteomics approach by performing mass spectrometry on "isolated" PEX material surgically removed from the anterior lens capsule of affected eyes. This approach led to the identification of LOXL1 protein and Apolipoprotein E (ApoE) in PEX material. Previously identified protein constituents, latent-transforming growth factor beta-binding protein-2, complement 3 and clusterin were also detected. Immunohistochemical analysis of lens capsules from affected eyes confirmed the presence of both LOXL1 and ApoE in pathological PEX deposits. ApoE is a novel component of these deposits. This is the first report where a direct analytical approach has led to the identification of LOXL1 in PEX deposits and is consistent with its detection in these deposits by immunolabelling in another recent report. LOXL1 is both genetically associated with PEX syndrome and present in pathological PEX deposits. Hence it clearly has an important and direct role in pathophysiology of the disease. In conclusion, additional as yet unknown components are present in pathological PEX deposits and mass spectrometry of "isolated" PEX material is an effective strategy for their identification. PMID- 19442660 TI - Local calcium-dependent mechanisms determine whether a cut axonal end assembles a retarded endbulb or competent growth cone. AB - The transformation of a cut axonal end into a growth cone (GC), after axotomy, is a critical event in the cascade leading to regeneration. In an earlier series of studies we analyzed the cellular cascades that transform a cut axonal end into a competent GC. We found that axotomy of cultured Aplysia neurons leads to a transient elevation of the free intracellular Ca2+ concentration ([Ca2+]i), calpain activation and localized proteolysis of submembranal spectrin. These events are associated with the formation of distinct microtubule (MT) based vesicle traps that accumulate anterogradely transported vesicles that fuse with the spectrin free plasma membrane in support of the growth process (Erez, H., Malkinson, G., Prager-Khoutorsky, M., De Zeeuw, C.I., Hoogenraad, C.C., and Spira, M.E. 2007. Formation of microtubule-based traps controls the sorting and concentration of vesicles to restricted sites of regenerating neurons after axotomy. J. Cell Biol. 176: 497-507.; Erez, H., and Spira, M.E. 2008. Local self assembly mechanisms underlie the differential transformation of the proximal and distal cut axonal ends into functional and aberrant growth cones. J. Comp. Neurol. 507: spc1.). Here we report that under conditions that limit calcium influx into the cut axonal end, axotomy leads to the formation of endbulbs (EBs) rather than to competent GCs. Under these conditions typical MT based vesicle traps are not formed, and Golgi derived vesicles concentrate at the very tip of the cut axon. Since under these conditions the spectrin barrier is not cleaved, vesicle fusion with the plasma membrane and actin polymerization are retarded and growth processes are impaired. We conclude that the immediate assembly of competent GC or an EB after axotomy is the outcome of autonomous local events that are shaped by the magnitudes of the [Ca2+]i gradients at the site of injury. PMID- 19442661 TI - Sarcoptes scabiei var. hominis: three-dimensional structure of a female imago and crusted scabies lesions by X-ray micro-CT. AB - The three-dimensional structure of scabies mites (Sarcoptes scabiei var. hominis) and keratin layers affected by crusted scabies lesions were obtained using X-ray computed tomography at sub-micrometer and micrometer resolution, respectively (X ray micro-CT). Clear three-dimensional images including internal structure of scabies mites were obtained. Utilizing reconstructed micro-CT data, the sections of the capitulum (head part), digestive organs, and legs are shown. The reconstructed capitulum shows a jaw-like structure capable of penetrating the keratin layer of the skin. The tip of the forelegs of female scabies mites has a flat disk structure that may be used to grasp the skin surface. The keratin layer of a crusted scabies lesion spontaneously exfoliated from a patient was also reconstructed by the X-ray micro-CT technique. Extracted sections from CT data revealed a network structure of tunnels made by scabies mites with numerous larvae and eggs inside the tunnels. PMID- 19442662 TI - Plasmodium falciparum: effect of Solanum nudum steroids on thiol contents and beta-hematin formation in parasitized erythrocytes. AB - We studied the effects on total thiols glutathione (GSH) and cysteine contents in Plasmodium falciparum in vitro when treated with four steroid derivatives and a sapogenin (Diosgenone) extracted from Solanum nudum. We also determined their capacity to inhibit beta-hematin formation. We showed that SN-1 (16alpha-acetoxy 26-hydroxycholest-4-ene-3,22-dione) increased total glutathione and cysteine concentrations while SN-4 (26-O-beta-d-glucopyranosyloxy-16alpha-acetoxycholest-4 ene-3,22-dione) decreased the concentration of both thiols. Acetylation in C16 was crucial for the effect of SN-1 while type furostanol and terminal glucosidation were necessary for the inhibitory properties of SN-4. The combination of steroids and buthionine sulfoximine, a specific inhibitor of a step-limiting enzyme in GSH synthesis, did not modify the glutathione contents. Finally, we found that SN-1 inhibited more than 80% of beta-hematin formation at 5.0mM, while the other steroids did not show any effect. PMID- 19442663 TI - Plasmodium falciparum: genetic and immunogenic characterisation of the rhoptry neck protein PfRON4. AB - The Apicomplexan parasites Toxoplasma and Plasmodium, respectively, cause toxoplasmosis and malaria in humans and although they invade different host cells they share largely conserved invasion mechanisms. Plasmodium falciparum merozoite invasion of red blood cells results from a series of co-ordinated events that comprise attachment of the merozoite, its re-orientation, release of the contents of the invasion-related apical organelles (the rhoptries and micronemes) followed by active propulsion of the merozoite into the cell via an actin-myosin motor. During this process, a tight junction between the parasite and red blood cell plasma membranes is formed and recent studies have identified rhoptry neck proteins, including PfRON4, that are specifically associated with the tight junction during invasion. Here, we report the structure of the gene that encodes PfRON4 and its apparent limited diversity amongst geographically diverse P. falciparum isolates. We also report that PfRON4 protein sequences elicit immunogenic responses in natural human malaria infections. PMID- 19442664 TI - Effects of intracerebroventricular administration of neuromedin U or neuromedin S in steers. AB - Although neuromedin U (NMU) and neuromedin S (NMS) are reported to modulate stress responses mainly through corticotropin-releasing hormone system in rodents, the in vivo effects of centrally administered NMU or NMS on stress regulation have not been fully elucidated in cattle. We examined adrenocorticotropic hormone levels, body temperature, and behavioral responses to intracerebroventricularly (ICV) administered rat NMU or rat NMS in steers. ICV NMU and NMS (0.2, 2, and 20 nmol/200 microl) evoked a dose-related increase in plasma cortisol concentrations (CORT). There was a significant time-treatment interaction for the time course of CORT (p<0.001). ICV NMU evoked a dose-related increase in rectal temperature (RT). There was a significant time-treatment interaction for the change in RT from pre-injection value (p<0.05). There was a significant difference among treatments in the percentage of time spent lying (Friedman's test, chi(2)=15.6, p<0.01) and in the total number of head shaking (Friedman's test, chi(2)=14.49, p<0.01). A high dose of NMS tended to shorten the duration of lying and increase the number of head shaking. These findings indicate that both central NMU and NMS might participate in controlling the hypothalamo-pituitary-adrenal axis, that central NMU might participate in controlling body temperature, and that central NMS is likely to be involved in behavioral activation in cattle. PMID- 19442665 TI - The scientific achievements of Karl Lederis: a tribute in the form of a special issue of the journal. PMID- 19442666 TI - Control of puberty in farmed fish. AB - Puberty comprises the transition from an immature juvenile to a mature adult state of the reproductive system, i.e. the individual becomes capable of reproducing sexually for the first time, which implies functional competence of the brain-pituitary-gonad (BPG) axis. Early puberty is a major problem in many farmed fish species due to negative effects on growth performance, flesh composition, external appearance, behaviour, health, welfare and survival, as well as possible genetic impact on wild populations. Late puberty can also be a problem for broodstock management in some species, while some species completely fail to enter puberty under farming conditions. Age and size at puberty varies between and within species and strains, and are modulated by genetic and environmental factors. Puberty onset is controlled by activation of the BPG axis, and a range of internal and external factors are hypothesised to stimulate and/or modulate this activation such as growth, adiposity, feed intake, photoperiod, temperature and social factors. For example, there is a positive correlation between rapid growth and early puberty in fish. Age at puberty can be controlled by selective breeding or control of photoperiod, feeding or temperature. Monosex stocks can exploit sex dimorphic growth patterns and sterility can be achieved by triploidisation. However, all these techniques have limitations under commercial farming conditions. Further knowledge is needed on both basic and applied aspects of puberty control to refine existing methods and to develop new methods that are efficient in terms of production and acceptable in terms of fish welfare and sustainability. PMID- 19442667 TI - Pharmacological characterization, localization and quantification of expression of gonadotropin receptors in Atlantic salmon (Salmo salar L.) ovaries. AB - The gonadotropins Fsh and Lh interact with their receptors (Fshr and Lhr, respectively) in a highly specific manner in mammals with little overlap in biological activities. In fish, the biological activities seem less clearly separated considering, for example, the steroidogenic potency of both Fsh and Lh. Important determinants of the biological activity are the specificity of hormone receptor interaction and the cellular site of receptor expression. Here, we report the pharmacological characterization of Atlantic salmon Fshr and Lhr, identify receptor-expressing cells in the ovary, and validate receptor mRNA quantification systems. For the pharmacological studies, we used highly purified coho salmon gonadotropins and found that the Fshr preferentially responded to Fsh, but was also activated by approximately 6-fold higher levels of Lh. The Lhr was specific for Lh and did not respond to Fsh. Photoperiod manipulation was used to generate ovarian tissue samples with largely differing stages of maturation. Specific real-time, quantitative (rtq) PCR assays revealed up to 40-fold (fshr) and up to 350-fold (lhr) changes in ovarian expression levels, which correlated well with the differences in ovarian weight, histology, and circulating oestrogen levels recorded in January and June, respectively. Vitellogenic ovaries were used to localise receptor-expressing cells by in situ hybridization. Granulosa cells of small and large vitellogenic follicles were positive for both receptors. Also theca cells of small and large vitellogenic follicles expressed fshr mRNA, while only in large vitellogenic follicles theca cells were (weakly) positive for lhr mRNA. While only ovulatory Lh levels seem high enough to cross-activate the Fshr, expression by both receptors by granulosa and theca cells suggests that homologous ligand receptor interaction will prevail. PMID- 19442668 TI - Relationship between virulence and repellency of entomopathogenic isolates of Metarhizium anisopliae and Beauveria bassiana to the termite Macrotermes michaelseni. AB - Termites encounter a diverse array of potentially useful and harmful fungi in their subterranean habitats. These vary from symbiotic to harmful species with varying levels of virulence. How these hemiedaphic insects survive in habitats with infective fungi is not well understood. Possible mediation of olfactory signals in avoiding contact with entomopathogenic fungi has been explored by a number of workers. In the present study, we initially found that Macrotermes michaelseni detected a virulent isolate of Metarhizium anisopliae from some distance and avoided direct physical contact. We hypothesized that there may be a relationship between virulence and repellency of different isolates of M. anisopliae and Beauveria bassiana to the termite. We compared these for selected isolates of the two fungi. Positive correlations between the two parameters for both sets of isolates of the fungi were obtained. The results show an interesting co-evolutionary phenomenon in which the termite's response to either M. anisopliae or B. bassiana is directly related to potential harm these fungi can inflict on the insect and that the virulent strains are more likely to be recognized from some distance and avoided. PMID- 19442669 TI - Analysis of ESTs generated from immune-stimulated hemocytes of larval Heliothis virescens. AB - Heliothis virescens immunome components responding to baculoviral and bacterial infection were identified from expressed sequence tags (ESTs) generated from an immune-stimulated larval hemocyte cDNA library. A total of 5548 ESTs were generated comprising 448 contigs and 1114 singletons, totaling 1606 putative transcripts 1101 of which had BLAST scores, including many known orthologs from other insect species. Orthologs of known or putative immune function were identified among them melanization pathway components, proteases, antibacterial proteins, lectins, bacteria-binding proteins, ferritins, scavenger receptors, cell surface receptors, signaling pathway components, and stress response enzymes. Additionally, many enzymes of central metabolism, cytoskeletal, mitochondrial, and ribosomal components, as well as transcriptional and translational regulators were identified. The effect of bacterial and baculoviral infection upon transcript levels of three identified immunome targets from among the ESTs was quantitated using real time PCR. Scolexin-B, C-type lectin and growth-blocking peptide binding protein transcripts were significantly elevated by bacterial infection. Per os infection with the baculovirus Helicoverpa zea single nucleopolyhedrovirus however did not significantly alter transcript levels of these three genes. The ESTs reported here are the first large scale report of the H. virescens immunome responding to entomopathogens, and represent a first step to a more complete transcriptome for this pest moth. PMID- 19442670 TI - A mathematical model of calcium-induced fluid secretion in airway epithelium. AB - Regulation of periciliary liquid (PCL) depth is of central importance to mucociliary clearance by the airway epithelium. Without adequate hydration mucociliary transport would cease, leading to build up of mucus in the airways, and impairing the clearance of any trapped inhaled particulates. Airway epithelial cells are known to release ATP under a number of stress conditions. Cell surface receptors bind ATP and trigger an intracellular calcium response which regulates the gating of specific ion channels on the apical and basolateral cell membranes. This shifts the electrochemical balance, resulting in the accumulation of Na(+) and Cl(-) in the periciliary liquid, and providing an osmotic driving force for water flux. In this study, we present a mathematical model of a single airway epithelial cell which describes the fluid secretion elicited after a rise in intracellular calcium. The model provides a basis to quantitatively analyse the influence of intracellular calcium signalling on fluid movement. The model demonstrates behaviour consistent with a number of experimental data on manipulating periciliary liquid volume and tonicity, and provides a quantitative basis for analysing the role of the different membrane ion channels in determining water flux following different physiological stimuli. PMID- 19442672 TI - Hepatic VASP upregulation in rats with secondary biliary cirrhosis by expression in the peribiliary vascular plexus. AB - INTRODUCTION/AIMS: Hepatic disorders in patients and animal models may be characterized by increased ductular proliferation and concomitant expansion of the peribiliary vascular plexus (PBP). VASP plays an essential role for the control of cell assembly during the formation of three-dimensional organ structures in the cardiovascular system. Here, we investigated hepatic VASP expression in response to bile duct ligation (BDL) of rats. METHODS: BDL was performed in male rats. Sham-operated rats served as controls. After 4 weeks, hepatic VASP expression was assessed by Western-blot analysis and immunohistochemical staining. RESULTS: Livers of BDL rats showed excessive formation of new bile ducts. VASP mRNA and protein expression was upregulated in whole liver homogenates from BDL rats. This upregulation was located to the expanding PBP in the areas of ductular proliferation. In patients with cirrhosis, hepatic VASP expression was upregulated compared to non-cirrhotic patients. DISCUSSION: VASP may play a role for vascular morphogenesis in the expanding PBP of BDL rats. PMID- 19442673 TI - The GnRH analogue triptorelin confers ovarian radio-protection to adult female rats. AB - There is a controversy regarding the effects of the analogues of the gonadotrophin-releasing hormone (GnRH) in radiotherapy. This has led us to study the possible radio-protection of the ovarian function of a GnRH agonist analogue (GnRHa), triptorelin, in adult, female rats (Rattus norvegicus sp.). The effects of the X-irradiation on the oocytes of ovarian primordial follicles, with and without GnRHa treatment, were compared, directly in the female rats (F(0)) with reproductive parameters, and in the somatic cells of the resulting foetuses (F(1)) with cytogenetical parameters. In order to do this, the ovaries and uteri from 82 females were extracted for the reproductive analysis and 236 foetuses were obtained for cytogenetical analysis. The cytogenetical study was based on the data from 22,151 metaphases analysed. The cytogenetical parameters analysed to assess the existence of chromosomal instability were the number of aberrant metaphases (2234) and the number (2854) and type of structural chromosomal aberrations, including gaps and breaks. Concerning the reproductive analysis of the ovaries and the uteri, the parameters analysed were the number of corpora lutea, implantations, implantation losses and foetuses. Triptorelin confers radio protection of the ovaries in front of chromosomal instability, which is different, with respect to the single and fractioned dose. The cytogenetical analysis shows a general decrease in most of the parameters of the triptorelin treated groups, with respect to their controls, and some of these differences were considered to be statistically significant. The reproductive analysis indicates that there is also radio-protection by the agonist, although minor to the cytogenetical one. Only some of the analysed parameters show a statistically significant decrease in the triptorelin-treated groups. PMID- 19442671 TI - A cerebrovascular response model for functional neuroimaging including dynamic cerebral autoregulation. AB - Functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) can be used to isolate an evoked response to a stimulus from significant background physiological fluctuations. Data analysis approaches typically use averaging or linear regression to remove this physiological baseline with varying degrees of success. Biophysical model based analysis of the functional hemodynamic response has also been advanced previously with the Balloon and Windkessel models. In the present work, a biophysical model of systemic and cerebral circulation and gas exchange is applied to resting state NIRS neuroimaging data from 10 human subjects. The model further includes dynamic cerebral autoregulation, which modulates the cerebral arteriole compliance to control cerebral blood flow. This biophysical model allows for prediction, from noninvasive blood pressure measurements, of the background hemodynamic fluctuations in the systemic and cerebral circulations. Significantly higher correlations with the NIRS data were found using the biophysical model predictions compared to blood pressure regression and compared to transfer function analysis (multifactor ANOVA, p<0.0001). This finding supports the further development and use of biophysical models for removing baseline activity in functional neuroimaging analysis. Future extensions of this work could model changes in cerebrovascular physiology that occur during development, aging, and disease. PMID- 19442674 TI - Effects of heavy-ion beams on chromosomes of common wheat, Triticum aestivum. AB - To investigate the nature of plant chromosomes irradiated by heavy-ion beams, the effects of nitrogen (N) and neon (Ne) ion beams on hexaploid wheat chromosomes were compared with those of X-ray. Chromosome aberrations, such as short, ring and dicentric chromosomes appeared in high frequency. The average numbers of chromosome breaks at LD-50 by irradiation with X-ray, N and Ne ion beams were 32, 20 and 20, respectively. These values may be underestimated because chromosome rearrangement without change in chromosome morphology was not counted. Thus, we subsequently used a wheat line with a pair of extra chromosomes from an alien species (Leymus racemosus) and observed the fate of the irradiated marker chromosomes by genomic in situ hybridization. This analysis revealed that 50Gy of neon beam induced about eight times more breaks than those induced by X-ray. This result suggests that heavy-ion beams induce chromosome rearrangement in high frequency rather than loss of gene function. This suggests further that most of the novel mutations produced by ion beam irradiation, which have been used in plant breeding, may not be caused by ordinary gene disruption but by chromosome rearrangements. PMID- 19442675 TI - Role of DNA damage and alterations in cytosine DNA methylation in rat liver carcinogenesis induced by a methyl-deficient diet. AB - Currently, cancer is recognized as a disease provoked by both genetic and epigenetic events. However, the significance of early genetic and epigenetic alterations with respect to carcinogenic process in general and to liver carcinogenesis in particular remains unexplored. A lack of knowledge regarding how specific alterations during early preneoplasia may be mechanistically related to tumor formation creates a major gap in understanding the role of these genetic and epigenetic abnormalities in carcinogenesis. In the present study we investigated the contribution of DNA damage and epigenetic alterations to liver carcinogenesis induced by a methyl-deficient diet. Feeding Fisher 344 rats a methyl-deficient diet for 9 weeks resulted in DNA damage and aberrant DNA methylation. This was evidenced by an early up-regulation of the base excision DNA repair genes, accumulation of 8-oxodeoxyguanosine and 3'OH-end strand breaks in DNA, pronounced global loss of DNA methylation, and hypermethylation of CpG islands in the livers of methyl-deficient rats. These abnormalities were completely restored in the livers of rats exposed to methyl-deficiency for 9 weeks after removal of the methyl-deficient diet and re-feeding a methyl sufficient diet. However, when rats were fed a methyl-deficient diet for 18 week and then given a methyl-sufficient diet, only DNA lesions were repaired. The methyl-sufficient diet failed to restore completely the altered DNA methylation status and prevent the progression of liver carcinogenesis. These results suggest that stable alterations in DNA methylation are a factor that promotes the progression of liver carcinogenesis. Additionally, the results indicate that epigenetic changes may be more reliable markers than DNA lesions of the carcinogenic process and carcinogen exposure. PMID- 19442676 TI - Mu wave suppression during the perception of meaningless syllables: EEG evidence of motor recruitment. AB - Motor involvement in speech perception has been recently studied using a variety of techniques. In the current study, EEG measurements from Cz, C3 and C4 electrodes were used to examine the relative power of the mu rhythm (i.e., 8-13 Hz) in response to various audio-visual speech and non-speech stimuli, as suppression of these rhythms is considered an index of 'mirror neuron' (i.e., motor) activity. Fourteen adult native English speaking females watched and listened to nine audio-video stimuli clips assembled from three different auditory stimuli (speech, noise, and pure tone) combined with three different video stimuli (speech, noise, and kaleidoscope-made from scrambling an image from the visual speech). Relative to the noise-noise (baseline condition), all visual speech conditions resulted in significant levels of suppression, a finding that is consistent with previous reports of mirror activity to visual speech and mu suppression to 'biological' stimuli. None of the non-speech conditions or conditions in which speech was presented via audition only resulted in any significant suppression of the mu rhythm in this population. Thus, visual speech perception appears to be more closely associated with motor activity than acoustic speech perception. It is postulated that in this study, the processing demands incurred by the task were insufficient for inducing significant mu suppression via acoustic speech only. The findings are discussed in theoretical contexts of speech perception and the mirror system. We suggest that this technique may offer a cost-efficient, non-invasive technique for measuring motor activity during speech perception. PMID- 19442677 TI - Neural correlates of chromostereopsis: an evoked potential study. AB - Chromostereopsis is an illusion of depth arising from colour contrast: ocular chromatic aberrations usually make red appear closer to the viewer than blue. Whereas this phenomenon is widely documented from the optical and psychophysical point of view, its neural correlates have not been investigated. To determine the cortical processing of this colour-based depth effect, visual evoked potentials (VEPs) to contrasts of colour were recorded in 25 subjects. Chromostereopsis was found with the stimuli combining spectra extremes. VEP amplitude but not latency effects were observed to colour depth cues, suggesting an underlying, depth specific slow negative wave, located using source modelling first in occipito parietal, parietal, then temporal areas. The component was larger over the right hemisphere consistent with RH dominance in depth processing, likely due to context-dependent top-down modulation. These results demonstrate that the depth illusion obtained from contrast of colour implicates similar cortical areas as classic binocular depth perception. PMID- 19442678 TI - Methyl-parathion decreases sperm function and fertilization capacity after targeting spermatocytes and maturing spermatozoa. AB - Paternal germline exposure to organophosphorous pesticides (OP) has been associated with reproductive failures and adverse effects in the offspring. Methyl-parathion (Me-Pa), a worldwide-used OP, has reproductive adverse effects and is genotoxic to sperm, possibly via oxidative damage. This study investigated the stages of spermatogenesis susceptible to be targeted by Me-Pa exposure that impact on spermatozoa function and their ability to fertilize. Male mice were exposed to Me-Pa (20 mg/kg bw, i.p.) and spermatozoa from epididymis-vas deferens were collected at 7 or 28 days post-treatment (dpt) to assess the effects on maturing spermatozoa and spermatocytes, respectively. Spermatozoa were examined for DNA damage by nick translation (NT-positive cells) and SCSA (%DFI), lipoperoxidation (LPO) by malondialdehyde production, sperm function by spontaneous- and induced-acrosome reactions (AR), mitochondrial membrane potential (MMP) by using the JC-1 fluorochrome, and fertilization ability by an in vitro assay and in vivo mating. Alterations on DNA integrity (%DFI and NT positive cells) in spermatozoa collected at 7 and 28 dpt, and decreases in sperm quality and induced-AR were observed; reduced MMP and LPO were observed at 7 dpt only. Negative correlations between LPO and sperm alterations were found. Altered sperm functional parameters evaluated either in vitro or in vivo were associated with reduced fertilization rates at both times. These results show that Me-Pa exposure of maturing spermatozoa and spermatocytes affects many sperm functional parameters that result in a decreased fertilizing capacity. Oxidative stress seems to be a likely mechanism of the detrimental effects of Me-Pa exposure in male germ cells. PMID- 19442679 TI - Evidence for toxicity differences between inorganic arsenite and thioarsenicals in human bladder cancer cells. AB - Arsenic toxicity is dependent on its chemical species. In humans, the bladder is one of the primary target organs for arsenic-induced carcinogenicity. However, little is known about the mechanisms underlying arsenic-induced carcinogenicity, and what arsenic species are responsible for this carcinogenicity. The present study aimed at comparing the toxic effect of DMMTA(V) with that of inorganic arsenite (iAs(III)) on cell viability, uptake efficiency and production of reactive oxygen species (ROS) toward human bladder cancer EJ-1 cells. The results were compared with those of a previous study using human epidermoid carcinoma A431 cells. Although iAs(III) was known to be toxic to most cells, here we show that iAs(III) (LC(50)=112 microM) was much less cytotoxic than DMMTA(V) (LC(50)=16.7 microM) in human bladder EJ-1 cells. Interestingly, pentavalent sulfur-containing DMMTA(V) generated a high level of intracellular ROS in EJ-1 cells. However, this was not observed in the cells exposed to trivalent inorganic iAs(III) at their respective LC(50) dose. Furthermore, the presence of N-acetyl cysteine completely inhibited the cytotoxicity of DMMTA(V) but not iAs(III), suggesting that production of ROS was the main cause of cell death from exposure to DMMTA(V), but not iAs(III). Because the cellular uptake of iAs(III) is mediated by aquaporin proteins, and because the resistance of cells to arsenite can be influenced by lower arsenic uptake due to lower expression of aquaporin proteins (AQP 3, 7 and 9), the expression of several members of the aquaporin family was also examined. In human bladder EJ-1 cells, mRNA/proteins of AQP3, 7 and 9 were not detected by reverse transcription polymerase chain reaction (RT PCR)/western blotting. In A431 cells, only mRNA and protein of AQP3 were detected. The large difference in toxicity between the two cell lines could be related to their differences in uptake of arsenic species. PMID- 19442680 TI - In vitro sensitivity of granulo-monocytic progenitors as a new toxicological cell system and endpoint in the ACuteTox Project. AB - The ACuteTox Project (part of the EU 6th Framework Programme) was started up in January 2005. The aim of this project is to develop a simple and robust in vitro strategy for prediction of human acute systemic toxicity, which could replace animal tests used for regulatory purposes. Our group is responsible for the characterization of the effect of the reference chemicals on the hematopoietic tissue. CFU-GM assay based on the culture of human mononuclear cord blood cells has been used to characterize the effects of the selected compounds on the myeloid progenitors. Previous results have shown the relevance of the CFU-GM assay for the prediction of human acute neutropenia after treatment of antitumoral compounds, and this assay has been recently approved by the ECVAM's Scientific Advisory Committee. Among the compounds included in the study there were pharmaceuticals, environmental pollutants and industrial chemicals. Eleven out of 55 chemicals did not show any cytotoxic effect at the maximum concentration tested. The correlation coefficients of CFU-GM IC50, IC70 and IC90 values with human LC50 values (50% lethal concentration calculated from time related sublethal and lethal human blood concentrations) were 0.4965, 0.5106 and 0.5142 respectively. Although this correlation is not improve respect to classical in vitro basal cytotoxicity tests such as 3T3 Neutral Red Uptake, chemicals which deviate substantially in the correlation with these assays (colchicine, digoxin, 5-Fluorouracil and thallium sulfate) fitted very well in the linear regression analysis of the CFU-GM progenitors. The results shown in the present study indicate that the sensitivity of CFU-GM progenitors correlates better than the sensitivity of HL-60 cells with human LC50 values and could help to refine the predictability for human acute systemic toxicity when a given chemical may affect to the hematopoietic myeloid system. PMID- 19442681 TI - Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity. AB - Flutamide, a widely used nonsteroidal anti-androgen, but not its bioisostere bicalutamide, has been associated with idiosyncratic drug-induced liver injury. Although the susceptibility factors are unknown, mitochondrial injury has emerged as a putative hazard of flutamide. To explore the role of mitochondrial sensitization in flutamide hepatotoxicity, we determined the effects of superimposed drug stress in a murine model of underlying mitochondrial abnormalities. Male wild-type or heterozygous Sod2(+/-) mice were injected intraperitoneously with flutamide (0, 30 or 100 mg/kg/day) for 28 days. A kinetic pilot study revealed that flutamide (100 mg/kg/day) caused approximately 10-fold greater exposure than the reported therapeutic mean plasma levels. Mutant (5/10), but not wild-type, mice in the high-dose group exhibited small foci of hepatocellular necrosis and an increased number of apoptotic hepatocytes. Hepatic GSSG/GSH, protein carbonyl levels, and serum lactate levels were significantly increased, suggesting oxidant stress and mitochondrial dysfunction. Measurement of mitochondrial superoxide in cultured hepatocytes demonstrated that mitochondria were a significant source of flutamide-enhanced oxidant stress. Indeed, mitochondria isolated from flutamide-treated Sod2(+/-) mice exhibited decreased aconitase activity as compared to vehicle controls. A transcriptomics analysis using MitoChips revealed that flutamide-treated Sod2(+/-) mice exhibited a selective decrease in the expression of all complexes I and III subunits encoded by mitochondrial DNA. In contrast, Sod2(+/-) mice receiving bicalutamide (50 mg/kg/day) did not reveal any hepatic changes. These results are compatible with our concept that flutamide targets hepatic mitochondria and exerts oxidant stress that can lead to overt hepatic injury in the presence of an underlying mitochondrial abnormality. PMID- 19442682 TI - C. elegans longevity pathways converge to decrease mitochondrial membrane potential. AB - Energy production via oxidative phosphorylation generates a mitochondrial membrane potential (DeltaPsi(m)) across the inner membrane. In this work, we show that a lower DeltaPsi(m) is associated with increased lifespan in Caenorhabditis elegans. The long-lived mutants daf-2(e1370), age-1(hx546), clk-1(qm30), isp 1(qm150) and eat-2(ad465) all have a lower DeltaPsi(m) than wild type animals. The lower DeltaPsi(m) of daf-2(e1370) is daf-16 dependent, indicating that the insulin-like signaling pathway not only regulates lifespan but also mitochondrial energetics. RNA interference (RNAi) against 17 genes shown to extend lifespan also decrease DeltaPsi(m). Furthermore, lifespan can be significantly extended with the uncoupler carbonylcyanide-3-chlorophenylhydrazone (CCCP), which dissipates DeltaPsi(m). We conclude that longevity pathways converge on the mitochondria and lead to a decreased DeltaPsi(m). Our results are consistent with the 'uncoupling to survive' hypothesis, which states that dissipation of the DeltaPsi(m) will extend lifespan. PMID- 19442683 TI - Neuroendocrinology of social information processing in rats and mice. AB - We reviewed oxytocin (OT), arginine-vasopressin (AVP) and gonadal hormone involvement in various modes of social information processing in mice and rats. Gonadal hormones regulate OT and AVP mediation of social recognition and social learning. Estrogens foster OT-mediated social recognition and the recognition and avoidance of parasitized conspecifics via estrogen receptor (ER) alpha (ERalpha) and ERbeta. Testosterone and its metabolites, including estrogens, regulate social recognition in males predominantly via the AVP V1a receptor. Both OT and AVP are involved in the social transmission of food preferences and ERalpha has inhibitory, while ERbeta has enhancing, roles. OT also enhances mate copying by females. ERalpha mediates the sexual, and ERbeta the recognition, aspects of the risk-taking enhancing effects of females on males. Thus, androgens and estrogens control social information processing by regulating OT and AVP. This control is finely tuned for different forms of social information processing. PMID- 19442684 TI - The NGF saga: from animal models of psychosocial stress to stress-related psychopathology. AB - The role of the neurotrophins Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) has been expanding over the last years from trophic factors involved in brain growth and differentiation, to much more complex messengers, involved in psycho-neuro-endocrine adaptations. Much of this research stems from a series of studies inspired by the life-long work of the Nobel laureate Rita Levi-Montalcini. A new field of research started when NGF was found to be released in the bloodstream as a result of psychosocial stressors in male mice. Subsequent studies have shown that, in humans, highly arousing situations also result in increased blood levels of NGF, underlying the unique role of this neurotrophin, compared to other neuroendocrine effectors, and its sensitivity to environmental variables endowed by a social nature. Data are reviewed to support the hypothesis that this neurotrophic factor, together with BDNF, could be involved in the neurobiological changes underlying physiological and pathological reactions to stress that can result in increased vulnerability to disease in humans, including risk for anxiety disorders, or in the complex pathophysiology associated with mood disorders. Indeed, numerous data indicate that neurotrophins are present in brain hypothalamic areas involved in the regulation of hypothalamic-pituitary-adrenal axis, circadian rhythms and metabolism. In addition, there is now evidence that, in addition to the nervous system, neurotrophins exert their effects in various tissue compartments as they are produced by a variety of non-neuronal cell types such as endocrine and immune cells, adipocytes, endothelial cells, keratinocytes, thus being in a position to coordinate brain and body reactions to external challenges. Aim of this review is to discuss the evidence suggesting a role for neurotrophins as multifunctional signaling molecules activated during allostatic responses to stressful events and their involvement in the complex pathophysiology underlying stress-related psychopathology. PMID- 19442686 TI - Characterisation and expression analysis of the chicken interleukin-7 receptor alpha chain. AB - Interleukin-7 (IL-7) is a central regulator of T cell survival and homeostasis and its expression is indicative for naive and memory T cells. We cloned chicken IL-7Ralpha (CHIL-7Ralpha) and determined its expression profile in chicken lymphocyte subpopulations. The predicted protein sequence contained 460 amino acids. The extracellular domain exhibited features typical of a type I cytokine receptor; a fibronectin type III domain and the GXWSXWS motif were conserved. ChIL-7Ralpha mRNA is highly expressed in lymphoid organs and in CD4+, CD8alpha+ and CD8beta+ cells. A monoclonal antibody was generated and expression of the protein investigated. ChIL-7Ralpha was expressed on CD4+ and CD8alpha+, but not CD8beta+, T cells, in contrast to the high mRNA expression levels in all of these cells. Upon polyclonal stimulation with ConA, IL-7Ralpha was rapidly down regulated on T cells, suggesting that in the chicken expression of this receptor might also be correlated to the T cell activation status. PMID- 19442685 TI - Neurosteroid production in the songbird brain: a re-evaluation of core principles. AB - Concepts of brain-steroid signaling have traditionally placed emphasis on the gonads and adrenals as the source of steroids, the strict dichotomy of early developmental ("organizational") and mature ("activational") effects, and a relatively slow mechanism of signaling through intranuclear receptors. Continuing research shows that these concepts are not inaccurate, but they are certainly incomplete. In this review, we focus on the song control circuit of songbird species to demonstrate how each of these concepts is limited. We discuss the solid evidence for steroid synthesis within the brain ("neurosteroidogenesis"), the role of neurosteroids in organizational events that occur both early in development and later in life, and how neurosteroids can act in acute and non traditional ways. The songbird model therefore illustrates how neurosteroids can dramatically increase the diversity of steroid-sensitive brain functions in a behaviorally-relevant system. We hope this inspires further research and thought into neurosteroid signaling in songbirds and other animals. PMID- 19442687 TI - Expression of essential B cell genes and immunoglobulin isotypes suggests active development and gene recombination during equine gestation. AB - Many features of the equine immune system develop during fetal life, yet the naive or immature immune state of the neonate renders the foal uniquely susceptible to particular pathogens. RT-PCR and immunohistochemical experiments investigated the progressive expression of developmental B cell markers and immunoglobulins in lymphoid tissues from equine fetus, pre-suckle neonate, foal, and adult horses. Serum IgM, IgG isotype, and IgA concentrations were also quantified in pre-suckle foals and adult horses. The expression of essential B cell genes suggests active development and gene recombination during equine gestation, including immunoglobulin isotype switching. The corresponding production of IgM and IgG proteins is detectable in a limited scale at birth. Although the equine neonate humoral response seems competent, B cell activation factors derived from antigen presenting cells and T cells may control critical developmental regulation and immunoglobulin production during the initial months of life. PMID- 19442688 TI - In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. AB - Based on the epidemiological association between maternal infection during pregnancy and enhanced risk of neurodevelopmental brain disorders in the offspring, a number of in-vivo models have been established in rats and mice in order to study this link on an experimental basis. These models provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, and to explore the critical neuroimmunological and developmental factors involved in shaping the vulnerability to infection-induced neurodevelopmental disturbances in humans. Here, we summarize the findings derived from numerous in-vivo models of prenatal infection and/or immune activation in rats and mice, including models of exposure to influenza virus, bacterial endotoxin, viral-like acute phase responses and specific pro inflammatory cytokines. Furthermore, we discuss the methodological aspects of these models in relation to their practical implementation and their translatability to the human condition. We highlight that these models can successfully examine the influence of the precise timing of maternal immune activation, the role of pro- and anti-inflammatory cytokines, and the contribution of gene-environment interactions in the association between prenatal immune challenge and postnatal brain dysfunctions. Finally, we discuss that in vivo models of prenatal immune activation offer a unique opportunity to establish and evaluate early preventive interventions aiming to reduce the risk of long lasting brain dysfunctions following prenatal exposure to infection. PMID- 19442689 TI - Suppression subtractive hybridisation allows selective sampling of metagenomic subsets of interest. AB - Metagenomic studies bypass the requirement of a pure culture for analysis, focusing instead on the genetic information present in a given sample. Metagenomics have been applied to various studies, with objectives ranging from genome reconstruction, gene prospecting and ecology. However, the use of metagenomics in comparative studies has been constrained by sequencing costs and computational limitations. Efforts are underway to improve current sequencing methods and reduce the expense involved. We suggest an alternative approach - pretreatment of the sample of interest to enrich for desired subsets prior to deep sequencing. In this study, we tested the use of suppression subtractive hybridisation (SSH) for in vitro separation of metagenomic samples based on temporal variance. Faecal samples were taken from pigs at different timepoints and extracted DNA was whole genome-amplified using multiple displacement amplification (MDA). A sample collected at 31 days of age was designated the tester while a 24 day sample was denoted the driver. Following hybridisation and subtraction, tester-specific sequences are expected to be enriched in the final sample while driver-specific and common sequences are removed. Using denaturing gel gradient electrophoresis (DGGE), we found that driver-specific bands were completely removed from all final profiles while an average of 70% of common bands were successfully subtracted. Final profiles retained an average of 70% of tester-specific sequences and new sequences contributed an average of 36% of the band mobilities found in the final profiles. Tester-unique sequences were inferred to make up 78% of the final profile after SSH. We expect that using subtractive hybridisation for separation of metagenomic samples into desired subsets will provide a more effective and targeted approach to comparative studies. PMID- 19442691 TI - Pepper chat fruit viroid: biological and molecular properties of a proposed new species of the genus Pospiviroid. AB - In autumn 2006, a new disease was observed in a glasshouse-grown crop of sweet pepper (Capsicum annuum L.) in the Netherlands. Fruit size of the infected plants was reduced up to 50%, and plant growth was also slightly reduced. Here we show that the disease is caused by a previously non-described viroid. The pepper viroid is transmitted by both mechanical inoculation and pepper seeds and, when inoculated experimentally, it infects several solanaceous plant species inducing vein necrosis and reduced fruit and tuber size in tomato and potato, respectively. The viroid RNA genome consists of 348 nucleotides and, with minor modifications, it has the central conserved and the terminal conserved regions characteristic of members of the genus Pospiviroid. Classification of the pepper viroid within the genus Pospiviroid is further supported by the presence and structure of hairpins I and II, the presence of internal and external RY motifs, and phylogenetic analyses. The primary structure of the pepper viroid only showed a maximum of 66% nucleotide sequence identity with other viroids, which is far below the main species demarcation limit of 90%. According to its biological and molecular properties, we propose to assign the pepper viroid to a new species within the genus Pospiviroid, and to name this new species Pepper chat fruit viroid. PMID- 19442692 TI - An injectable drug delivery platform for sustained combination therapy. AB - We report the development of a series of physical hydrogel blends composed of hyaluronan (HA) and methyl cellulose (MC) designed for independent delivery of one or more drugs, from 1 to 28 days, for ultimate application in spinal cord injury repair strategies. To achieve a diversity of release profiles we exploit the combination of fast diffusion-controlled release of dissolved solutes from the HAMC itself and slow drug release from poly(lactide-co-glycolide) particles dispersed within the gel. Delivery from the composite hydrogels was demonstrated using the neuroprotective molecules NBQX and FGF-2, which were released for 1 and 4 days, respectively; the neuroregenerative molecules dbcAMP and EGF, and proteins alpha-chymotrypsin and IgG, which were released for 28 days. alpha chymotrypsin and IgG were selected as model proteins for the clinically relevant neurotrophin-3 and anti-NogoA. Particle loaded hydrogels were significantly more stable than HAMC alone and drug release was longer and more linear than from particles alone. The composite hydrogels are minimally swelling and injectable through a 30 gauge/200 microm inner diameter needle at particle loads up to 15 wt.% and particle diameters up to 15 microm. PMID- 19442690 TI - Genetic characterization of Rabies virus isolated from cattle between 1997 and 2002 in an epizootic area in the state of Sao Paulo, Brazil. AB - The biogeographical history of rabies can be reconstructed using molecular data. This work describes the genetic characterization of the Rabies virus variant that circulates in the Desmodus rotundus (vampire bat) population in an epizootic area and is transmitted to herbivorous livestock. The N and G genes of this virus were sequenced, and the phylogenetic trees generated were topologically concordant. Three genetic clusters were identified in the epizootic area and were designated RD1, RD2 and RD3. The results show that the origins of the epizootics in areas RD1 and RD2 were different and that the epizootic in area RD3 was the result of expansion of that in area RD2. The two genes analyzed are conserved, and their identities, which are greater than 98%, were maintained over time and space. The genetic sequences in this study were compared with others retrieved from GenBank, and the high identity of the N and G genes was also shown to be maintained over time and space. The results suggest that the D. rotundus lineages of the Rabies virus from the Atlantic coast of South America are highly conserved. PMID- 19442693 TI - Protein splicing: A versatile tool for drug discovery. AB - The judicious application of intein technologies to biological problems has resulted in powerful tools for biomedical research. Inteins are intervening sequences that excise themselves from precursor proteins and ligate the surrounding sequences. Variations of intein chemistry have been used to create tagless protein purification strategies, specifically label expressed proteins for biochemical assays, design biosensors, produce microarrays, and synthesize cyclic peptide libraries for inhibitor studies. Moreover, recent advances in small molecule triggered protein splicing allow for tunable post-translational control of protein function in vivo. Inteins are now positioned as an essential tool to study the mechanism of disease progression and validate drug candidates. Yet these tiny proteins have more tricks to play. Recent progress in gene therapy and drug targeting suggest a bright future where split inteins mediate in vivo reconstruction of large therapeutic proteins and target drugs to a specified site of action. Inteins are rapidly becoming valuable tools for drug discovery and drug delivery. PMID- 19442694 TI - The involvement of substance P in the induction of aggressive behavior. AB - Aggression is a complex social behavior that involves a similarly complex neurochemical background. The involvement of substance P (SP) and its potent tachykinin receptor (NK1) in the induction of both defensive rage and predatory attack appears to be a consistent finding. However, an overall understanding of the nature of the SP involvement in the induction of aggressive behavior has not yet been fully achieved. The aim of this review is to summarize and present the current knowledge with regards to the role of SP in the induction of aggressive behavior and to synopsize: (a) its biochemical profile, and (b) the exact anatomical circuits through which it mediates all types of aggressive behavior. Future studies should seriously consider the potential use of this knowledge in their quest for the treatment of mood and anxiety disorders. PMID- 19442695 TI - Melanin-concentrating hormone and melanin-concentrating hormone receptors in mammalian skin physiopathology. AB - To date, there is a dearth of evidence to support functions for melanin concentrating hormone (MCH) and melanin-concentrating hormone receptors (MCH-R) in mammalian skin physiology including pigmentation, inflammation and immune responses and skin cell proliferation. Much research is therefore still needed to define the roles of the hormone and its receptors in mammalian skin. This will be a crucial step to identifying pathogenic mechanisms that may involve the MCH/MCH R system in the context of inflammatory and autoimmune skin diseases as well as skin cancers. The following review summarizes the studies which have been carried out to examine the expression and function of MCH and MCH-R in mammalian skin. Recent findings with regard to humoral immune responses to the MCH-R1 in patients with the skin depigmenting disease vitiligo are also discussed. PMID- 19442696 TI - Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood-brain barrier: An in situ cerebral perfusion study. AB - Docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids are n-3 polyunsaturated fatty acids with a therapeutic potential for CNS diseases. Here, using an in situ brain perfusion technique in mice, we show that [(14)C]-DHA and [(14)C]-EPA readily cross the mouse blood-brain barrier (BBB) with brain transport coefficients (Clup) of 48+/-3microlg(-1)s(-1) and 52+/-4microlg(-1)s(-1), respectively. Mechanical capillary depletion of brain homogenates showed that less than 10% of [(14)C]-DHA or [(14)C]-EPA remained in endothelial cells of the brain vasculature, demonstrating that both molecules fully crossed the BBB. Addition of bovine serum albumin decreased the Clup of [(14)C]-DHA to 0.6+/ 0.3microlg(-1)s(-1), indicating that binding to albumin reduced importantly, but not totally, the passage of DHA through the BBB. The Clup of [(14)C]-DHA or [(14)C]-EPA was not saturable at concentration up to 100microM, suggesting that these compounds crossed the BBB by simple diffusion. However, long-term high-DHA dietary consumption reduced the Clup of [(14)C]-DHA to 33+/-6microlg(-1)s(-1) ( 20%, p<0.01). These results confirm that the brain uptake of DHA or EPA perfused with a physiological buffer is comparable to highly diffusible drugs like diazepam, and can be modulated by albumin binding and chronic dietary DHA intake. PMID- 19442697 TI - PPARgamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. AB - Peroxisome proliferator-activated receptor (PPAR)gamma stimulation provides protection in several models of neurological disorders, but the mechanisms underlying these effects remain to be fully elucidated. Here we have studied whether two PPARgamma agonists, pioglitazone and rosiglitazone, prevent loss of differentiated SH-SY5Y cells transiently exposed to glucose deprivation (GD). Nanomolar drug concentrations prevented GD-induced cell loss in a concentration- and time-dependent manner. These effects were abolished by malonate, a reversible mitochondrial Complex II inhibitor, while significantly potentiated by pyruvate, thus suggesting that they are related to mitochondrial function. During cell pretreatment, PPARgamma agonists promoted biogenesis of functional mitochondria, as indicated by the up-regulation of PPARgamma coactivator (PGC)-1alpha, NRF1, TFAM, cytochrome c oxidase subunit (CO) I and CO IV, and the increased level of mtDNA, while did not significantly change mitochondrial membrane potential. In addition, the analysis of the concentration-response and time-course curves for the protective effects and the up-regulation of mitochondrial biogenesis markers suggests that mitochondrial biogenesis and cell loss prevention are related effects. In conclusion our data indicate that a prolonged PPARgamma stimulation, by repeated administration of nanomolar pioglitazone or rosiglitazone concentrations, decreases GD-induced loss of differentiated SH-SY5Y cells. In addition, they suggest that mitochondrial biogenesis may contribute to these effects. PMID- 19442698 TI - Adopting alternatives for the regulatory monitoring of shellfish for paralytic shellfish poisoning in Canada: Interface between federal regulators, science and ethics. AB - To ensure the safety of Canada's shellfish, the Canadian Shellfish Sanitation Program (CSSP) relies on the mouse bioassay to detect toxins known to cause paralytic shellfish poisoning (PSP). This assay uses a large number of mice and requires death as an endpoint. Canadian research has led to the development of a pre-column High Performance Liquid Chromatography (HPLC) method that is more sensitive and more reliable than the mouse bioassay. However, it is not being used by Canadian regulators despite its acceptance by the AOAC and adoption by the United Kingdom. An ethnography study of stakeholders in the CSSP was conducted to determine the opportunities and obstacles to adopting analytical testing methods. The results of the study indicate that the major obstacles are a lack of certified reference materials (CRMs) and the direction of resources towards the development of new instrument-based methods rather than towards the refinement of the existing pre-column HPLC method for regulatory use. To move away from the mouse bioassay, Canada should invest in: basic research to develop a complete set of CRMs for PSP toxins; method refinement to increase sample throughput; and exercises to gain international acceptance of the pre-column HPLC method. PMID- 19442699 TI - Malathion-induced testicular toxicity in male rats and the protective effect of vitamins C and E. AB - Sexually mature male Wistar rats (weighing 300-320 g and each group 6 animals) were given malathion (27 mg/kg; 1/50 of the LD(50) for an oral dose) and/or vitamin C (200mg/kg)+vitamin E (200mg/kg) daily via gavage for 4 weeks. The sperm counts, sperm motility, sperm morphology, FSH, LH, and testosterone levels, and histopathological changes in the testes of these rats, were investigated at the end of the 4th week. By the end of 4th week, rats given malathion alone, or in combination with vitamins C and E, had significantly lower sperm counts and sperm motility, and significantly higher abnormal sperm numbers, than the untreated control rats. The rats given malathion alone or in combination with vitamins also had significantly lower plasma FSH, LH and testosterone levels than the control rats. Co-treatment of malathion-exposed rats with vitamins E and C had a protective effect on sperm counts, sperm motility and abnormal sperm numbers, but not on plasma FSH, LH and testosterone levels. Light microscopic investigations revealed that 4 weeks of malathion exposure was associated with necrosis and edema in the seminiferous tubules and interstitial tissues. Degenerative changes in the seminiferous tubules were also observed in the rats which received malathion and supplemented with vitamins C and E, but milder histopathological changes were observed in the interstitial tissues. Thus, it appears that vitamins C and E ameliorate malathion testicular toxicity but are not completely protective. PMID- 19442700 TI - Enantiomer-specific, bifenthrin-induced apoptosis mediated by MAPK signalling pathway in Hep G2 cells. AB - Enantioselectivity in toxicology, and health risk of chiral xenobiotics have become important topics at the forefront of chemistry and toxicology research. Our previous results showed that cis-bifenthrin (cis-BF) induced cytotoxicity and genotoxicity in human amnion epithelial (FL) cells, in an enantioselective manner. However, the exact molecular mechanisms of synthetic pyrethroid-induced, enantioselective apoptosis and cytotoxicity remain unclear. In this study, enantiomers of the synthetic pyrethroid-based insecticide, cis-BF, were separated on selected chiral columns by HPLC. Enantioselectivity in cytotoxicity and apoptosis, mediated by the mitogen-activated protein kinase (MAPK) signalling pathway, were evaluated in the human hepatocellular liver carcinoma (Hep G2) cell line. Exposure to 1S-cis-BF resulted in increased levels of phosphorylated JNK (Jun-N-terminal Kinases)/MAPKs, while exposure to 1R-cis-BF did not affect phosphorylated JNK levels. Pre-treatment with the JNK inhibitor SP600125, blocked 1S-cis-BF-induced cytotoxicity and apoptosis. In addition, 1S-cis-BF enhanced the production of ROS, while pre-treatment with the antioxidant agent MnTBAP resulted in decreased phosphorylation of JNK. To the best of our knowledge, this is the first report demonstrating that cis-BF-induced apoptosis might occur, at least in part, through the enantioselective activation of JNK/MAPK signalling pathway in Hep G2 cells. The results suggest that enantioselectivity should be considered when evaluating eco-toxicological effects and health risks of chiral contaminants, and could also improve the understanding of molecular mechanisms responsible for chiral chemical-induced cytotoxicity and apoptosis. PMID- 19442701 TI - Binding properties of the complex formed by the Arabidopsis TALE homeodomain proteins STM and BLH3 to DNA containing single and double target sites. AB - We have analyzed the DNA-binding properties of the complex formed by the Arabidopsis TALE homeodomain (HD) proteins STM and BLH3 in comparison with those of the individual proteins. In vitro DNA-binding assays indicated that complex formation increases binding affinity for sequences carrying either a single target site or two such sites arranged in tandem. Complex formation is not correlated with the establishment of new detectable contacts as deduced from missing-nucleoside experiments. Increased binding was also observed when using BLH3 with a mutation that renders the HD unable to bind DNA, suggesting that only the STM functional HD is necessary for tight binding by the complex. Yeast one hybrid assays using single or double target sites showed that the effect of complex formation is more dramatic for the double target site and that under these conditions competition for binding by the individual proteins is reduced. The results indicate that even if complex formation produces an increase in binding to DNA sequences containing either one or two target sites, the relative increase in binding produced after complex formation is dependent on the type of target sequence that is considered. This differential effect of complex formation on binding may have implications in the regulatory properties of these transcription factors within the cell. PMID- 19442702 TI - Maximizing specificity and yield of PCR by the quantum dot itself rather than property of the quantum dot surface. AB - We found that semiconductor quantum dots (QDs) dramatically improved both product yield and specificity of PCR. The concentration of QDs is important for improving PCR amplification. In the presence of appropriate concentration of mercaptoacetic acid (MAA)-coated QDs, specificity and yield of PCR were enhanced. Also, strong nonspecific bands and weaker smeared bands were eliminated. At lower annealing temperatures (25-45 degrees C), addition of MAA-coated QDs into the PCR reagent produced specific PCR products without nonspecific sequence amplification. MAA alone did not improve PCR amplification. Streptavidin (SA) surface modified QDs with different size also effectively improved the specificity of PCR, demonstrating that the observed effect was not due to property of the QD surface but instead due to the QD itself. Bovine Serum Albumin (BSA) could relieve Taq polymerase from MAA-coated QDs in PCR by interaction with QDs and therefore imply that QDs improve specificity of PCR by interaction with Taq polymerase. These results demonstrate that QDs, added to reaction mixes at appropriate concentrations, can increase PCR yield and improve PCR specificity, even at low annealing temperatures. We assume that many different surface modified polymeric nanoparticles might have similar effects. PMID- 19442703 TI - Evolution of cellular automata with memory: The Density Classification Task. AB - The Density Classification Task is a well known test problem for two-state discrete dynamical systems. For many years researchers have used a variety of evolutionary computation approaches to evolve solutions to this problem. In this paper, we investigate the evolvability of solutions when the underlying Cellular Automaton is augmented with a type of memory based on the Least Mean Square algorithm. To obtain high performance solutions using a simple non-hybrid genetic algorithm, we design a novel representation based on the ternary representation used for Learning Classifier Systems. The new representation is found able to produce superior performance to the bit string traditionally used for representing Cellular automata. Moreover, memory is shown to improve evolvability of solutions and appropriate memory settings are able to be evolved as a component part of these solutions. PMID- 19442704 TI - Peripheral and spinal antihyperalgesic activity of najanalgesin isolated from Naja naja atra in a rat experimental model of neuropathic pain. AB - Snake venoms are a rich source of various compounds that have applications in medicine and biochemistry. Recently, it has been demonstrated that najanalgesin isolated from the venom of Naja naja atra exerts analgesic effects on acute pain in mice. The objective of this study was to evaluate the antinociceptive effect of najanalgesin in a rat model of neuropathic pain, induced by L5 spinal nerve ligation and transaction. We observed that intraperitoneal (i.p.) administration of najanalgesin produced significant increase in hind paw withdrawal latency (HWL) in response to both mechanical and thermal stimulation. Moreover, a single dose of najanalgesin was able to induce antinociceptive activity that lasted for 1 week. Intrathecal injection of najanalgesin increased the HWL in response to mechanical stimuli. The antinociceptive effect of najanalgesin administered intrathecally was partly inhibited by intrathecal injection of naloxone or atropine. These results demonstrate that najanalgesin has antinociceptive effects on the central and peripheral system in the rat neuropathic pain model. The opioid receptor and muscatinic receptor are involved in najanalgesin-induced antinociception in the spinal cord. This research supports the possibility of using najanalgesin as a novel pharmacotherapeutic agent for neuropathic pain. PMID- 19442705 TI - SNAT1 and a family with high rates of suicidal behavior. AB - Several lines of evidence suggest that suicide may have, in part, a genetic predisposition. In this study, we identified a family with high rates of suicidal behavior and assessed brain gene expression levels in the proband. A neuronally expressed solute carrier for glutamine (Sodium-coupled neutral amino acid transporter 1 (SNAT1), also known as solute carrier family 38, member 1 (SLC38A1)) was identified as severely decreased across all brain regions. Follow up analysis by semi-quantitative polymerase chain reaction (qPCR) and Western blot confirmed the reduction of SNAT1. We categorized the SNAT1 gene in human brain, cloned the gene promoter and assessed in silico the expression pattern of SNAT1 in >25 tissues from human. Complete DNA sequencing of the SNAT1 gene was performed in the family and 276 controls. The family was homozygous for rare alleles which suggests a possible association between low expression of SNAT1 and suicidal behavior. PMID- 19442706 TI - The anti-amnesic effects of luteolin against amyloid beta(25-35) peptide-induced toxicity in mice involve the protection of neurovascular unit. AB - Luteolin (3',4',5,7-tetrahydroxyflavone) is an important member of the flavonoid family. It exhibits strongly anti-inflammatory, antioxidant and phytoestrogen like activities. In the present study, we examined the anti-amnesic and protective effects of luteolin against Abeta(25-35)-induced toxicity in mice. Mice were given an i.c.v. injection of aggregated Abeta(25-35) peptide. The learning and memory impairments, ultrastructural changes of cerebral cortex, cerebrovascular dysfunction and neuronal changes were detected after oral administration of luteolin continuously for 8 days. Our results demonstrate that oral administration of luteolin for 8 days for those Abeta(25-35)-induced amnesic mice conferred robust neurovascular protection in Abeta(25-35)-induced amnesia, involving the improvement of the spatial learning and memory capabilities, the modulation of microvascular function, the increase of regional cerebral blood flow values, the clearance of reactive oxygen species, the improvement of cholinergic neuronal system, and the increase of brain-derived neurotrophic factor level and its receptor tyrosine kinase B expression in cerebral cortex. PMID- 19442708 TI - Two new furostanol saponins from Tribulus terrestris L. AB - Two new furostanol glycosides, named tribufurosides I (1) J (2), were isolated from the fruits of Tribulus terrestris L. by a combination of chemical and spectroscopic methods. Its structures were established as 26-O-beta-D glucopyranosyl-(25S)-5alpha-furost-12-one-2alpha,3beta,22alpha,26-tetraol-3-O beta-D-glucopyranosyl (1-->2)-beta-d-glucopyranosyl (1-->4)-beta-d galactopyranoside (1) and 26-O-beta-D-glucopyranosyl-(25R)-5alpha-furost-20(22) en-12-one-2alpha,3beta,26-triol-3-O-beta-D-glucopyranosyl (1-->4)-beta-D galactopyranoside (2). PMID- 19442707 TI - Hippocampal spine-associated Rap-specific GTPase-activating protein induces enhancement of learning and memory in postnatally hypoxia-exposed mice. AB - Spine-associated Rap-specific GTPase-activating protein (SPAR) is a postsynaptic protein that forms a complex with postsynaptic density (PSD)-95 and N-methyl-d aspartate receptors (NMDARs), and morphologically regulates dendritic spines. Mild intermittent hypoxia (IH, 16.0% O(2), 4 h/day for 4 weeks) is known to markedly enhance spatial learning and memory in postnatal developing mice. Here, we report that this effect is correlated with persistent increases in SPAR expression as well as long-term potentiation (LTP) in the hippocampus of IH exposed mice. Furthermore, an infusion of SPAR antisense oligonucleotides into the dorsal hippocampus disrupted elevation of SPAR expression, preventing enhanced hippocampal LTP in IH-exposed developing mice and also reducing LTP in normoxic mice, without altering basal synaptic transmission. In SPAR antisense treated mice, acquisition of the Morris water maze spatial learning task was impaired, as was memory retention in probe trails following training. This study provides the first evidence that SPAR is functionally required for synaptic plasticity and contributes to the IH-induced enhancement of spatial learning and memory in postnatal developing mice. PMID- 19442709 TI - A new iridoid from Adenosma caeruleum R. Br. AB - A new iridoid glycoside, adenosmoside, together with five known phenylpropanoids, crenatoside, verbascoside, cistanoside F, campneoside I, and campneoside II and two known flavonoids, apigenin 7-O-beta-D-glucuronopyranoside and apigenin 7-O beta-D-glucopyranoside, were isolated from the aerial parts of Adenosma caeruleum R. Br. Their structures were elucidated by spectral evidence. PMID- 19442710 TI - General 4-week toxicity study with EMS in the rat. AB - In this subacute toxicity study, ethyl methanesulfonate (EMS) was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 20, 60 and 180/120 mg/kg body weight (bw)/day for a period of 28 days (for 19 days in the high-dose group). A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 10 animals per sex, which were sacrificed after 28 days, respectively 19 days in the high-dose group, of treatment. Additional five rats per sex and group were treated accordingly and then allowed a 14 days treatment-free recovery period. Additional six rats per sex and group (three rats per sex in the control group) were treated accordingly and used for hemoglobin adduct analysis after EMS exposure. All animals survived until their scheduled necropsy. Treatment with EMS had a direct dose-dependent effect on food consumption and consequently on body weight at doses > or =20mg/kgbw/day in male rats and at > or =60 mg/kgbw/day in females rats. Hence, treatment with the high dose of 180 mg/kgbw/day had to be interrupted for 9 days after which, the animals were re-dosed at 120 mg/kgbw/day. This dose was also poorly tolerated over the remaining two treatment weeks causing again a marked reduction in food consumption and body weight. A dose of 60 mg/kgbw/day was moderately tolerated over 4 weeks treatment with mean daily food consumption and body weight distinctly lower than in controls. Primary targets of systemic toxicity were the hematopoietic system, thymolymphatic system and sexual organs. Characteristic changes in hematology parameters were decreased red blood cell counts, hematocrit, and hemoglobin concentration. White blood cell counts were also decreased due to reduced lymphocyte and granulocyte populations of each fraction. The corresponding histopathology findings were fatty atrophy of bone marrow and minimal hypocellularity of the white pulp of the spleen. Similarly, treatment with EMS caused an involution of the thymolymphatic system characterized by decreased organ weight of thymus, lymph nodes, and spleen microscopically associated with atrophy of the thymus and hypocellularity of Peyer's patches, lymph nodes and the white pulp of the spleen. The effects on sexual organs included lower organ weight/reduced size for testes, epididymides, seminal vesicles, prostate, and uterus. Tubular atrophy, single cell necrosis of the germ cells and in epididymides reduced spermatozoa were recorded microscopically. The described findings occurred at doses of 60 and 180/120 mg/kgbw/day and were dose-dependent with regard to incidence and severity. Other target organs were the pancreas (acinar cell vacuolation), thyroid gland (follicular cell hypertrophy), and salivary gland (secretory depletion of convoluted ducts). The systemic exposure to EMS was monitored by hemoglobin ethylvaline adduct measurement. The concentration of hemoglobin ethylvaline adducts was linear with the dose and accumulated 11-26-fold over the treatment period. In summary, decreases in food consumption and body weight were the dose limiting effects of treatment with EMS. Organ toxicity was characterized by depression of cell proliferation (hematopoiesis and spermatogenesis) and changes suggestive of reduced metabolism and/or physiological imbalances (e.g. thymolymphatic system and thyroid gland) without signs of inflammatory or necrotic lesions. For some findings, especially the effects on the thymolymphatic system and sexual organs, it cannot be excluded that starvation-like condition contributed to the occurrence of such changes. The low dose of 20 mg/kgbw/day was basically free of adverse effects despite of a clear evidence for hemoglobin adducts. PMID- 19442711 TI - Comparison of solid dispersions produced by supercritical antisolvent and spray freezing technologies. AB - Oxeglitazar is a new orally administered poorly water soluble active substance used in the treatment of type II diabetes. The objective of this work was to improve its dissolution kinetics using supercritical antisolvent (SAS) and spray freezing (SF) techniques. Oxeglitazar was formulated with various excipients, including: Poloxamer 188 and 407, polyethylene glycol (PEG) 8000 and polyvinylpyrrolidone (PVP) K17 in a 1:1 weight ratio. In the SAS technology, pharmaceutical ingredients were dissolved in an appropriate solvent, and the feed solution was dispersed through a capillary nozzle in supercritical CO(2) (SC CO(2)). Dichloromethane (DCM), chloroform (CHCl(3)), and a binary co-solvent system of chloroform-ethanol (EtOH/CHCl(3) 50:50, v/v%) were tested. In the SF process, tert-butanol (tBuOH) was used as solvent. The feed solution was injected into liquid nitrogen through a capillary nozzle located above the surface of the boiling nitrogen. Frozen particles were collected and freeze-dried for 30 h. Formulations were compared in terms of particle morphology, particle size, flow properties, crystallinity, polymorphic purity, residual solvent content, precipitation yield, drug content, specific surface area and dissolution kinetics. SAS and SF processed formulations exhibited enhanced dissolution rates. Within 5 min, the amount of dissolved drug varied from 31.6 to 64.3% for SAS and from 77.9 to 96.9% for freeze-dried formulations while only 30.5% was dissolved from raw drug. Apart from oxeglitazar/PVP K17, SAS prepared solid dispersions were characterized by high crystallinity and acicular shape. Freeze-dried formulations consisted of porous spherical particles with high amorphous content (94.2-100%). PMID- 19442712 TI - Chitosan-phospholipid blend for sustained and localized delivery of docetaxel to the peritoneal cavity. AB - Localized and sustained delivery of chemotherapeutics presents a "magic bullet" effect by providing high drug concentrations at the target site, extended drug exposure and reduced systemic toxicity. In the present study, an injectable chitosan-phospholipid (PoLi(gel)) blend is put forth as a strategy to achieve sustained and localized delivery of docetaxel (DTX) following intraperitoneal (IP) administration. The stability of the blend was confirmed in vitro, by turbidity measurements and attributed to specific molecular interactions and the organization of the materials within the blend, as evidenced by FTIR analysis and confocal laser scanning microscopy, respectively. The chitosan and phospholipid were found to colocalize in regions surrounding a mean object area of 11.2mum(2) with colocalization coefficients of 43% and 46% for the chitosan and phospholipid, respectively. The PoLi(gel) blend afforded sustained drug release as seen both in vitro (2.4+/-0.7% DTX per day) and in vivo (4.4+/-0.7% DTX per day). Constant concentrations of DTX were observed over a 2-week period in plasma and relevant peritoneal tissues, with no signs of toxicity or inflammation, following IP administration of the blend in healthy CD-1 mice. At DTX doses of 28.8 and 19.2mg/kg, the blend showed significant tumor inhibition of 87.3+/-9.3% and 74.1+/-25.9%, respectively, in a murine xenograft model of human ovarian adenocarcinoma. This localized delivery system has shown excellent potential for sustained IP treatment of cancers, such as ovarian, that reside in the peritoneal cavity. PMID- 19442713 TI - Dexamethasone protects auditory hair cells against TNFalpha-initiated apoptosis via activation of PI3K/Akt and NFkappaB signaling. AB - BACKGROUND: Tumor necrosis factor alpha (TNFalpha) is associated with trauma induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment). HYPOTHESIS: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival. MATERIALS AND METHODS: Organ of Corti explants challenged with an ototoxic level of TNFalpha was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNFalpha-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNFalpha ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity. RESULTS: The general caspase inhibitor Boc-d-fmk prevented TNFalpha induced AHC death. There was a significant reduction (p<0.05) in the efficacy of Dex otoprotection against TNFalpha ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NFkappaB (NFkappaB-I). CONCLUSION: Dex treatment protects hair cells against TNFalpha apoptosis in vitro by activation of PI3K/Akt and NFkappaB signaling. PMID- 19442714 TI - Biotechnological production of 2,3-butanediol--current state and prospects. AB - Biotechnological production of 2,3-butanediol (hereafter referred to as 2,3-BD) from wastes and excessive biomass is a promising and attractive alternative for traditional chemical synthesis. In the face of scarcity of fossil fuel supplies the bio-based process is receiving a significant interest, since 2,3-BD may have multiple practical applications (e.g. production of synthetic rubber, plasticizers, fumigants, as an antifreeze agent, fuel additive, octane booster, and many others). Although the 2,3-BD pathway is well known, microorganisms able to ferment biomass to 2,3-BD have been isolated and described, and attempts of pilot scale production of this compound were made, still much has to be done in order to achieve desired profitability. This review summarizes hitherto gained knowledge and experience in biotechnological production of 2,3-BD, sources of biomass used, employed microorganisms both wild type and genetically improved strains, as well as operating conditions applied. PMID- 19442715 TI - Microbial cells as catalysts for stereoselective red-ox reactions. AB - Enzyme catalyzed reactions are commonly used at laboratory or industrial scale. Contrarily, the whole cell catalyzed reactions are restricted to special cases. The tremendous advances in the last years in Molecular Biology and more specifically in Metabolic Engineering and Directed Enzyme Evolution have opened the door to create tailor-made microorganisms or "designer bugs" for industrial purposes. Whole cell catalysts can be much more readily and inexpensively prepared than purified enzymes and the enzymes - inside the cells - are protected from the external environment and stabilized by the intracellular medium. Three situations have traditionally been considered convenient to select the use of whole cell catalyzed processes against the free enzyme catalyzed process: i) when the enzyme is intracellular; ii) when the enzyme needs a cofactor to carry out the catalytic act and iii) in the development of multienzymatic processes. Red-ox reactions represent the molecular basis for energy generation in the cell. These reactions are catalyzed by intracellular enzymes and are cofactor dependent as red-ox reactions need electron carriers as helpers in reduction reactions (gain of electrons) or oxidation (loss of electrons). In this review we present an overview of the state of the art of red-ox biotransformations catalyzed by whole cells - wild-type or genetically engineered microorganisms. Stereoselective reductions, hydroxylations of arenes and unfunctionalized alkanes, alkene monooxygenation, and Baeyer-Villiger reactions are among the processes described along the text, focusing in their chemo-, regio- and stereoselectivity. PMID- 19442716 TI - Fetal outcome after technetium scintigraphy in early pregnancy. AB - OBJECTIVE: Occasionally, either for urgent diagnostic reasons or by accident, pregnant women are exposed to technetium scintigraphy, the consequences of which were unknown, due to lack of systematic data. Therefore, clinical data was needed to assess the risk and safety of technetium scintigraphy with respect to prenatal development. METHODOLOGY: Requests for information with regard to technetium scintigraphy from pregnant women or their physicians were followed by the Berlin Institute for Clinical Teratology. A prospective observational cohort study was performed using data collected between 1991 and 2008. Pregnancy outcome for a cohort of pregnant women exposed to Tc-99m-scintigraphy of thyroid (n=102) or bone (n=20) during pregnancy was compared with a control group without teratogenic exposure (n=366). RESULTS: Major birth defects were no more common in the study group than in the control group (OR 1.00; 95% CI 0.23-3.38) and no specific pattern of birth defects was found. Spontaneous abortion rate (OR 0.51), preterm deliveries, and birth measurements of newborns were not significantly different from controls. CONCLUSION: This prospective observational study suggests that the inadvertent exposure to Tc-99m-scintigraphy in early pregnancy is relatively safe for the fetus. PMID- 19442717 TI - Acyl-CoA-induced generation of reactive oxygen species in mitochondrial preparations is due to the presence of peroxisomes. AB - Preparations of rat liver mitochondria, but not of brain and heart mitochondria, produce large quantities of reactive oxygen species (ROS) in the presence of palmitoyl-CoA and other long-chain acyl-CoAs. Palmitoyl-CoA inhibited respiration of rat liver mitochondria with glutamate plus malate or with succinate as substrate. However, ROS production induced by acyl-CoA was independent of respiration inhibition, as it was also observed in antimycin A- and rotenone inhibited mitochondria and in submitochondrial particles in the absence of respiratory substrates (other than acyl-CoA). Increased ROS production by acyl CoA in rat liver mitochondrial preparations was observed when measured in the external medium using Amplex red as a probe, but not inside mitochondria using the internal fluorescent probe MitoSOX or aconitase activity as the "intrinsic" indicator of ROS generation in the matrix compartment. Stimulation by acyl-CoA of ROS generation was higher in "light" mitochondrial preparations that were enriched in peroxisomes, as assayed by urate oxidase. It is concluded that stimulation of ROS production in preparations of rat liver mitochondria could be ascribed to contaminating peroxisomes. Preparations of rat brain and heart mitochondria were not or were much less contaminated with peroxisomes, as indicated by low urate oxidase activity. PMID- 19442718 TI - Recent advances in understanding the roles of Cdk5 in synaptic plasticity. AB - The molecular composition of the postsynaptic density is modified during synaptic plasticity, which forms the molecular basis of learning and memory. Such changes in synaptic composition depends in part on the intricate regulation of phosphorylation of specific proteins via different protein kinases, including a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). However, the mechanisms underlying the involvement of Cdk5 in neural plasticity remain elusive. Recently, the identification of a number of synaptic proteins as substrates or interacting proteins with Cdk5 provides important clues on how this kinase modulates the efficacy of synaptic transmission. In this review, we summarize the recent findings to illustrate the multi-faceted roles of Cdk5 in synaptic plasticity through affecting dendritic spine formation, ion channel conductance, protein expression, and transcription in the postsynaptic neurons. Importantly, dysregulation of Cdk5 has been linked to Alzheimer's disease, which involves perturbations in synaptic functions and memory formation. Understanding the mechanisms by which Cdk5 regulates synaptic plasticity may therefore provide important insights in the design of novel therapeutic strategies for neurodegenerative diseases. PMID- 19442719 TI - The Ca2+-dependent protease Calpain A regulates Cactus/I kappaB levels during Drosophila development in response to maternal Dpp signals. AB - Regulation of NF kappaB activity is central to many processes during development and disease. Activation of NF kappaB family members depends on degradation of inhibitory I kappaB proteins. In Drosophila, a nuclear gradient of the NF kappaB/c-rel protein Dorsal subdivides the embryonic dorsal-ventral axis, defining the extent and location of mesodermal and ectodermal territories. Activation of the Toll pathway directs Dorsal nuclear translocation by inducing proteosomal degradation of the I kappaB homologue Cactus. Another mechanism that impacts on Dorsal activation involves the Toll-independent pathway, which regulates constitutive Cactus degradation. We have shown that the BMP protein Decapentaplegic (Dpp) inhibits Cactus degradation independent of Toll. Here we report on a novel element of this pathway: the calcium-dependent protease Calpain A. Calpain A knockdowns increase Cactus levels, shifting the Dorsal gradient and dorsal-ventral patterning. As shown for mammalian I kappaB, this effect requires PEST sequences in the Cactus C-terminus, implying a conserved role for calpains. Alteration of Calpain A or dpp results in similar effects on Dorsal target genes. Epistatic analysis confirms Calpain A activity is regulated by Dpp, indicating that Dpp signals increase Cactus levels through Calpain A inhibition, thereby interfering with Dorsal activation. This mechanism may allow coordination of Toll, BMP and Ca(2+) signals, conferring precision to Dorsal-target expression domains. PMID- 19442720 TI - Effects of polyoxyethylene (40) stearate on the activity of P-glycoprotein and cytochrome P450. AB - The present study was aimed to investigate the effects of polyoxyethylene (40) stearate (PS), a non-ionic surfactant, on the activity of P-glycoprotein (P-gp) and six major cytochrome P450 (CYP) isoforms. An in vitro diffusion chamber system was utilized to estimate the effects of PS concentration on the transport characteristics of Rhodamine 123 (R123) and Rhodamine 110 (R110), a standard P-gp substrate and nonsubstrate, respectively, across the excised intestinal segments of rat. Caco-2 cells were cultured to investigate the mechanisms by estimating the effects of PS on intracellular ATP levels, P-gp ATPase activity and membrane fluidity. The obtained results showed that PS inhibited P-gp mediated efflux in a concentration-dependent manner mainly by modulating substrate-stimulated P-gp ATPase activity. On the other hand, human liver microsomes were utilized to examine the inhibitive potential of PS on six major CYP isoforms. Inhibitive potential on two of these CYP2C9 and CYP2C19 was found to be clinically significant. In conclusion, PS is potentially useful as a pharmaceutical ingredient to improve the oral bioavailability of coadministered P-gp substrates and substrates for certain CYP isoforms. PMID- 19442721 TI - Design and influence of gamma-irradiation on the biopharmaceutical properties of nanoparticles containing an antigenic complex from Brucella ovis. AB - Despite vaccination campaigns, brucellosis is still one of the most common bacterial zoonosis in the world. This work describes the development of a novel formulation strategy to the delivery of the Brucella ovis antigenic extract (HS) into ovine mucosal surfaces. Thus, HS was entrapped in conventional and mannosylated poly(anhydride) nanoparticles by the solvent displacement method, and the resulting nanosystems were gamma-irradiated to accomplish the sterilization required for the ophthalmic administration route. Sterilization, at either 10 kGy or 25 kGy, did not modify the size, morphology and antigen content of the nanoparticles. Similarly, the integrity and antigenicity of the entrapped antigen were not affected by gamma-irradiation. The 25 kGy gamma-irradiation dose seemed to influence negatively the HS release from the carriers. However, and in accordance with the Pearson's correlation, all the release patterns followed a similar tendency. Furthermore, the stability of the vaccine systems on lachrymal and nasal ovine fluids, showed that gamma-irradiation had no significant effects on the vaccine systems. Since all the vaccine systems accomplished the pharmacopoeial biological tests required for gamma-irradiation doses under 25 kGy, these results are highly suggestive for the use of HS loaded poly(anhydride) nanoparticles as an efficient vaccine delivery system for brucellosis immunoprophylaxis, especially for ophthalmic administration. PMID- 19442722 TI - Improvement of oral bioavailability of flurbiprofen from flurbiprofen/beta cyclodextrin inclusion complex by action of cinnarizine. AB - Improvement of the oral bioavailability of flurbiprofen (Flu) after oral administration of flurbiprofen/beta-cyclodextrin inclusion complex (Flu/beta-CD) by the action of cinnarizine (CN) was investigated. Flu and Flu/beta-CD were administered orally to fasted rats at a dose of 20mg/kg as Flu. Thirty minutes after drug administration, CN dissolved in pH 4.0 buffer solution or pH 4.0 buffer solution alone was administered to the rats. The dose of CN was 0.17 mg/kg. Blood samples were taken from rats and Flu concentrations in plasma samples were determined by HPLC. It was found from the comparison of Flu and Flu with CN (Flu+CN) that CN had no effect on plasma concentrations of Flu after oral administration of Flu. The mean plasma levels after oral administration of Flu/beta-CD with CN (Flu/beta-CD+CN) were larger not only than those of Flu and Flu+CN but also than those of Flu/beta-CD. The value of C(max) in Flu/beta-CD+CN was significantly larger than that of Flu/beta-CD. This is considered to be caused by the action of CN as a competing agent. This mechanism was supported by the result of solubility study in which Flu solubility in beta-CD solution decreased with the addition of CN. It was found from these results that CN had strong ability as a competing agent in vivo. PMID- 19442723 TI - Comparative evaluation of polymeric and amphiphilic cyclodextrin nanoparticles for effective camptothecin delivery. AB - Camptothecin (CPT) is a potent anticancer agent. The clinical application of CPT is restricted by poor water solubility and instability under physiological conditions. Solubilization and stabilization of CPT were realized through nanoparticulate systems of amphiphilic cyclodextrins, poly(lactide-co-glycolide) (PLGA) or poly-epsilon-caprolactone (PCL). Nanoparticles were prepared with nanoprecipitation technique, whereas cyclodextrin nanoparticles were prepared from preformed inclusion complexes of CPT with amphiphilic cyclodextrins. Polymeric nanoparticles, on the other hand, were loaded with CPT:HP-beta-CD inclusion complex to solubilize and stabilize the drug. Mean particle sizes were under 275 nm, and polydispersity indices were lower than 0.2 for all formulations. Drug-loading values were significantly higher for amphiphilic cyclodextrin nanoparticles when compared with those for PLGA and PCL nanoparticles. Nanoparticle formulations showed a significant controlled release profile extended up to 12 days for amphiphilic cyclodextrin nanoparticles and 48h for polymeric nanoparticles. Anticancer efficacy of the nanoparticles was evaluated in comparison with CPT solution in dimethyl sulfoxide (DMSO) on MCF-7 breast adenocarcinoma cells. Amphiphilic cyclodextrin nanoparticles showed higher anticancer efficacy than PLGA or PCL nanoparticles loaded with CPT and the CPT solution in DMSO. These results indicated that CPT-loaded amphiphilic cyclodextrin nanoparticles might provide a promising carrier system for the effective delivery of this anticancer drug having bioavailability problems. PMID- 19442724 TI - VEGF-controlled release within a bone defect from alginate/chitosan/PLA-H scaffolds. AB - VEGF and its receptors constitute the key signaling system for angiogenic activity in tissue formation, but a direct implication of the growth factor in the recruitment, survival and activity of bone forming cells has also emerged. For this reason, we developed a composite (alginate/chitosan/PLA-H) system that controls the release kinetics of incorporated VEGF to enhance neovascularization in bone healing. VEGF release kinetics and tissue distribution were determined using iodinated ((125)I) growth factor. VEGF was firstly encapsulated in alginate microspheres. To reduce the high in vitro burst release, the microspheres were included in scaffolds. Matrices were prepared with alginate (A-1, A-2), chitosan (CH-1, CH-2) or by coating the CH-1 matrix with a PLA-H (30 kDa) film (CH-1-PLA), the latter one optimally reducing the in vitro and in vivo burst effect. The VEGF in vitro release profile from CH-1-PLA was characterized by a 13% release within the first 24h followed by a constant release rate throughout 5 weeks. For VEGF released from composite scaffolds in vitro, bioactivity was maintained above 90% of the expected value. Despite the fact that the in vivo release rate was slightly faster, a good in vitro-in vivo correlation was found. The VEGF released from CH-1 and CH-1-PLA matrices implanted into the femurs of rats remained located around the implantation site with a negligible systemic exposure. These scaffolds provided a bone local GF concentration above 10 ng/g during 2 and 5 weeks, respectively, in accordance to the in vivo release kinetics. Our data show that the incorporation of VEGF into the present scaffolds allows for a controlled release rate and localization of the GF within the bone defect. PMID- 19442725 TI - Cutaneous lycopene and beta-carotene levels measured by resonance Raman spectroscopy: high reliability and sensitivity to oral lactolycopene deprivation and supplementation. AB - Carotenoids, naturally occurring lipophilic micronutrients, possess an antioxidant activity associated with protection from damage induced by free radicals. The present study investigated an innovative non-invasive method to measure cutaneous levels of lycopene and beta-carotene and to monitor the distribution of orally administered lactolycopene in human skin and plasma. A double-blind placebo-controlled randomized study was performed in 25 volunteers, who were under a lycopene-deprived diet (4 weeks prior to study until end of the study) and orally received either lactolycopene or placebo for 12 weeks. Skin and plasma levels of lycopene and beta-carotene were monitored monthly using Raman spectroscopy and HPLC, respectively. Cutaneous levels of lycopene and beta carotene monitored by resonance Raman spectroscopy showed high reliability. Irrespective of the investigated area, cutaneous levels were sensitive to lycopene deprivation and to oral supplementation; the forehead showed the closest correlation to lycopene variation in plasma. Plasma and skin levels of lycopene were both sensitive to oral intake of lactolycopene and, interestingly, also skin levels of beta-carotene. Thus, oral supplementation with lycopene led to an enrichment of beta-carotene in human skin, possibly due to the fact that carotenoids act in the skin as protection chains, with a natural protection against free radicals. PMID- 19442726 TI - Biopharmaceutical classification of drugs using intrinsic dissolution rate (IDR) and rat intestinal permeability. AB - The solubility and dissolution rate of active ingredients are of major importance in preformulation studies of pharmaceutical dosage forms. In the present study, passively absorbed drugs are classified based on their intrinsic dissolution rate (IDR) and their intestinal permeabilities. IDR was determined by measuring the dissolution of a non-disintegrating disk of drug, and effective intestinal permeability of tested drugs in rat jejunum was determined using single perfusion technique. The obtained intrinsic dissolution rate values were in the range of 0.035-56.8 mg/min/cm(2) for tested drugs. The minimum and maximum intestinal permeabilities in rat intestine were determined to be 1.6 x 10(-5) and 2 x 10( 4)cm/s, respectively. Four classes of drugs were defined: Category I: P(eff,rat)>5 x 10(-5) (cm/s) or P(eff,human)>4.7 x 10(-5) (cm/s), IDR>1(mg/min/cm(2)), Category II: P(eff,rat)>5 x 10(-5) (cm/s) or P(eff,human)>4.7 x 10(-5) (cm/s), IDR<1(mg/min/cm(2)), Category III: P(eff,rat)<5 x 10(-5) (cm/s) or P(eff,human)<4.7 x 10(-5) (cm/s), IDR>1 (mg/min/cm(2)) and Category IV: P(eff,rat)<5 x 10(-5) (cm/s) or P(eff,human)<4.7 x 10(-5) (cm/s), IDR<1(mg/min/cm(2)). According to the results obtained and proposed classification of drugs, it is concluded that drugs could be categorized correctly based on their IDR and intestinal permeability values. PMID- 19442727 TI - Assessment of the percutaneous penetration of cisplatin: the effect of monoolein and the drug skin penetration pathway. AB - It was intended to examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different concentrations of monoolein (MO) as well as to verify the main barrier for CIS skin penetration. In vitro skin penetration of CIS was studied from propylene glycol (PG) solutions containing 0%, 5%, 10%, and 20% of MO using Franz-type diffusion cell and porcine ear skin. Pretreatment experiments with MO and experiments with skin without stratum corneum (SC) were also carried out. Skin penetration studies of CIS showed that the presence of MO doubled the drug permeation through the intact skin. However, permeation studies through the skin without SC caused only a small enhancement of CIS permeation compared to intact skin. Moreover, pretreatment of skin with MO formulations did not show any significant increase in the flux of the drug. In conclusion, MO did not act as a real penetration enhancer for CIS, but it increased the drug partition to the receptor solution improving CIS transdermal permeation. The absence of improvement in drug permeation by MO pretreatment and by the removal of SC indicates that the SC is not the main barrier for the permeation of the metal coordination compound. PMID- 19442728 TI - A comparative study of different release apparatus in generating in vitro-in vivo correlations for extended release formulations. AB - The importance of hydrodynamics in the development of in vitro-in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state. PMID- 19442729 TI - Hyaluronan concentration within a 3D collagen matrix modulates matrix viscoelasticity, but not fibroblast response. AB - The use of 3D extracellular matrix (ECM) microenvironments to deliver growth inductive signals for tissue repair and regeneration requires an understanding of the mechanisms of cell-ECM signaling. Recently, hyaluronic acid (HA) has been incorporated in collagen matrices in an attempt to recreate tissue specific microenvironments. However, it is not clear how HA alters biophysical properties (e.g. fibril microstructure and mechanical behavior) of collagen matrices or what impact these properties have on cell behavior. The present study determined the effects of varying high molecular weight HA concentration on 1) the assembly kinetics, fibril microstructure, and viscoelastic properties of 3D type I collagen matrices and 2) the response of human dermal fibroblasts, in terms of morphology, F-actin organization, contraction, and proliferation within the matrices. Results showed increasing HA concentration up to 1 mg/ml (HA:collagen ratio of 1:2) did not significantly alter fibril microstructure, but did significantly alter viscoelastic properties, specifically decreasing shear storage modulus and increasing compressive resistance. Interestingly, varied HA concentration did not significantly affect any of the measured fibroblast behaviors. These results show that HA-induced effects on collagen matrix viscoelastic properties result primarily from modulation of the interstitial fluid with no significant change to the fibril microstructure. Furthermore, the resulting biophysical changes to the matrix are not sufficient to modulate the cell-ECM mechanical force balance or proliferation of resident fibroblasts. These results provide new insight into the mechanisms by which cells sense and respond to microenvironmental cues and the use of HA in collagen-based biomaterials for tissue engineering. PMID- 19442730 TI - Effect of high-dose dexamethasone on endothelial haemostatic gene expression and neutrophil adhesion. AB - Glucocorticoid usage especially at high doses is complicated by adverse outcomes such as thrombotic events or acceleration of inflammatory response in conditions like myeloma and osteonecrosis. The mechanism(s) through which high-dose dexamethasone (HDDEXA) causes vascular injury remains unclear. We hypothesized that HDDEXA sensitizes endothelial cells (EC) to the effect of inflammatory mediators and modulates endothelial haemostatic gene expression and leukocyte adhesion. Human umbilical vein endothelial cells (HUVECs) were grown in the absence or presence of HDDEXA and were also tested in the presence or absence of tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) or thrombin. mRNA and protein expression were measured and the functional consequences of HDDEXA preconditioning on cell adhesion molecules (CAM) were determined by agonist-mediated leukocyte adhesion assay. Treatment with HDDEXA resulted in an increased induction of CAM, tissue factor and von Willebrand factor, while down regulating thrombomodulin and urokinase. HDDEXA alone had no effect on adhesion but resulted in enhanced TNF-alpha- and LPS-mediated adhesion of neutrophils. Together, these findings suggest that HDDEXA sensitizes HUVEC to the effect of inflammatory mediators and induces a pro-adhesive environment in primary EC. This finding is of importance when glucocorticoid usage is required at therapeutic high doses in patients with or without thrombotic risk factors. PMID- 19442731 TI - The Anopheles gambiae salivary protein gSG6: an anopheline-specific protein with a blood-feeding role. AB - The Anopheles gambiae salivary gland protein 6 (gSG6) is a small protein specifically found in the salivary glands of adult female mosquitoes. We report here the expression of a recombinant form of the protein and we show that in vivo gSG6 is expressed in distal-lateral lobes and is secreted with the saliva while the female mosquito probes for feeding. Injection of gSG6 dsRNA into adult A. gambiae females results in decreased gSG6 protein levels, increased probing time and reduced blood feeding ability. gSG6 orthologs have been found so far only in the salivary glands of Anopheles stephensi and Anopheles funestus, both members of the Cellia subgenus. We report here the gSG6 sequence from five additional anophelines, four species of the A. gambiae complex and Anopheles freeborni, a member of the subgenus Anopheles. We conclude that gSG6 plays some essential blood feeding role and was recruited in the anopheline subfamily most probably after the separation of the lineage which gave origin to Cellia and Anopheles subgenera. PMID- 19442732 TI - High level expression of B7H1 molecules by keratinocytes suppresses xeno- and allo-reactions by inducing type I regulatory T cells. AB - We previously reported that keratinocytes (KCs) could express B7H1 molecules and suppress allogeneic antigen-mediated immune responses through induction of IL-10 expressing T cells. The aims of this study were to investigate whether KCs could also suppress xene-antigen-mediated reactions as well as the role of B7H1 in KC induced immunosuppression. Human T cells and porcine iliac artery endothelial cells (PIECs) were co-cultured to set up the mixed lymphocyte and endothelial reaction (MLER), to which KCs were added in order to examine their inhibitory effects on lymphoproliferation. We found that KCs can suppress xenogeneic MLER in vitro. Mechanism analysis suggested that KCs can induce human type I regulatory T (Tr1) cells, which in turn potently suppress xeno- and allo-reactions partly through IL-10. The Tr1 induction was closely associated with a high level of B7H1 expression in KCs. Our results shed light on the mechanisms of antigen presenting cell dependent Tr1 differentiation, and have implications for the strategy of developing Tr1 cells to prevent clinical diseases. PMID- 19442734 TI - Synchronized gamma oscillations (30-50 Hz) in the amygdalo-hippocampal network in relation with seizure propagation and severity. AB - In this study, we demonstrate that gamma oscillations (30-50 Hz) recorded in the local field potentials (LFP) of the hippocampus are a marker of temporal lobe seizure propagation and that the level of LFP synchrony in the amygdalo hippocampal network, during these oscillations, is related to the severity of seizures. Sprague-Dawley rats were given a single systemic dose of kainic acid (KA; 6 mg/kg, i.p.) and local field potential activity (1-475 Hz) of the dorsal hippocampus, the amygdala and the neocortex was recorded. Of 135 ictal discharges, 55 (40.7%) involved both limbic structures. We demonstrated that 78.2% of seizures involving both the hippocampus and amygdala showed hippocampal gamma oscillations. Seizure duration was also significantly correlated with the frequency of hippocampal gamma oscillations (r2=0.31, p<0.01) and LFP synchrony in the amygdalo-hippocampal network (r2=0.21, p<0.05). These results suggest that gamma oscillations in the amygdalo-hippocampal network could facilitate long range synchrony and participate in the propagation of seizures. PMID- 19442733 TI - Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations. AB - Rett syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder associated with the characteristic neuropathology of dendritic spines common in diseases presenting with mental retardation (MR). Here, we present the first quantitative analyses of dendritic spine density in postmortem brain tissue from female RTT individuals, which revealed that hippocampal CA1 pyramidal neurons have lower spine density than age-matched non-MR female control individuals. The majority of RTT individuals carry mutations in MECP2, the gene coding for a methylated DNA-binding transcriptional regulator. While altered synaptic transmission and plasticity has been demonstrated in Mecp2-deficient mouse models of RTT, observations regarding dendritic spine density and morphology have produced varied results. We investigated the consequences of MeCP2 dysfunction on dendritic spine structure by overexpressing ( approximately twofold) MeCP2-GFP constructs encoding either the wildtype (WT) protein, or missense mutations commonly found in RTT individuals. Pyramidal neurons within hippocampal slice cultures transfected with either WT or mutant MECP2 (either R106W or T158M) showed a significant reduction in total spine density after 48 h of expression. Interestingly, spine density in neurons expressing WT MECP2 for 96 h was comparable to that in control neurons, while neurons expressing mutant MECP2 continued to have lower spine density than controls after 96 h of expression. Knockdown of endogenous Mecp2 with a specific small hairpin interference RNA (shRNA) also reduced dendritic spine density, but only after 96 h of expression. On the other hand, the consequences of manipulating MeCP2 levels for dendritic complexity in CA3 pyramidal neurons were only minor. Together, these results demonstrate reduced dendritic spine density in hippocampal pyramidal neurons from RTT patients, a distinct dendritic phenotype also found in neurons expressing RTT associated MECP2 mutations or after shRNA-mediated endogenous Mecp2 knockdown, suggesting that this phenotype represent a cell-autonomous consequence of MeCP2 dysfunction. PMID- 19442735 TI - The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. AB - Mutant superoxide dismutase type 1 (MTSOD1), the most common known cause of familial amyotrophic lateral sclerosis (FALS), is believed to cause FALS as a result of a toxicity of the protein. MTSOD1s with full dismutase enzymatic activity (e.g., G37R) and without any enzymatic activity (e.g., G85R) cause FALS, demonstrating that the ability of MTSOD1 to cause FALS is not dependent on the dismutase activity; however, it remains unclear whether MTSOD1 dismutase activity can influence disease phenotype. In the present study, we selectively knocked down G85R expression in particular cell types of G85R mice. Results following knockdown of G85R in motor neurons (MNs)/interneurons of G85R mice were similar to results from a published study involving knockdown of G37R in G37R mice; however, G85R knockdown in microglia/macrophages induced a prolonged early and late disease phase while G37R knockdown in the same cells only affected late phase. These results show that: (i) MN as well as non-MN expression of G85R, like G37R, has a significant effect on disease in transgenic mice - indicating the role of non-cell autonomous degeneration in both dismutase-active and inactive MTSOD1s. (ii) The effect of MTSOD1 expression in microglia/macrophages varies with different mutants, and may be influenced by the MTSOD1's dismutase activity. PMID- 19442737 TI - c-Myc regulates the coordinated transcription of brain disease-related PDCD10 SERPINI1 bidirectional gene pair. AB - Two brain disease-related genes, one coding for the protease inhibitor SERPINI1 which is down-regulated in brain tumors, and the other for the PDCD10 programmed cell death gene which is often mutated in cerebral cavernous malformation, are closely adjacent in a head-to-head configuration and separated by only 851 bp on human chromosome 3q26. The 851-bp intergenic region contains a GC-rich 175-bp minimal bidirectional promoter which is essential for transcriptional activation of the two flanking genes. The oncogenic c-Myc transcription factor was identified to bind to a non-canonical E-box element (5'-CATGCG-3') of the minimal bidirectional promoter to drive both gene expressions. Methylation at the specific C nucleotide within the E-box sequence (5'-CATG(m)CG-3'), however, would severely interfere with the binding of c-Myc to the E-box. These results suggest that c-Myc plays an important role in regulating the coordinated transcription of the PDCD10-SERPINI1 bidirectional gene pair, and is possibly involved in differential expressions of these two neighboring genes in central nervous system diseases such as brain cancer. PMID- 19442736 TI - The synaptic CT carbohydrate modulates binding and expression of extracellular matrix proteins in skeletal muscle: Partial dependence on utrophin. AB - The CT carbohydrate, Neu5Ac/Neu5Gcalpha2,3[GalNAcbeta1,4]Galbeta1,4GlcNAcbeta-, is specifically expressed at the neuromuscular junction in skeletal myofibers of adult vertebrates. When Galgt2, the glycosyltransferase that creates the synaptic beta1,4GalNAc portion of this glycan, is overexpressed in extrasynaptic regions of the myofiber membrane, alpha dystroglycan becomes glycosylated with the CT carbohydrate and this coincides with the ectopic expression of synaptic dystroglycan-binding proteins, including laminin alpha4, laminin alpha5, and utrophin. Here we show that both synaptic and extrasynaptic forms of laminin and agrin have increased binding to the CT carbohydrate compared to sialyl-N acetyllactosamine, its extrasynaptically expressed precursor. Muscle laminins also show increased binding to CT-glycosylated muscle alpha dystroglycan relative to its non-CT-containing glycoforms. Overexpression of Galgt2 in transgenic mouse skeletal muscle increased the mRNA expression of extracellular matrix (ECM) genes, including agrin and laminin alpha5, as well as utrophin, integrin alpha7, and neuregulin. Increased expression of ECM proteins in Galgt2 transgenic skeletal muscles was partially dependent on utrophin, but utrophin was not required for Galgt2-induced changes in muscle growth or neuromuscular development. These experiments demonstrate that overexpression of a synaptic carbohydrate can increase both ECM binding to alpha dystroglycan and ECM expression in skeletal muscle, and they suggest a mechanism by which Galgt2 overexpression may inhibit muscular dystrophy and affect neuromuscular development. PMID- 19442738 TI - High-throughput bisulfite sequencing in mammalian genomes. AB - DNA methylation is a critical epigenetic mark that is essential for mammalian development and aberrant in many diseases including cancer. Over the past decade multiple methods have been developed and applied to characterize its genome-wide distribution. Of these, reduced representation bisulfite sequencing (RRBS) generates nucleotide resolution DNA methylation bisulfite sequencing libraries that enrich for CpG-dense regions by methylation-insensitive restriction digestion. Here we provide an extensive, optimized protocol for generating RRBS libraries and discuss the power of this strategy for methylome profiling. We include information on sequence analysis and the relative coverage over genomic regions of interest for a representative mouse MspI generated RRBS library. Contemporary sequencing and array-based technologies are compared against sample throughput and coverage, highlighting the variety of options available to investigate methylation on the genome-scale. PMID- 19442739 TI - Cost-effective sequence-based nonhuman primate MHC class I genotyping from RNA. AB - The major histocompatibility complex (MHC) class I region of nonhuman primates (NHPs) is highly polymorphic and has undergone complex segmental duplications such that the number of expressed genes differs between individuals. In addition the relative abundance of transcripts varies more than 100-fold between NHP class I genes. This unparalleled complexity makes rapid, efficient class I genotyping difficult for NHPs. The 'gold standard' of cDNA library construction, screening and sequencing is both costly and labor-intensive. Several rapid genotyping methods have been utilized, but all require some degree of prior sequence knowledge. Here, we describe a method for sequence-based MHC class I genotyping which reduces cost by (1) pooling molecularly barcoded class I cDNA-PCR amplicons for cloning and (2) targeting sequencing of a region of concentrated polymorphism spanning the two exons encoding the peptide binding domain. This method can efficiently genotype both known and novel MHC class I alleles. In addition, full length cDNA amplicons with novel sequences can be resequenced in their entireties to expand the repertoire of characterized MHC class I sequences for NHPs. PMID- 19442740 TI - Two routes for production and purification of Fab fragments in biopharmaceutical discovery research: Papain digestion of mAb and transient expression in mammalian cells. AB - Fab (fragment that having the antigen binding site) of a monoclonal antibody (mAb) is widely required in biopharmaceutical research and development. At Centocor, two routes of Fab production and purification were used to enable a variety of research and development efforts, particularly, crystallographic studies of antibody-antigen interactions. One route utilizes papain digestion of an intact monoclonal antibody for Fab fragment production. After digestion, separation of the Fab fragment from the Fc (fragment that crystallizes) and residual intact antibody was achieved using protein A affinity chromatography. In another route, His-tagged Fab fragments were obtained by transient expression of an appropriate construct in mammalian cells, and typical yields are 1-20mg of Fab fragment per liter of cell culture. The His-tagged Fab fragments were first captured using immobilized metal affinity chromatography (IMAC). To provide high quality protein sample for crystallization, Fabs from either proteolytic digestion or from direct expression were further purified using size-exclusion chromatography (SEC) and/or ion-exchange chromatography (IEC). The purified Fab fragments were characterized by mass spectrometry, SDS-PAGE, dynamic light scattering, and circular dichroism. Crystallization experiments demonstrated that the Fab fragments are of high quality to produce diffraction quality crystals suitable for X-ray crystallographic analysis. PMID- 19442742 TI - Role of maternally derived immunity in fish. AB - Maternal immunity is of paramount importance for protection of young ones at early stage of life since the immune factors of an immunocompetent female are transferred transplacentally or through colostrum, milk or yolk to an immunologically naive neonate. Both innate and adaptive type of immunity are transferred of from mother to offspring in fishes. These factors include immunoglobulin (Ig)/antibody, complement factors, lysozymes, protease inhibitors like alpha macroglobulin, different types of lectins and serine proteases like molecules. Among different types of Ig viz. IgM, IgD, IgT/IgZ and IgM-IgZ chimera types, IgM is present in most of the teleostean fishes. In teleosts, IgM either as a reduced/breakdown product or monomeric form is usually transferred to the offsprings. The maternally derived IgM usually persists for a limited duration, exhausts within the completion of yolk absorption process, and completely disappears thereafter during larval stages. Maternal transfer of immunity which provides defense to embryo and larvae depends upon the health as well as the immune status of brood fish. The overall health status of brood fish can affect breeding performances, quality seed production and protection of offsprings. However, factors such as age, maturation, reproductive behaviour and nutrition (micro and macro-nutrients) may affect the immunity in brood fishes. Besides these, seasonal changes such as photoperiods, temperature, adverse environmental conditions, and stress conditions like handling, crowding, and water pollution/contamination can also affect the immunity of brood fishes. The maintenance of the brood stock immunity at high level during vitellogenesis and oogenesis, is utmost important for reducing mortalities at larval/post larval stages through maximum/optimum transfer of maternal immunity. Brood stock immunization prior to breeding as well as selective breeding among the disease resistant families might be the ideal criteria for producing quality seed. PMID- 19442741 TI - Molecular cloning, genomic structure, polymorphism and expression analysis of major histocompatibility complex class IIA and IIB genes of half-smooth tongue sole (Cynoglossus semilaevis). AB - Major histocompatibility complex (MHC) genes play an important role in the immune response of vertebrates. Its function is to present foreign peptide to the T cell. In order to study the function and molecular polymorphism of class II genes in teleost, the full lengths of MHC class IIA and IIB cDNA were cloned from half smooth tongue sole by homology cloning and rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR). Genomic organizations, molecular polymorphism, and expression profiles of class IIA and IIB were examined to study the function in fish. As in other teleost, four exons and three introns were identified in half-smooth tongue sole class IIA gene, five exons and four introns were identified in class IIB gene. The deduced amino acid sequence of class IIA had 27.3-69.8% identity with those of mammal and teleost. Nine class IIA alleles were identified from four individuals. Four different alleles observed in a single individual may infer the existence of two loci at least. The deduced amino acid sequence of class IIB had 7.9-71.9% identity with those of other species. Fifteen class IIB alleles were identified. Six different alleles observed in a single individual may suggest that there are at least three loci in class IIB genes. Real-time quantitative RT-PCR demonstrated that the MHC class IIA and IIB were ubiquitously expressed in twelve normal tissues. Challenge of half-smooth tongue sole with the pathogenic bacteria, Vibrio anguillarum, resulted in significant changes in the expression of MHC IIA and IIB mRNA in three tissues. PMID- 19442743 TI - Lost in localization: a minimal middle way. AB - Commentaries by Derrfuss and Mar (Derrfuss, J., Mar, R., 2009. Lost in localization: the need for a universal coordinate database. Neuroimage.) and Nielsen (Nielsen, F.A., 2009. Lost in localization: a solution with neuroinformatics 2.0? Neuroimage.) outline the need for a universal coordinate database and some possible approaches to creating one. I highlight the issue of minimal or maximal database scope and advocate a bottom-up approach to this problem. PMID- 19442744 TI - Neural correlates of risk prediction error during reinforcement learning in humans. AB - Behavioral studies have shown for decades that humans are sensitive to risk when making decisions. More recently, brain activities have been shown to be correlated with risky choices. But an important gap needs to be filled: How does the human brain learn which decisions are risky? In cognitive neuroscience, reinforcement learning has never been used to estimate reward variance, a common measure of risk in economics and psychology. It is thus unknown which brain regions are involved in risk learning. To address this question, participants completed a decision-making task during fMRI. They chose repetitively from four decks of cards and each selection was followed by a stochastic payoff. Expected reward and risk differed among the decks. Participants' aim was to maximize payoffs. Risk and reward prediction errors were calculated after each payoff based on a novel reinforcement learning model. For reward prediction error, the strongest correlation was found with the BOLD response in the striatum. For risk prediction error, the strongest correlation was found with the BOLD responses in the insula and inferior frontal gyrus. We conclude that risk and reward prediction errors are processed by distinct neural circuits during reinforcement learning. Additional analyses revealed that the BOLD response in the inferior frontal gyrus was more pronounced for risk aversive participants, suggesting that this region also serves to inhibit risky choices. PMID- 19442745 TI - Cognitive reappraisal modulates expected value and prediction error encoding in the ventral striatum. AB - In addiction, loss of prefrontal inhibitory control is believed to contribute to impulsivity. To improve cognitive therapy approaches, it is important to determine whether cognitive control strategies can generally influence reward processing at the neural level. We investigated the effects of one such strategy- namely, reappraisal (distancing from feelings)--on neural reward processing in 16 healthy subjects by utilizing event-related functional magnetic resonance imaging (fMRI). In a monetary incentive delay task, expected reward value (expecting to win 0.50 euro vs. 0.10 euro) and outcome valence (win vs. omission) were varied. An attenuation of expected value and a modulation of prediction error (PE) coding caused by distancing were found in right vs. left ventral striatum (VST) in the expectation vs. outcome period, respectively. Distancing from reward feelings recruited a right hemispheric fronto-parietal network. Moreover, self-reported reappraisal success (decrease of feelings by distancing) showed a trend toward positive correlation with activation in the rostral cingulate zone and the lateral orbitofrontal cortex, both part of the regulation network. Our results expand upon recent findings by showing that cognitive control over reward processing impacts not only the expectation period but also the reward signals in the outcome period. Moreover, increased recruitment of prefrontal reflective subsystems might enhance deliberate control over both reward processing and hedonic experience. PMID- 19442746 TI - The temporal dynamics of insula activity to disgust and happy facial expressions: a magnetoencephalography study. AB - The insula has consistently been shown to be involved in processing stimuli that evoke the emotional response of disgust. Recently, its specificity for processing disgust has been challenged and a broader role of the insula in the representation of interoceptive information has been suggested. Studying the temporal dynamics of insula activation during emotional processing can contribute valuable information pertaining to this issue. Few studies have addressed the insula's putative specificity to disgust and the dynamics of its underlying neural processes. In the present study, neuromagnetic responses of 13 subjects performing an emotional continuous performance task (CPT) to faces with disgust, happy, and neutral expressions were obtained. Magnetic field tomography extracted the time course of bilateral insula activities. Right insula activation was stronger to disgust and happy than neutral facial expressions at about 200 ms after stimulus onset. Later only at about 350 ms after stimulus onset the right insula was activated stronger to disgust than happy facial expressions. Thus, the early right insula response reflects activation to emotionally arousing stimuli regardless of valence, and the later right insula response differentiates disgust from happy facial expressions. Behavioral performance but not the insula activity differed between 100 ms and 1000 ms presentation conditions. Present findings support the notion that the insula is involved in the representation of interoceptive information. PMID- 19442747 TI - MRI estimates of brain iron concentration in normal aging: comparison of field dependent (FDRI) and phase (SWI) methods. AB - Different brain structures accumulate iron at different rates throughout the adult life span. Typically, striatal and brain stem structures are higher in iron concentrations in older than younger adults, whereas cortical white matter and thalamus have lower concentrations in the elderly than young adults. Brain iron can be measured in vivo with MRI by estimating the relaxivity increase across magnetic field strengths, which yields the Field-Dependent Relaxation Rate Increase (FDRI) metric. The influence of local iron deposition on susceptibility, manifests as MR phase effects, forms the basis for another approach for iron measurement, Susceptibility-Weighted Imaging (SWI), for which imaging at only one field strength is sufficient. Here, we compared the ability of these two methods to detect and quantify brain iron in 11 young (5 men, 6 women; 21 to 29 years) and 12 elderly (6 men, 6 women; 64 to 86 years) healthy adults. FDRI was acquired at 1.5 T and 3.0 T, and SWI was acquired at 1.5 T. The results showed that both methods detected high globus pallidus iron concentration regardless of age and significantly greater iron in putamen with advancing age. The SWI measures were more sensitive when the phase signal intensities themselves were used to define regions of interest, whereas FDRI measures were robust to the method of region of interest selection. Further, FDRI measures were more highly correlated than SWI iron estimates with published postmortem values and were more sensitive than SWI to iron concentration differences across basal ganglia structures. Whereas FDRI requires more imaging time than SWI, two field strengths, and across-study image registration for iron concentration calculation, FDRI appears more specific to age-dependent accumulation of non-heme brain iron than SWI, which is affected by heme iron and non-iron source effects on phase. PMID- 19442748 TI - Improving the reliability of manual and automated methods for hippocampal and amygdala volume measurements. PMID- 19442749 TI - Correlations and anticorrelations in resting-state functional connectivity MRI: a quantitative comparison of preprocessing strategies. AB - Resting-state data sets contain coherent fluctuations unrelated to neural processes originating from residual motion artefacts, respiration and cardiac action. Such confounding effects may introduce correlations and cause an overestimation of functional connectivity strengths. In this study we applied several multidimensional linear regression approaches to remove artificial coherencies and examined the impact of preprocessing on sensitivity and specificity of functional connectivity results in simulated data and resting state data sets from 40 subjects. Furthermore, we aimed at clarifying possible causes of anticorrelations and test the hypothesis that anticorrelations are introduced via certain preprocessing approaches, with particular focus on the effects of regression against the global signal. Our results show that preprocessing in general greatly increased connection specificity, in particular correction for global signal fluctuations almost doubled connection specificity. However, widespread anticorrelated networks were only found when regression against the global signal was applied. Results in simulated data sets compared with result of human data strongly suggest that anticorrelations are indeed introduced by global signal regression and should therefore be interpreted very carefully. In addition, global signal regression may also reduce the sensitivity for detecting true correlations, i.e. increase the number of false negatives. Concluding from our results we suggest that is highly recommended to apply correction against realignment parameters, white matter and ventricular time courses, as well as the global signal to maximize the specificity of positive resting-state correlations. PMID- 19442750 TI - Dissociable neural representations of grammatical gender in Broca's area investigated by the combination of satiation and TMS. AB - Along with meaning and form, words can be described on the basis of their grammatical properties. Grammatical gender is often used to investigate the latter as it is a grammatical property that is independent of meaning. The left inferior frontal gyrus (IFG) has been implicated in the encoding of grammatical gender, but its causal role in this process in neurologically normal observers has not been demonstrated. Here we combined verbal satiation with transcranial magnetic stimulation (TMS) to demonstrate that subpopulations of neurons within Broca's area respond preferentially to different classes of grammatical gender. Subjects were asked to classify Italian nouns into living and nonliving categories; half of these words were of masculine and the other half of feminine grammatical gender. Prior to each test block, a satiation paradigm (a phenomenon in which verbal repetition of a category name leads to a reduced access to that category) was used to modulate the initial state of the representations of either masculine or feminine noun categories. In the No TMS condition, subjects were slower in responding to exemplars to the satiated category relative to exemplars of the nonsatiated category, implying that the neural representations for different classes of grammatical gender are partly dissociable. The application of TMS over Broca's area removed the behavioral impact of verbal (grammatical) satiation, demonstrating the causal role of this region in the encoding of grammatical gender. These results show that the neural representations for different cases of a grammatical property within Broca's area are dissociable. PMID- 19442751 TI - Memory performance correlates with gray matter density in the ento-/perirhinal cortex and posterior hippocampus in patients with mild cognitive impairment and healthy controls--a voxel based morphometry study. AB - Voxel based morphometry (VBM) is a useful tool to assess differences in brain morphology between groups of patients and healthy controls. In addition, VBM enables the performance of regression analyses to determine potential correlations between performance on cognitive tests and variations in local brain morphology. Prior VBM studies investigating patients with mild cognitive impairment (MCI) have revealed different patterns of local brain atrophy. In order to extend previous findings, we investigated 18 patients with MCI and 18 age- and gender-matched healthy controls. All participants underwent extensive neuropsychological testing in addition to undergoing anatomical scanning with magnetic resonance imaging (MRI). Cohort analysis revealed bilateral decreases in gray matter density in the medial temporal lobes (MTLs) and neocortical regions of the temporal lobes in patients with MCI. Moreover, regression analyses demonstrated a correlation between immediate verbal recall and gray matter density in the left perirhinal/entorhinal cortex, while delayed free recall correlated with gray matter density in the left hippocampus. It has been proposed that performance in the immediate recall is supported by the so-called "episodic buffer", a component of working memory that contributes to the maintenance of integrated memory traces. Accordingly, our results suggest that anatomical regions associated with verbal long-term and verbal working memory are structurally segregated within the left MTL. PMID- 19442752 TI - Sub-centimeter scale functional organization in human inferior frontal gyrus. AB - Functional areas in sensory/motor cortices are usually organized, on a finer scale, in a seamless manner along related functional units that represent, for example, certain visual fields to analyze and certain body parts to control. However, fine-scale functional organization in the prefrontal cortex has rarely been reported. In the present functional magnetic resonance imaging study, we show an example of sub-centimeter scale functional organization in the posterior part of the inferior frontal gyrus (IFG) in the right hemisphere. The spatial relationship was examined in the same subjects with regard to the activations associated with response inhibition and negative feedback processing, which are known to activate similar right IFG regions. We found that these activations were segregated, the activation during response inhibition being more caudal than that during feedback processing, and that the distance between the two activations was only 8.7 mm. Examination of the two-dimensional surface mapping of individual subjects confirmed that the two activations were located in adjacent but different regions. These results provide a specific example of a pair of functionally characterized regions that are located in the close vicinity within the right IFG. PMID- 19442753 TI - Effect of compound plate composition on measurement of hERG current IC(50) using PatchXpress. AB - Inhibition of the human ether-a-go-go-related gene (hERG) potassium channel by pharmaceutical agents can lead to acquired long QT syndrome and the generation of potentially lethal arrhythmias. Higher throughput automated patch clamp systems, such as PatchXpress, can greatly increase the speed and capacity of evaluation of pharmaceutical compounds for hERG blocking activity. A factor that may affect the IC(50) value of a compound measured in this system is the composition of the multi-well compound plate. Hydrophobic compounds may adsorb to the surfaces of multi-well plates resulting in a reduction in the effective concentration of the compound delivered to the cell and altered IC(50) values. In the present study, we investigated the effects of four different compound plates--glass vials, non binding polystyrene, hydrophilic polystyrene, and polystyrene--on determination of IC(50)s for four compounds--sotalol, dofetilide, cisapride, and bepridil- which ranged in hydrophobicity. In addition, we investigated the effects of incubation time in the compound plate on determination of IC(50)s. hERG currents were measured using the PatchXpress 7000A Automated Parallel Patch Clamp System (Molecular Devices Corporation; Sunnyvale, CA) and hERG channels stably expressed in HEK293 cells. The results suggest that more hydrophobic compounds may adsorb to non-binding polystyrene, hydrophilic, and polystyrene compound plates versus glass plates, especially with increasing time on the plates, resulting in altered IC(50) values. PMID- 19442755 TI - April 2009: an outbreak of swine-origin influenza A(H1N1) virus with evidence for human-to-human transmission. AB - A swine-origin influenza A(H1N1) virus is currently responsible for an outbreak of infections in the human population, with laboratory-confirmed cases reported in several countries and clear evidence for human-to-human transmission. We provide a description of the outbreak at the end of April 2009, and a brief review of the zoonotic potential of swine influenza viruses. PMID- 19442754 TI - Signaling, physiological functions and clinical relevance of the G protein coupled estrogen receptor GPER. AB - GPR30, now named GPER1 (G protein-coupled estrogen receptor1) or GPER here, was first identified as an orphan 7-transmembrane G protein-coupled receptor by multiple laboratories using either homology cloning or differential expression and subsequently shown to be required for estrogen-mediated signaling in certain cancer cells. The actions of estrogen are extensive in the body and are thought to be mediated predominantly by classical nuclear estrogen receptors that act as transcription factors/regulators. Nevertheless, certain aspects of estrogen function remain incompatible with the generally accepted mechanisms of classical estrogen receptor action. Many recent studies have revealed that GPER contributes to some of the actions of estrogen, including rapid signaling events and rapid transcriptional activation. With the introduction of GPER-selective ligands and GPER knockout mice, the functions of GPER are becoming more clearly defined. In many cases, there appears to be a complex interplay between the two receptor systems, suggesting that estrogen-mediated physiological responses may be mediated by either receptor or a combination of both receptor types, with important medical implications. PMID- 19442756 TI - TLR2-dependent mast cell activation contributes to the control of Mycobacterium tuberculosis infection. AB - Mast Cells (MCs) express toll-like receptor 2 (TLR2), a receptor known to be triggered by several major mycobacterial ligands and involved in resistance against Mycobacterium tuberculosis (MTB) infection. This study investigated whether adoptive transfer of TLR2 positive MCs (TLR2(+/+)) corrects the increased susceptibility of TLR2(-/-) mice to MTB infection. TLR2(-/-) mice displayed increased mycobacterial burden, diminished myeloid cell recruitment and proinflammatory cytokine production accompanied by defective granuloma formation. The reconstitution of these mice with TLR2(+/+) MCs, but not TLR2(-/-), confers better control of the infection, promotes the normalization of myeloid cell recruitment associated with reestablishment of the granuloma formation. In addition, adoptive transfer of TLR2(+/+) MC to TLR2(-/-) mice resulted in regulation of the pulmonary levels of IL-beta, IL-6, TNF-alpha, enhanced Th1 response and activated CD8(+) T cell homing to the lungs. Our results suggest that activation of MCs via TLR2 is required to compensate the defect in protective immunity and inability of TLR2(-/-) mice to control MTB infection. PMID- 19442757 TI - RNA interference as a gene knockdown technique. AB - Not many scientific breakthroughs bring significant advances simultaneously in both basic research and translational applications like the discovery of RNA interference. Along with the elucidation of the RNA interference pathway and the discovery of its participation in crucial biological events, a branch of science has grown to utilize the RNA interference pathway as a biotechnology for both basic and applied research. Small interference RNA, plasmid-, and virus-encoded short-hairpin RNA are now regular reagents in the tool box of biologists to knockdown the expression of specific genes posttranscriptionally. Efforts have also been made to develop RNA interference based therapeutics into reality. Many concerns about the RNA interference technique have now been answered through research and development, although hurdles are still present. In this review, the RNA interference/microRNA pathway is briefly introduced followed with a detailed summary about the design and application of the RNA interference experiments, along with examples of the utilization of the RNA interference technology in animal cells and model organisms. Recent progresses and current concerns are also highlighted. Two techniques, namely morpholino and external guide sequence, are discussed as complementary gene knockdown technology. RNA interference technology, along with several other alternative gene knockdown techniques, is now indispensable to modern biological and medical research. PMID- 19442758 TI - The influence of thresholds on the risk assessment of carcinogens in food. AB - The risks from exposure to chemical contaminants in food must be scientifically assessed, in order to safeguard the health of consumers. Risk assessment of chemical contaminants that are both genotoxic and carcinogenic presents particular difficulties, since the effects of such substances are normally regarded as being without a threshold. No safe level can therefore be defined, and this has implications for both risk management and risk communication. Risk management of these substances in food has traditionally involved application of the ALARA (As Low as Reasonably Achievable) principle, however ALARA does not enable risk managers to assess the urgency and extent of the risk reduction measures needed. A more refined approach is needed, and several such approaches have been developed. Low-dose linear extrapolation from animal carcinogenicity studies or epidemiological studies to estimate risks for humans at low exposure levels has been applied by a number of regulatory bodies, while more recently the Margin of Exposure (MOE) approach has been applied by both the European Food Safety Authority and the Joint FAO/WHO Expert Committee on Food Additives. A further approach is the Threshold of Toxicological Concern (TTC), which establishes exposure thresholds for chemicals present in food, dependent on structure. Recent experimental evidence that genotoxic responses may be thresholded has significant implications for the risk assessment of chemicals that are both genotoxic and carcinogenic. In relation to existing approaches such as linear extrapolation, MOE and TTC, the existence of a threshold reduces the uncertainties inherent in such methodology and improves confidence in the risk assessment. However, for the foreseeable future, regulatory decisions based on the concept of thresholds for genotoxic carcinogens are likely to be taken case by-case, based on convincing data on the Mode of Action indicating that the rate limiting variable for the development of cancer lies on a critical pathway that is thresholded. PMID- 19442759 TI - Risk assessment of genotoxic mutagens with thresholds: a brief introduction. PMID- 19442760 TI - Detection of K-ras mutations in azoxymethane-induced aberrant crypt foci in mice using LNA-mediated real-time PCR clamping and mutant-specific probes. AB - Azoxymethane, a rodent colon-specific carcinogen, induce DNA damage, and causes proto-oncogene K-ras point mutations and subsequent tumor formation if DNA damage is not repaired or removed. The present study was designed to detect and characterize K-ras mutations in azoxymethane (AOM)-induced aberrant crypt foci (ACF) in mice, and determine whether dietary supplementation of selenium influences K-ras mutations frequency in ACF using a new PCR technique of locked nucleic acid-mediated real-time PCR clamping combined with mutant-specific probes. K-ras mutations were identified in 33% of AOM-induced ACF. In addition to G to A transition mutation, specific G to T transversion mutation was also identified for the first time in mouse ACF. Furthermore, selenium intake was associated with reduced ACF formation and reduced K-ras mutations rate, respectively, from 112 and 37% in mice fed control diet to 65 and 14% in mice fed selenium-containing diet (p < 0.05). This is the first report of the use of one step LNA-mediated real-time PCR clamping to detect K-ras mutations in AOM-induced colon cancer model. It is highly sensitive and can be applied to the detection of early genetic alterations in carcinogen-based animal models. PMID- 19442761 TI - Purification and biochemical characterization of lysosomal acid phosphatases (EC 3.1.3.2) from blood stream forms, Trypanosoma brucei brucei. AB - Three Acid phosphatases (ACP) were isolated and characterized from the lysosomes of blood stream forms of Trypanosoma brucei by a combination of isopynic and differential centrifugation through Ficoll, organic solvent precipitation, ion exchange on DEAE cellulose 52 and size exclusion chromatography on Sephadex G-75 columns. The purified ACP emerged as three distinct peaks (ACP I, ACP II and ACP III) with high specific activities and they moved homogeneously on 12% SDS-PAGE each as a single band with relative molecular weight of 36 kDa, 25 kDa and 45 kDa respectively. The purified enzymes were active at an optimum pH and temperature of 5.5 and 40 degrees C respectively. The enzyme activities appeared to be ACP because their activities were enhanced at low pH values and inhibited by the acid phosphatase inhibitor, sodium fluoride. ACP I and ACP II were sensitive to l tartrate while ACP III was insensitive to l tartrate. The kinetic analysis of the purified enzyme (ACP I, ACP II and ACP III) determined using para nitrophenylphosphate as substrate gave KM values of 0.2 mM, 0.15 mM and 0.5 mM. Monofunctional group sulfhydryl group inhibitors; HgCl2, and AgCl2 strongly inhibited the activity of ACP III and millimolar concentrations of dithiothreitol and iodoacetamide activated and inhibited the activity of the ACP III respectively, suggesting the involvement of thiol groups at the active site of the enzyme. Thus, differentiating it from ACP I and ACP II. The implication of these findings in relation to the pathology of trypanosomosis is discussed. PMID- 19442762 TI - A methodology for eliciting and modeling exceptions. AB - Exceptions in safety-critical systems must be addressed during conceptual design and risk analysis. We developed a conceptual model of exceptions, a methodology for eliciting and modeling exceptions, and templates for modeling them in an extension of the Object-Process Methodology (OPM)-a system analysis and design methodology and language that uses a single graphical model for describing systems, including their timing exceptions, which has been shown to be an effective modeling methodology. Using an antibiotics treatment guideline as a case study, we demonstrate the value of our approach in eliciting and modeling exceptions that occur in clinical care systems. PMID- 19442763 TI - Results from recent spaceflight experiments (1). AB - Since the flight of Sputnik 2 in 1957 the effects of weightlessness on the cardiovascular regulation are subject of physiological research. This introduction gives a short summary of the further development of cardiovascular research related to weightlessness which was subject of the contributions to the first part of this workshop. PMID- 19442764 TI - Fluorescent mesoporous silica nanotubes incorporating CdS quantum dots for controlled release of ibuprofen. AB - Mesoporous silica nanotubes (MSNTs) and amine-functionalized MSNTs (NH(2)-MSNTs) have been successfully synthesized via a sol-gel route using needle-like CaCO(3) nanoparticles as inorganic templates and post-modification with 3 aminopropyltriethoxysilane. Subsequently, the preformed nanotubes were functionalized with blue fluorescent CdS quantum dots, as demonstrated by transmission electron microscopy and confocal laser scanning microscopy. The morphology and microstructure of the produced materials were characterized by scanning electron microscopy and N(2) adsorption-desorption measurements. A comparative study of the capacity of several kinds of nanotube materials to store ibuprofen indicated that the drug-loading amount in CdS-NH(2)-MSNTs (CdS incorporated NH(2)-MSNTs) could reach up to 740 mg/g silica, similar to that in as-prepared MSNTs (762 mg/g silica) and NH(2)-MSNTs (775 mg/g silica). Drug release studies in simulated body fluid revealed that the loaded ibuprofen released from amine-functionalized systems at a significantly lower release rate as compared to that from amine-free systems, and the incorporation of CdS quantum dots had nearly no effect on the ibuprofen release process. Further study on the ibuprofen release from CdS-NH(2)-MSNTs in other media, i.e. borate buffer saline, pure water and normal saline, indicated that CdS-NH(2)-MSNTs are pH- and ion sensitive drug carriers, which should facilitate controlled drug delivery and disease therapy. PMID- 19442765 TI - Nanohydroxyapatite/poly(ester urethane) scaffold for bone tissue engineering. AB - Biodegradable viscoelastic poly(ester urethane)-based scaffolds show great promise for tissue engineering. In this study, the preparation of hydroxyapatite nanoparticles (nHA)/poly(ester urethane) composite scaffolds using a salt leaching-phase inverse process is reported. The dispersion of nHA microaggregates in the polymer matrix were imaged by microcomputed X-ray tomography, allowing a study of the effect of the nHA mass fraction and process parameters on the inorganic phase dispersion, and ultimately the optimization of the preparation method. How the composite scaffold's geometry and mechanical properties change with the nHA mass fraction and the process parameters were assessed. Increasing the amount of nHA particles in the composite scaffold decreased the porosity, increased the wall thickness and consequently decreased the pore size. The Young's modulus of the poly(ester urethane) scaffold was improved by 50% by addition of 10 wt.% nHA (from 0.95+/-0.5 to 1.26+/-0.4 MPa), while conserving poly(ester urethane) viscoelastic properties and without significant changes in the scaffold macrostructure. Moreover, the process permitted the inclusion of nHA particles not only in the poly(ester urethane) matrix, but also at the surface of the scaffold pores, as shown by scanning electron microscopy. nHA/poly(ester urethane) composite scaffolds have great potential as osteoconductive constructs for bone tissue engineering. PMID- 19442766 TI - Sonochemically prepared BSA microspheres containing Gemcitabine, and their potential application in renal cancer therapeutics. AB - This report demonstrates the formation and characterization of sonochemically prepared bovine serum albumin (BSA)-Gemzar (Gemcitabine) microspheres and shows their increased anticancer activity compared to pristine Gemzar. The amount of loaded Gemzar was determined by light absorption measurements. The BSA-Gemzar composite was analyzed and characterized by optical microscopy and scanning electron microscopy. The release kinetics of Gemzar from the proteinaceous microspheres was tested. The BSA-Gemzar composite was examined for its anticancer activity (in vitro) in renal cancer cells (RCC, 786-O cells) using [(3)H]thymidine incorporation assays. It was found that the influence of the Gemzar-loaded microspheres on the cancer cells was significantly greater than that of an equimolar concentration of pristine Gemzar. PMID- 19442767 TI - Chemodynamics underlying N-acetyl cysteine-mediated bone cement monomer detoxification. AB - Methyl methacrylate (MMA)-based bone cement monomer is cytotoxic. N-Acetyl cysteine (NAC), a cysteine derivative, may alleviate this toxicity by inactivating the monomer components with its sulfhydryl moiety. This study examined the chemical interaction dynamics between bone cement monomer and NAC resulting in detoxification of the monomer. A monomer/NAC mixture was prepared by mixing and incubating a commercially available MMA-based bone cement monomer with NAC for various time periods of 1 min, 1h, 6h and 24h. Rat bone marrow-derived osteoblastic cells were cultured with either the monomer/NAC mixture or the monomer alone. Only 17% of the cells were viable 24h after seeding in the culture containing the monomer alone. The proliferation rate and alkaline phosphatase activity of the cells were substantially reduced under this condition. In contrast, when cultured with the monomer/NAC mixture, the viability and function of the cells were improved with increasing time of monomer/NAC incubation. For instance, the monomer/NAC mixture that was pre-reacted for 1 min increased cell viability from 17% to 55%. The monomer/NAC mixture that was pre-reacted for 24h nearly completely restored cell viability, proliferation and ALP activity to the level of an untreated control culture. The DPPH radical-scavenging capacity of monomer/NAC mixture decreased with an increase in their reaction time, indicating time-dependent depletion of the NAC anti-oxidant moiety. Within the limit of this experimental condition, these data demonstrate the immediate initiation and rapid completion of bone cement monomer/NAC interaction, resulting in abrogation of the monomer's cytotoxicity. PMID- 19442768 TI - Analysis method and characterization of the antioxidant capacity of vitamin E interactive polysulfone hemodialyzers. AB - The lipophilic antioxidant vitamin E was used as a surface modifier (or coating agent) of hollow-fiber hemodialyzer membranes with the aim of increasing their biocompatibility and preventing oxidative stress, which are the main clinical drawbacks in hemodialysis (HD) therapy. At present, the redox chemistry of vitamin E-modified dialyzers is not well characterized and there is no standard method to assess the antioxidant capacity of these biomembranes under conditions that simulate those observed during HD therapy. With this study, we developed an original online method to determine the antioxidant capacity of vitamin E modified dialyzer membranes during circulation experiments. This method is based on a spectrophotometric assay known as the ferric reducing/antioxidant power assay (FRAP). The principle of FRAP and its application to the qualitative and quantitative assessment of miniaturized polysulfone (PS)-based vitamin E-modified dialyzers (PS-VE) were verified by the accurate in vitro analysis of the iron catalyzed oxidation of vitamin E. The antioxidant capacity of miniaturized PS-VE samples assessed in this study was of 14.5 microM Fe(2+), which corresponded to the transformation of nearly one-third of the vitamin E bound to the hollow-fiber membrane to its oxidation end product alpha-tocopherol quinone. This method shows good reproducibility and intra- and inter-assay precision, and can be easily adapted to determine the redox activity of every type of vitamin E-modified dialyzers during technological investigation, manufacturing control and clinical research. PMID- 19442769 TI - Ab initio elastic properties and tensile strength of crystalline hydroxyapatite. AB - We report elastic constant calculation and a "theoretical" tensile experiment on stoichiometric hydroxyapatite (HAP) crystal using an ab initio technique. These results compare favorably with a variety of measured data. Theoretical tensile experiments are performed on the orthorhombic cell of HAP for both uniaxial and biaxial loading. The results show considerable anisotropy in the stress-strain behavior. It is shown that the failure behavior of the perfect HAP crystal is brittle for tension along the z-axis with a maximum stress of 9.6 GPa at 10% strain. Biaxial failure envelopes from six "theoretical" loading tests show a highly anisotropic pattern. Structural analysis of the crystal under various stages of tensile strain reveals that the deformation behavior manifests itself mainly in the rotation of the PO(4) tetrahedron with concomitant movements of both the columnar and axial Ca ions. These results are discussed in the context of mechanical properties of bioceramic composites relevant to mineralized tissues. PMID- 19442770 TI - Genome-wide insights into the patterns and determinants of fine-scale population structure in humans. AB - Studying genomic patterns of human population structure provides important insights into human evolutionary history and the relationship among populations, and it has significant practical implications for disease-gene mapping. Here we describe a principal component (PC)-based approach to studying intracontinental population structure in humans, identify the underlying markers mediating the observed patterns of fine-scale population structure, and infer the predominating evolutionary forces shaping local population structure. We applied this methodology to a data set of 650K SNPs genotyped in 944 unrelated individuals from 52 populations and demonstrate that, although typical PC analyses focus on the top axes of variation, substantial information about population structure is contained in lower-ranked PCs. We identified 18 significant PCs, some of which distinguish individual populations. In addition to visually representing sample clusters in PC biplots, we estimated the set of all SNPs significantly correlated with each of the most informative axes of variation. These polymorphisms, unlike ancestry-informative markers (AIMs), constitute a much larger set of loci that drive genomic signatures of population structure. The genome-wide distribution of these significantly correlated markers can largely be accounted for by the stochastic effects of genetic drift, although significant clustering does occur in genomic regions that have been previously implicated as targets of recent adaptive evolution. PMID- 19442773 TI - Better than nothing or savvy risk-reduction practice? The importance of withdrawal. PMID- 19442771 TI - DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. AB - Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. ATD is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations. We first excluded IFT80 in a series of 26 fetuses and children belonging to 14 families diagnosed with either ATD or SRP type III. Studying a consanguineous family from Morocco, we mapped an ATD gene to chromosome 11q14.3-q23.1 in a 20.4 Mb region and identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. Among the five families, 3/5 were diagnosed with ATD and 2/5 included pregnancies terminated for SRP type III. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. From this study, we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group. PMID- 19442774 TI - Theory-based strategies for improving contraceptive use: a systematic review. AB - BACKGROUND: Theories and models help explain how behavior change occurs. We systematically reviewed randomized controlled trials that examined theory-based interventions for improving contraceptive use. STUDY DESIGN: We searched electronic databases for eligible trials. Primary outcomes included pregnancy and contraceptive use. We calculated the odds ratio for dichotomous outcomes and the mean difference for continuous data. RESULTS: Of 14 included trials, 10 showed positive results for a theory-based group: 2 of 10 studies with pregnancy or birth data, 4 of 9 addressing contraceptive use (for contraception) and 5 of 9 with condom use (to prevent HIV/sexually transmitted infections). An experimental group had favorable results for six of seven trials based on Social Cognitive Theory, two based on other social cognition models and two using motivational interviewing. Most interventions focused on adolescents and involved multiple sessions. CONCLUSIONS: Effects were not consistent across outcomes and comparisons. The field could benefit from thorough use of single theories and better reporting on intervention implementation. PMID- 19442775 TI - Intrauterine devices for adolescents: a systematic review. AB - BACKGROUND: The appropriateness of IUDs for adolescents remains unsettled, as does the definition of the term adolescent. Unplanned pregnancy among teenagers remains epidemic, and long-acting methods, such as IUDs, offer the promise of top tier effectiveness. STUDY DESIGN: We conducted a systematic review of the literature concerning IUD use in adolescents using MEDLINE, Popline, EMBASE and CINAHL databases. RESULTS: Six cohort studies and seven case-series reports met our inclusion criteria; none included IUDs in current use in the United States. Overall, continuation rates were high and cumulative pregnancy rates low, ranging from 2% at 6 months to 11% at 48 months. Compared with combined oral contraceptives, IUDs had similar or better continuation rates; pregnancy rates were similar at 2 years. IUD expulsion rates may be inversely related to age. CONCLUSIONS: The literature on IUD use among adolescents is scanty and obsolete. Nevertheless, published reports were generally reassuring. Randomized controlled trials and cohort studies comparing contemporary IUDs with other methods are urgently needed. PMID- 19442776 TI - Association between efficacy and body weight or body mass index for two low-dose oral contraceptives. AB - BACKGROUND: This analysis investigated the association of oral contraceptive efficacy with body weight and body mass index (BMI) for hypothesis-generating purposes. STUDY DESIGN: Data were from a randomized, parallel-group trial of 180/215/250 mcg of norgestimate (NGM)/25 mcg of ethinyl estradiol (EE) (given to 1671 women) and 1 mg of norethindrone acetate (NETA)/20 mcg of EE (given to 1139 women). Pregnancies were evaluated across BMI deciles and by BMI and body weight dichotomies. A Pearl index was calculated for each treatment group. The relative risk (RR) of pregnancy was calculated with a Cox proportional hazards model. RESULTS: The Pearl index for women who received NGM/EE was 2.36 [95% confidence interval (CI)=1.33-3.40]; for those who received NETA/EE, the Pearl index was 3.29 (95% CI=1.81-4.77). Consistent, weak positive associations between weight and pregnancy risk were found. Overall, for women with a BMI >or=25 kg/m(2) (compared with women with a BMI <25 kg/m(2)), the RR of pregnancy was 1.84 (95% CI=0.98-3.45); that for women who received NGM/EE was 1.39 (95% CI=0.57-3.40), whereas that for women who received NETA/EE was 2.49 (95% CI=1.01-6.13). For women with a body weight >or=70 kg (compared with women with a body weight <70 kg), the RR was 1.25 (95% CI=0.63-2.46); that for women who received NGM/EE was 1.41 (95% CI=0.56-3.54), whereas that for women who received NETA/EE was 1.12 (95% CI=0.40-3.12). CONCLUSION: Women in the higher body weight or BMI category showed a small increase in the risk of pregnancy with these oral contraceptives, but this increase was not statistically significant overall or for either formulation studied. PMID- 19442777 TI - Bleeding pattern, tolerance and patient satisfaction with a drospirenone containing oral contraceptive evaluated in 3488 women in Europe, the Middle East and Canada. AB - BACKGROUND: This study was conducted to assess the bleeding pattern, tolerance and patient satisfaction associated with an oral contraceptive (OC) containing 3 mg of drospirenone and 30 mcg of ethinyl estradiol under real-life conditions. STUDY DESIGN: A multicenter, prospective and observational six-cycle study was conducted in 12 countries in Europe, the Middle East and Canada. The efficacy variables included an assessment of bleeding patterns, premenstrual symptoms of water retention and patient satisfaction as determined by a visual analog scale. RESULTS: A total of 3488 women was enrolled in the study. The percentage of women with intermenstrual bleeding decreased from 27.9% at baseline to 5.4% at the end of Cycle 6, while dysmenorrhea decreased from 67% to 17.7%. Also, amenorrhea decreased from 21.3% to 7.5%. The decreases in all three parameters were statistically significant (p<.0001). Approximately 70% of the women reported abdominal bloating and/or breast tenderness at baseline and less than 38% did so at the end of Cycle 6 (p<.0001). Patient satisfaction increased for all investigated items. Upon completion of the study, 86.2% of the women answered "yes" to continuing treatment with this OC. CONCLUSION: The OC containing 3 mg of drospirenone and 30 mcg of ethinyl estradiol has beneficial effects on bleeding pattern, symptoms of water retention and patient satisfaction. PMID- 19442778 TI - A nationwide cohort study of the use of the levonorgestrel intrauterine device in New Zealand adolescents. AB - BACKGROUND: While the use of the levonorgestrel intrauterine device (LNG-IUD) is well established in the adult population, there have been no research studies specifically on the use of the LNG-IUD in adolescents. STUDY DESIGN: A nationwide cohort study of 179 adolescents in New Zealand using the LNG-IUD, by means of a follow-up questionnaire to their practitioner, was conducted to determine the indications for insertion of the LNG-IUD and to establish patterns of use, including duration of use and reasons for removal. RESULTS: The study, with a 94% response rate, demonstrated that the most common indication for use was menorrhagia (17%); 29% of adolescents had an "off-label" primary indication. There was a 1-year continuation rate of 85%. The cumulative incidence of expulsion was 8%. CONCLUSION: The results of this study should be reassuring for practitioners and adolescents considering use of the LNG-IUD. However, further research is required into the safety and efficacy of the LNG-IUD in adolescents especially in the management of off-label indications. PMID- 19442779 TI - Study on a novel copper-containing composite for contraception. AB - BACKGROUND: The copper-containing intrauterine devices (Cu-IUDs) are being increasingly used worldwide as an effective contraception for family planning. To avoid abnormal bleeding, pain, partial and complete expulsion, which are associated with the burst release of cupric ions during the first few days, a novel cross-linked composite based on polyvinyl alcohol (PVA) that contained cupric ions, but not metallic copper, was developed by our research team. STUDY DESIGN: As a logical extension of our previous work, the corrosion products and release behavior of this composite after immersing in simulated body fluid (SBF) for 1 year were studied by X-ray fluorescence spectroscopy (XRF), X-ray diffraction (XRD) and atomic absorption spectrophotometry (AAS). RESULTS: No other new elements, such as P, Cl and Ca, appeared on the surface of the composite, and no Cu(2)O was formed after immersing in SBF for 1 year, indicating that the effectiveness of copper can be greatly improved. Furthermore, no significant change on time dependence was found for the release rates of cupric ions in the composite compared with that of metallic copper, suggesting the absent burst release of cupric ions in the composite. CONCLUSION: The present in vitro long-term data suggest that this novel copper-containing composite has potential as a substitute for conventional materials used in the manufacture of IUDs. PMID- 19442781 TI - Uterine artery embolization to treat hemorrhage following second-trimester abortion by dilatation and surgical evacuation. AB - BACKGROUND: This study was conducted to review cases of second-trimester postabortal hemorrhage (PAH) occurring at a private women's health facility that were treated with uterine artery embolization (UAE). METHODS: A retrospective review was conducted on all second-trimester terminations performed at a private women's health facility between 1999 and 2006. Cases of PAH treated with UAE were reviewed in detail, reviewing progress, operative and discharge notes along with anesthesia records. RESULTS: Fifteen cases of PAH were identified among 3936 second-trimester terminations that were performed. Seven cases were identified in which UAE was used to treat PAH. Etiologies leading to hemorrhage varied in the seven cases as did the presence of coexisting factors such as infection and anatomic lesions. All cases were successfully treated by UAE, requiring no additional surgical intervention. CONCLUSION: Given the success of embolization, we offer this as an alternative to exploratory surgery and hysterectomy and as a first-line approach in cases of PAH after conservative management strategies have failed. PMID- 19442780 TI - Pharmacy worker practices related to use of misoprostol for abortion in one Mexican state. AB - BACKGROUND: Pharmacies are important sites for access to health information and medications in Mexico. Most workers are not trained in health issues and may provide inaccurate information to consumers. Misoprostol is used by women throughout Mexico for early abortion and often is purchased from pharmacies. This study aims to understand the practices of pharmacy workers when asked for advice about and medications for abortion, in particular misoprostol. STUDY DESIGN: A random sample of pharmacies in both urban and rural areas of one state of Mexico included both chain and independent pharmacies (n=169). Two mystery clients (MCs) visited the pharmacies, requesting medication for "bringing down the period" and then asking for misoprostol. MCs recorded information about the interactions following each visit in standardized formats. Bivariate comparisons were made between spontaneous and prompted discussions of misoprostol. Associations were considered statistically significant at alpha<.05. RESULTS: Ninety percent of pharmacy workers attending to the MCs discussed misoprostol as an abortifacient, either spontaneously or after being prompted by the MCs. Misoprostol was for sale in most (61%) of these pharmacies. The majority of pharmacy workers (75%) did not request a prescription. Over 75% of all pharmacy workers provided the MCs referral to trained medical providers with whom they could seek a follow-up visit. Sixteen percent of pharmacy workers suggested a regimen consistent with evidence and recommendations for using misoprostol for early abortion. Regimens that were underdosages were common, and few workers recommended a potentially harmful overdosage. Instructions about side effects and risks were rare. The price of misoprostol ranged from 900 to 1800 pesos (US$83-167) for a bottle of 28 tablets (200 mcg each) or US$4.07 per tablet, on average. CONCLUSIONS: Pharmacy workers in both urban and rural areas of Mexico are increasingly becoming aware of misoprostol as an effective abortifacient and are willing to provide the information to consumers. However, their information is limited and often inaccurate. Strategies need to be developed so that they receive timely and correct information, consistent with evidence-based recommendations. The legal context of abortion in Mexico (with restrictions in every state, except Mexico City), the restricted registration of misoprostol as a therapeutic agent only for gastric ulcers and the fact that the majority of pharmacy workers are not considered to be health workers are among the most important barriers to advances in training pharmacy workers in the correct application of misoprostol. PMID- 19442782 TI - Two routes of administration for misoprostol in the treatment of incomplete abortion: a randomized clinical trial. AB - BACKGROUND: This study was conducted to compare the safety, effectiveness and acceptability of 400 mcg sublingual misoprostol and 600 mcg oral misoprostol for treatment of incomplete abortion. STUDY DESIGN: We used an open-label randomized controlled trial conducted from July 2005 to August 2006 in a large tertiary level maternity hospital in Antananarivo, Madagascar, and a large tertiary level hospital in Chisinau, Moldova. Three hundred consenting women seeking treatment for clinically diagnosed incomplete abortion with uterine size or =100 nM deltamethrin, WT open time histograms at -40 mV were best-fit by two exponentials (time constants, 0.49+/-0.03 ms (tau(o,fast,WT)) and 5.2+/-0.5 ms (tau(o,slow,WT)). The population of long duration openings and tau(o,slow,WT) increased when the concentration of deltamethrin was raised, but tau(o,fast,WT) was unaffected. Qualitatively similar results were obtained for the M874 channel, but with > or =10 nM deltamethrin. Deltamethrin also caused a negative shift in the relationships between channel opening probability (P(op)) and membrane potential and first latency and membrane potential, suggesting that the pyrethroid binds to the closed channel. Selectivity for Na was increased by the pyrethroid (10 microM, WT; 1 microM, mutant). PMID- 19442820 TI - The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. AB - The endoplasmic reticulum (ER) is a principal site for protein synthesis, protein folding, calcium storage, and calcium signaling. Thapsigargin (TG), an inducer of ER stress, inhibits ER-associated Ca(2+)-ATPase and disrupts Ca(2+) homeostasis. ER stress plays an important pathogenetic role in Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, and prion protein diseases. This study was conducted to evaluate the protective mechanisms of Scrophularia ningpoensis (SN) extracts and chemicals on TG-stimulated U-87MG cells. In this study, the recovery activities of E-harpagoside (EHA), harpagide (HA), 8-O-E-p-methoxycinnamoylharpagide (MH), aucubin (AB), cinnamic acid (CA), p coumaric acid (pCA), p-methoxycinnamic acid methyl ester (MME), caffeic acid (CFA), ferulic acid (FA), and (E)-p-methoxycinnamic acid (MA) on TG-stimulated U 87MG cells were evaluated. The results revealed that SN, MME, CFA, and MH showed considerable recovery effects. Therefore, SN, MME, CFA, and MH were selected to evaluate the gene expression profile of U-87MG cells by using microarray analysis and real-time RT-PCR. The results of this analysis revealed that cell cycle, proliferation, protein folding, and anti-apoptosis-related genes were up regulated in SN, MME, CFA, and MH-treated U-87MG cells. In addition, significant decreases in apoptosis, the MAPK signaling pathway, and mitochondria-related gene expressions were observed in SN-, MME-, CFA-, and MH-treated U-87MG cells. Thus, SN, MME, CFA, and MH might affect neurodegenerative diseases. PMID- 19442821 TI - A multianalyte profile of serum proteins to screen for toxicological effects of anticholinesterase insecticides in the rat. AB - The development of high throughput biochemical screens could be useful to assess the broad spectrum of physiological effects of environmental toxicants. To explore the prospect of using a screen in an in vivo exposure scenario, we applied a commercially available multianalyte profile (MAP) of 58 serum biomarkers to rats exposed acutely to two anticholinesterase insecticides, chlorpyrifos (CHP) and carbaryl (CAR). Male, Long-Evans rats were dosed orally with 30 mg/kg CHP, 75 mg/kg CAR or the corn oil vehicle. Doses were selected based on their equivalent physiological effects (hypothermia and reduced motor activity). The animals were terminated 24h or 7 days after dosing. Serum was collected and analyzed for 58 biomarkers consisting primarily of cytokines, chemokines, and a few hormones. There were changes in six analytes (four up, two down) following CHP and eight analytes (five up, three down) following CAR at 24h. There were significant changes in only two biomarkers when measured 7 days after dosing with CHP. Overall, the MAP detected a broad spectrum of unique effects for CHP and CAR. It is concluded that the MAP is a useful tool to screen for in vivo effects of environmental toxicants and its use could lead to the discovery of novel mechanisms of action. PMID- 19442822 TI - Neurotoxic and immunotoxic effects of Indole-3-butyric acid on rats at subacute and subchronic exposure. AB - This study was carried out to investigate the neurotoxic and immunotoxic effects of Indole-3-butyric acid (IBA), a plant growth regulator (PGR), on rats at subacute and subchronic exposure. The neurotoxic effects of IBA were evaluated by measuring the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Biomarkers selected for immunotoxic monitoring were the activities of adenosine deaminase (ADA) and myeloperoxidase (MPO) in various tissues of rats exposed to 25 and 50 ppm dosages of IBA for 20 and 45 days. Results showed that the administrations of IBA decreased AChE and BChE activities in some tissues of the rats treated with both dosages and periods of IBA. With regard to the immunotoxic effects, ADA activity significantly decreased whereas MPO activity increased after subacute and subchronic exposure with both dosages in most of the tissues of rats compared with controls. The observations presented led us to conclude that the administrations of IBA at subacute and subchronic exposure decreased AChE, BChE and ADA activities whereas increased MPO activity in various tissues of rats. This may reflect the potential role of these parameters as useful biomarkers for toxicity of IBA. PMID- 19442823 TI - Intrathecal delivery of fluorescent labeled butyrylcholinesterase to the brains of butyrylcholinesterase knock-out mice: visualization and quantification of enzyme distribution in the brain. AB - Exogenously delivered butyrylcholinesterase (BChE) has proven to be an efficient bioscavenger against highly toxic organophosphorus poisons and nerve agents. The scavenger properties of BChE when delivered via intramuscular, intravenous, subcutaneous, or intraperitoneal routes are limited to the body's peripheral sites because the 340 kDa enzyme does not cross the blood-brain barrier (BBB). Overcoming the BBB is an important step toward evaluating the neuroprotective properties of BChE within the central nervous system (CNS). This study examines the feasibility of delivering BChE to the brain and spinal cord by intrathecal (IT) injection. Mice completely devoid of BChE were injected intrathecally with either BChE (80 units) that was labeled with near-infrared fluorescent dye (BChE/IRDye) or a molar equivalent amount of carboxylate dye. The BChE/IRDye and carboxylate dye were tracked using an in vivo imaging system demonstrating the real-time distribution of BChE in the brain and the residence time in the brain and spinal cord through 25 h post-dosing. BChE/IRdye levels in the brain peaked at 6h post-dosing. BChE enzyme activity was quantified in plasma and brain sections by BChE activity assays of plasma and of perfused tissues. Average BChE activity levels were 0.6 units/g in the brains of mice treated with BChE/IRDye at 4h post-dosing. Intense fluorescent signal in the cortex, dentate gyrus and ventricles of the brain at 25 h post-dosing was visualized by confocal microscopy and the presence of BChE was confirmed with activity assays of frozen sections. This procedure proved to be an efficient, safe and rapid method to deliver BChE to the CNS of mice, providing a research tool for determining neural protection by BChE following OP exposure. PMID- 19442824 TI - Co-treatment with riluzole, a neuroprotective drug, ameliorates the 3 acetylpyridine-induced neurotoxicity in cerebellar Purkinje neurones of rats: behavioural and electrophysiological evidence. AB - Riluzole has been shown to possess neuroprotective effects in a variety of neurological and animal model of diseases, including motor diseases. However, the mechanism(s) by which riluzole preserves the intrinsic electrophysiological characteristics of neuronal membrane has not been fully delineated. Ataxia is a clinical manifestation of disturbance in coordinated motor activity, which may be caused by cerebellar impairment. Here, the in vivo neuroprotective effect of riluzole on the intrinsic activity of Purkinje cells (PCs) in a rat model of cerebellar ataxia induced by 3-acetylpyridine (3-AP) was studied. Behavioural assessment tests, histological examination and whole cell patch clamp recording under current clamp conditions were used to explore the possible protective effect of riluzole against induction of ataxia with 3-AP treatment. Combined treatment with riluzole and 3-AP not only almost completely prevented the neuronal degeneration in cerebellar Purkinje cells layer but also the development of ataxia, which occurred following injection of 3-AP alone and partially improved the motor behaviour in comparison with ataxic rats. The normal firing behaviour and action potential characteristics of Purkinje neurones were preserved. The amplitude of both fast after hyperpolarization potential (fAHP) and post train after hyperpolarization potential, a marker of slow AHP (sAHP), along with the duration of post train AHP, which play an important role in regulating the firing behaviour were restored to the control conditions. These findings suggest that riluzole-induced neuroprotection may be mediated at least in part by activation of Ca(2+)-dependent K(+) channel function. PMID- 19442825 TI - The intranigral injection of tissue plasminogen activator induced blood-brain barrier disruption, inflammatory process and degeneration of the dopaminergic system of the rat. AB - Tissue-type plasminogen activator (tPA) is the only drug approved for the treatment of thromboembolic stroke, but it might lead to some neurotoxic side effects. tPA is a highly specific serine proteinase, one of the two principal plasminogen activators and one of the three trypsin-like serine proteinases of the tissue kallikrein family. We have observed that tPA injection in the SN leads to the degeneration of the dopaminergic neurons in a dose-dependent manner, without affecting the GABAergic neurons. We also found that tPA injected in the substantia nigra of rats produced the disruption of the blood-brain barrier (BBB) integrity, the induction of microglial activation, the loss of astroglia and the expression of aquaporin 4 (AQP4), as well as an increase in the expression of NMDA receptors and the brain derived neurothrophic factor (BDNF). All these effects, along with the changes produced in the phosphorylated forms of several MAP kinases and the transcription factor CREB, and the increase in the expression of nNOS and iNOS observed under our experimental conditions, could be involved in the loss of dopaminergic neurons. PMID- 19442826 TI - BNIP3 up-regulation and mitochondrial dysfunction in manganese-induced neurotoxicity. AB - The central nervous system (CNS) appears to be the critical target of manganese (Mn), and neurotoxicity has been the focus of most of the health effects of manganese. In brain, the mechanism underlying the Mn-induced cell death is not clear. We have previously demonstrated that NFkappabeta induction and the activation of nitric oxide synthase through reactive oxygen species (ROS) represent a proximate mechanism for Mn-induced neurotoxicity. In this study, an immortalized dopaminergic cells were used to characterize the cell death signaling cascade activated by manganese. Exposure to Mn resulted in a time and concentration-related loss of cell viability as observed by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and live/dead cell assay. Mn increased BNIP3 expression within 3h and continued to increase up to 24h exposure followed by a concentration-related apoptotic death as determined by TUNEL. Further, Mn treatment resulted in accumulation of reactive oxygen species and mitochondrial dysfunction with loss of mitochondrial membrane potential and release of cytochrome c. Antioxidants significantly reduced Mn-induced BNIP3 expression and attenuated cell death, demonstrating the role of oxidative stress in BNIP3 induction. Blocking BNIP3 up-regulation with a transcription or a translational inhibitor reduced the response to manganese. Cell death by manganese was reduced in the presence of CsA (PT pore inhibitor). In addition, knockdown of BNIP3 by small interfering RNA (siRNA) improved mitochondrial recovery and reduced neuronal cell loss suggesting that constitutive expression of BNIP3 plays a role in Mn-induced neurotoxicity by regulating mitochondrial functions. These findings indicate a potential detrimental role of BNIP3 in manganese-induced neuronal cell death. PMID- 19442827 TI - Hyperalgesia induced by oral stavudine administration to rats does not depend on spinal neuronal cell death, or on spinal or systemic inflammatory cytokine secretion, or metabolic dysregulation. AB - To investigate possible mechanisms of the hyperalgesia induced by the nucleoside reverse transcriptase inhibitor (NRTI) stavudine in rats, we examined neuronal death and inflammatory cytokine secretion in the spinal cord, and cytokine and lactate secretion in the plasma. Stavudine (50 mg kg(-1)) or placebo was administered orally to Sprague-Dawley rats once daily for three or six weeks. In one group, rats' responses to a blunt noxious mechanical stimulus applied to their tails were recorded before and at the end of the period of stavudine or placebo administration. Spinal cords excised from these rats after three and six weeks of stavudine or placebo administration were examined for neuronal necrosis and apoptosis. In a second group of rats, plasma and spinal cord samples collected after three and six weeks of placebo or stavudine administration were examined for changes in CINC-1, IL-6, adiponectin (plasma only) and lactate (plasma only) concentration. Daily stavudine administration induced mechanical hyperalgesia within three weeks, which was sustained until week six, but the hyperalgesia was not associated with neuronal apoptosis or necrosis, or elevated IL-6 concentrations in the spinal cord. The spinal cord concentration of CINC-1 increased, but only after six weeks of stavudine administration, when the hyperalgesia had been established for over three weeks. Stavudine administration did not affect the plasma concentration of IL-6, CINC-1, adiponectin or lactate. Thus, neither peripheral nor central inflammatory cytokine secretion, or neuronal death, or metabolic dysregulation contributed to the development of hyperalgesia in our model of stavudine-induced hyperalgesia in rats. PMID- 19442828 TI - Labile iron pool and ferritin content in developing rat brain gamma-irradiated in utero. AB - This study was aimed to assess the content of total Fe, Ferritin (Ft) and labile Fe pool (LIP) in developing rat brain exposed in utero to 1 Gy of gamma irradiation. A significant increase (2.3-fold) in the total Fe content of the fetal rat brain irradiated in utero was observed from 1 to 4h post-irradiation, as compared to the content in non-irradiated brain. Ft was analyzed by immunoblotting. The Ft protein was composed by 20 kDa subunits. According to the analysis of the band density in the Western blot, the Ft content decreased by 77+/-15% 2h after gamma-irradiation, as compared to the values in non-irradiated samples. The effect of gamma-irradiation on the LIP was studied by both electron paramagnetic resonance (EPR) and by a fluorescence technique employing calcein (CA). A reduction on the LIP was detected at 2h post-irradiation, independently of the methodology employed for the assay. Since NO content increased in the same time frame of LIP decreasing, a protective role for NO is suggested in fetal rat brain exposed to gamma-irradiation. The data presented in this work are the first experimental evidence suggesting that, as part of the network of the cellular response to limit irradiation-dependent injury, a complex interaction between Fe and NO could be triggered. PMID- 19442829 TI - Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration. AB - Diadenosine tetraphosphate (AP(4)A), two adenosine moieties bridged by four phosphates, is an endogenous purinergic ligand found in brain. Previous studies have shown that AP(4)A reduced neurodegeneration caused by the dopaminergic neurotoxin 6-hydroxydopamine in rat striatum and substantia nigra. The purpose of this study was to determine whether AP(4)A is protective against methamphetamine (MA)-mediated toxicity. Primary neuronal cultures were prepared from rat embryonic (E14-E15) ventral mesencephalic tissue. Cultures treated with 2mM MA exhibited decreased tyrosine hydroxylase (TH) immunoreactivity and increased cleaved caspase-3 immunoreactivity and TUNEL labeling. All these changes were lessened by pretreatment with AP(4)A. The protective effect of AP(4)A was also found in vivo. Adult Sprague-Dawley rats were injected with AP(4)A (25 microg/20 microl) or vehicle intracerebroventricularly followed by 4 doses of MA (5 or 10 mg/kg), given subcutaneously every 2h. Administration of MA reduced locomotor activity 1 day after injection, which was significantly antagonized by the pretreatment with AP(4)A. Using immunohistochemical analysis, TH fiber density at the substantia nigra pars reticulata was found reduced while cleaved caspase-3 immunoreactivity in striatum was increased after MA treatment; these responses were also significantly antagonized by AP(4)A. Taken together, our data show that AP(4)A has protective effects against MA-mediated toxicity both in vitro and in vivo. The mechanism of action involves suppression of MA-induced apoptosis. PMID- 19442830 TI - Acute sodium tungstate inhalation is associated with minimal olfactory transport of tungsten (188W) to the rat brain. AB - Olfactory transport of represents an important mechanism for direct delivery of certain metals to the central nervous system (CNS). The objective of this study was to determine whether inhaled tungsten (W) undergoes olfactory uptake and transport to the rat brain. Male, 16-week-old, Sprague-Dawley rats underwent a single, 90-min, nose-only exposure to a Na(2)(188)WO(4) aerosol (256 mg W/m(3)). Rats had the right nostril plugged to prevent nasal deposition of (188)W on the occluded side. The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 3, 7, and 21 days post exposure. Gamma spectrometry (n=7 rats/time point) was used to compare the levels of (188)W found on the left and right sides of the nose and brain and blood to determine the contribution of olfactory uptake to brain (188)W levels. Respiratory and olfactory epithelial samples from the side with the occluded nostril had significantly lower end-of-exposure (188)W levels confirming the occlusion procedure. Olfactory bulb, olfactory tract/tubercle, striatum, cerebellum, rest of brain (188)W levels paralleled blood (188)W concentrations at approximately 2-3% of measured blood levels. Brain (188)W concentrations were highest immediately following exposure, and returned to near background concentrations within 3 days. A statistically significant difference in olfactory bulb (188)W concentration was seen at 3 days post-exposure. At this time, (188)W concentrations in the olfactory bulb from the side ipsilateral to the unoccluded nostril were approximately 4-fold higher than those seen in the contralateral olfactory bulb. Our data suggest that the concentration of (188)W in the olfactory bulb remained low throughout the experiment, i.e., approximately 1-3% of the amount of tungsten seen in the olfactory epithelium suggesting that olfactory transport plays a minimal role in delivering tungsten to the rat brain. PMID- 19442831 TI - Evaluation of pathways involved in pentachlorophenol-induced apoptosis in rat neurons. AB - Pentachlorophenol (PCP) (C(6)HCl(5)O) is a synthetic toxic organochloride fungicide for humans which exhibit neurotoxic properties. In the present research, we describe the potential pathways implicated in PCP-induced apoptosis in an acute model of toxicity in rat cerebellar granule neurons (CGNs). In our experiments, acute exposure of CGNs to micromolar concentrations of PCP induced the transcriptional activity of genes related to the classical apoptosis pathway (caspase 3, caspase 8, Bad), oxidative stress and glutathione metabolism (glutathione peroxidase-1, catalase, glutathione-S-transferase-3 and superoxide dismutase-1), and mitogenic response (cyclin D1, cdk2, cdk4, cdkn2b). Results from Western blot also shown significative increases in the expression of cyclins D1, E and A and cdk4. The mitogenic response was also related to a significative increase in the phosphorylation of retinoblastoma protein (Rb). PCP would cause apoptosis up-regulating the transcriptional activity of p53 gene and also increasing their activation by phosphorylation, concomitant with a decrease in the sirtuin 1 content. In conclusion, acute exposure of CGNs to PCP induces the classical p53 apoptotic pathway, promotes the up-regulation of several genes related to oxidative stress and the over-expression of molecules involved in the cell cycle control. PMID- 19442832 TI - A single exposure to alcohol during brain development induces microencephaly and neuronal losses in genetically susceptible mice, but not in wild type mice. AB - Maternal alcohol abuse during pregnancy can damage the fetal brain and lead to fetal alcohol syndrome (FAS). Despite public warnings discouraging alcohol use during pregnancy, many pregnant women continue to drink intermittently because they do not believe that occasional exposures to alcohol can be harmful to a fetus. However, because of genetic differences, some fetuses are much more susceptible than others to alcohol-induced brain injury. Thus, a relatively low quantity of alcohol that may be innocuous to most fetuses could damage a genetically susceptible fetus. Neuronal nitric oxide synthase (nNOS) can protect developing mouse neurons against alcohol toxicity by synthesizing neuroprotective nitric oxide. This study examined whether a single exposure to alcohol, which causes no evident injury in wild type mice, can damage the brains of mice genetically deficient for nNOS (nNOS-/- mice). Wild type and nNOS-/- mice received intraperitoneal injections of alcohol (0.0, 2.2, or 4.4mg/g body weight) either as a single dose on postnatal day (PD) 4 or as repeated daily doses over PD4-9. Brain volumes and neuronal numbers within the hippocampus and cerebral cortex were determined on PD10. Alcohol exposure on PD4-9 restricted brain growth and caused neuronal death in both strains of mice, but the severity of microencephaly and neuronal loss were more severe in the nNOS-/- mice than in wild type. The 4.4 mg/g alcohol dose administered on PD4 alone caused significant neuronal loss and microencephaly in the nNOS-/- mice, while this same dose caused no evident injury in the wild type mice. Thus, during development, a single exposure to alcohol can injure a genetically vulnerable brain, while it leaves a wild type brain unaffected. Since the genes that confer alcohol resistance and vulnerability in developing humans are unknown, any particular human fetus is potentially vulnerable. Thus, women should be counseled to consume no alcohol during pregnancy. PMID- 19442833 TI - Exposure to methamidophos at adulthood elicits depressive-like behavior in mice. AB - Epidemiologic studies have suggested that organophosphate exposure is associated with an increased risk of depression and suicide. Considering that the neurobiological basis of this association is not well understood, in the present study we evaluated the depressive-like behavior of Swiss mice subchronically exposed to the organophosphate methamidophos at adulthood. From postnatal days 60 to 89 (PN60-PN89), one of two concentrations of methamidophos [higher dose (HiD): 5.25 microg/ml; lower dose (LoD): 1.31 microg/ml] or vehicle was administered in the drinking water. Immobile behavior, an animal model of depressive behavior, was assessed in the forced swimming and tail suspension tests either during (PN88) or after (PN99) the exposure period. On the subsequent day (PN89 or PN100), the Rota-rod and endurance swimming tests were used to evaluate motor performance. Brain acetylcholinesterase activity was quantified. During exposure, the LoD group presented increased immobility in the tail suspension test when compared to controls. The HiD group presented increased immobility in the forced swimming test when compared to LoD and control groups, an effect that emerged after cessation of exposure. There were no motor performance alterations. During exposure, acetylcholinesterase activity was inhibited in the HiD (43%) and LoD (15%) groups. After exposure, enzyme activity was reduced (25%) only in the HiD group. There were no signs of systemic toxicity. There were no correlations between acetylcholinesterase activity and behavioral measures. Our results indicate that methamidophos at doses below the threshold for systemic toxicity induces depressive-like behavior in adult mice. PMID- 19442834 TI - Organizational effects of DDE on brain vasotocin system in male Japanese quail. AB - p,p'-DDE, or ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl), is the main metabolite of the pesticide DDT, or 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane. It is an androgen receptor antagonist and testosterone hydroxylase modulator that is also more persistent than its parent compound. In a previous study we demonstrated that embryonic exposure to different doses of p,p'-DDE accelerated onset of puberty in females and reduced male reproductive behavior. In the present study we investigated the long-term effects of the exposure to p,p'-DDE on the differentiation of male Japanese quail (Coturnix japonica) limbic circuits related to male copulatory behavior: the parvocellular vasotocin (VT) system. We observed a decrease in the density of VT-immunoreactive fibers within the medial preoptic nucleus, bed nucleus of the stria terminalis, and lateral septum in p,p'-DDE-treated birds, while no differences could be detected in the magnocellular neurons of the supraoptic nucleus. In particular the lowest dose of p,p'-DDE causes the highest decrease of VT immunoreactivity. This study provides further evidence for VT system sensitivity towards endocrine disrupting chemicals and demonstrates that the VT system may be an appropriate and sensitive biomarker for early p,p'-DDE exposure in birds. PMID- 19442835 TI - Comparing fish-mercury exposed Amazonian children: Should not we consider thimerosal-preserved vaccines? PMID- 19442836 TI - PCR detection of African horse sickness virus serogroup based on genome segment three sequence analysis. AB - A nested reverse transcriptase (RT) polymerase chain reaction (RT-PCR), for rapid detection of African horse sickness virus (AHSV) double-stranded ribonucleic acid (dsRNA) in cell culture and tissue samples, was developed and evaluated. Using an outer pair of primers (P1 and P2), selected from genome segment three of AHSV serotype 6 (AHSV-6), the RT-PCR-based assay resulted in amplification of a 890 base pair (bp) primary PCR product. RNAs from the nine vaccine strains of AHSV, and a number of AHSV field isolates including the Central African isolates of AHSV-9 and AHSV-6, propagated in cell cultures, were detected by this assay. A second pair of nested primers (P3 and P4) was used to produce a 240-bp PCR product. The RT-PCR described below detected as little as 0.1 fg of AHSV RNA, which is equivalent to six viral particles. The nested amplification confirmed the integrity of the primary PCR product and increased the sensitivity of the PCR assay by at least 1000-fold. Application of this RT-PCR assay to clinical samples resulted in direct detection of AHSV dsRNA from blood and a variety of tissue samples collected from equines infected experimentally and naturally. The specificity studies indicated that the primary or the nested PCR products were not amplified from, closely related orbiviruses including, bluetongue virus (BTV) prototypes serotypes 1, 2, 4, 10, 16 and 17; epizootic hemorrhagic disease of deer virus (EHDV) prototypes serotypes 1 and 2; EHDV-318, Sudanese isolates of palyam serogroup of orbiviruses; total nucleic acid extracts from uninfected Vero cells; or unfractionated blood from horses and donkeys that were AHSV seronegative and virus isolation negative. The RT-PCR provides a valuable tool for study of the epidemiology of AHSV and can be recommended for rapid diagnosis during an outbreak of the disease among susceptible equines. PMID- 19442837 TI - Immunoglobulin G antibody response in children and adults with acute dengue 3 infection. AB - Using a serological test, different criteria have been established for classifying a case as primary or secondary dengue virus infection. Considering the dengue epidemiological situation in Cuba, IgG antibody response to dengue virus infection in serum samples from children and adults with a dengue 3 infection, in Havana city during the 2001-2002 epidemic was evaluated. Samples were collected on days 5-7 of fever onset and tested by an ELISA inhibition. A total of 713 serum samples positive for IgM antibody, 93 from children and 620 from adult patients were studied. Serum samples collected from healthy blood donors and patients not infected with dengue were included as controls. An IgG primary infection pattern was observed in sera collected from children, with titers of < or =20 in the 89.3% of the patients, while both, a primary and secondary patterns were observed in sera collected from adult patients with titers of < or =20 (13.4%) and > or =1280 (83.9%), respectively. These results permitted the definition of a primary or secondary case of dengue virus infection in serum samples collected during the acute phase of dengue virus infection. PMID- 19442838 TI - Detection of HIV-1 in alternative specimen types using the APTIMA HIV-1 RNA Qualitative Assay. AB - Peripheral blood mononuclear cells (PBMCs), saliva, seminal plasma, and dried blood spots were evaluated as specimen types for the APTIMA HIV-1 RNA Qualitative Assay (APTIMA HIV-1 Assay), which employs a target capture step to recover HIV-1 specific sequences from complex specimen types. Analytical sensitivity studies were carried out using samples that were either diluted or eluted with a buffered detergent and spiked with different concentrations of HIV-1 ranging from 1 to 10,000 copies/mL. PBMC samples spiked with HIV-1 had comparable analytical sensitivity to HIV-1 spiked plasma with a 95% limit of detection of 13.1 and 17.2 copies/mL, respectively. Analytical sensitivity in seminal plasma specimens diluted 1:5 and saliva diluted 1:2 was comparable to HIV-1 spiked dilution buffer alone. Whole blood and dried blood spot specimens spiked with HIV-1 had equivalent reactivity at 250 copies/spot (5000 copies/mL). However, the 95% limit of detection values were significantly different (293.7 copies/mL for whole blood and 2384 copies/mL for dried blood spot specimens). No significant effect on analytical sensitivity was observed when one HIV-1 positive dried blood spot punch was pooled with up to 9 HIV-1 negative dried blood spot punches. Together, these studies demonstrate that the APTIMA HIV-1 RNA Qualitative Assay can be used to process a diverse array of specimen types with minimal impact on analytical sensitivity for most specimen types. PMID- 19442839 TI - Surround optical fiber immunoassay (SOFIA): an ultra-sensitive assay for prion protein detection. AB - We describe the development of a new technology (SOFIA) and demonstrate its utility by establishing a sensitive and specific assay for PrP(Sc). SOFIA is a surround optical fiber immunoassay which is comprised of a set of specific monoclonal antibodies and comprehensive capture of high energy fluorescence emission. In its current format, this system is capable of detecting less than 10 attogram (ag) of hamster, sheep and deer recombinant PrP. Approximately 10 ag of PrP(Sc) from 263 K-infected hamster brains can be detected with similar lower limits of PrP(Sc) detection from the brains of scrapie-infected sheep and deer infected with chronic wasting disease. These detection limits allow protease treated and untreated material to be diluted beyond the point where PrP(C), non specific proteins or other extraneous material may interfere with PrP(Sc) signal detection and/or specificity. This not only eliminates the issue of specificity of PrP(Sc) detection but also increases sensitivity since the possibility of partial PrP(Sc) proteolysis is no longer a concern. SOFIA will likely lead to early antemortem detection of transmissible encephalopathies and is also amenable for use with additional target amplification protocols. SOFIA represents a sensitive means for detecting specific proteins involved in disease pathogenesis and/or diagnosis that extends beyond the scope of the transmissible spongiform encephalopathies. PMID- 19442840 TI - Simultaneous detection of enterovirus 70 and coxsackievirus A24 variant by multiplex real-time RT-PCR using an internal control. AB - Epidemics of acute hemorrhagic conjunctivitis are always explosive and extensive, and have been recognized as a serious international public health problem. Enterovirus 70 and coxsackievirus A24 variant have been identified as the major etiological agents in acute hemorrhagic conjunctivitis outbreaks worldwide. A novel multiplex real-time RT-PCR assay was developed for simultaneous detection, identification and quantitation of enterovirus 70 and coxsackievirus A24 variant. The specificity, sensitivity and reproducibility of the method were analyzed and 125 clinical samples were tested using this method. No cross-reactivity with other enteroviruses strains was detected. The detection limits achieved were 10 copies/tube of enterovirus 70 and 100 copies/tube of coxsackievirus A24 variant respectively, and the addition of the internal control does not compromise the sensitivity or specificity. One hundred and twenty five clinical samples were tested and the results were consistent with the results obtained by using virus isolation followed by neutralization and sequencing of VP1 region. Due to its high specificity, sensitivity and elimination of false negative results by the internal control, this assay is suitable for both research applications and rapid clinical diagnosis of enterovirus 70 and coxsackievirus A24 variant. PMID- 19442841 TI - Non-infectious plasmid engineered to simulate multiple viral threat agents. AB - The aim of this study was to design and construct a non-virulent simulant to replace several pathogenic viruses in the development of detection and identification methods in biodefense. A non-infectious simulant was designed and engineered to include the nucleic acid signature of VEEV (Venezuelan Equine Encephalitis virus), Influenza virus, Rift Valley Fever virus, Machupo virus, Lassa virus, Yellow Fever virus, Ebola virus, Eastern Equine Encephalitis virus, Junin virus, Marburg virus, Dengue virus, and Crimean-Congo virus, all in a single construct. The nucleic acid sequences of all isolates available for each virus species were aligned using ClustalW software in order to obtain conserved regions of the viral genomes. Specific primers were designed to permit the identification and differentiation between viral threat agents. A chimera of 3143 base pairs was engineered to produce 13 PCR amplicons of different sizes. PCR amplification of the simulant with virus-specific primers revealed products of the predicted length, in bands of similar intensity, and without detectable unspecific products by electrophoresis analysis. The simulant described could reduce the need to use infectious viruses in the development of detection and diagnostic methods, and could also be useful as a non-virulent positive control in nucleic acid-based tests against biological threat agents. PMID- 19442842 TI - An improved method of DNA isolation suitable for PCR-based detection of begomoviruses from jute and other mucilaginous plants. AB - A relatively quick and inexpensive modified cetyl trimethylammonium bromide method for extraction of DNA from leaf materials containing large quantities of mucilage is described. The modification including use of more volume of extraction buffer and dissolving crude nucleic acid pellet in 1 M NaCl, reduced markedly the viscosity of the mucilage and thus in the final purification step yielded a larger quantity of mucilage-free DNA suitable for subsequent PCR-based detection of begomoviruses. The method was standardized with jute samples with yellow mosaic disease and validated with different other mucilaginous-hosts with low titre of begomoviruses. DNA isolated using this method showed consistency in yield and compatibility with PCR for detection of begomoviruses from different mucilaginous plant species. The method was compared for efficacy with other reported methods and it was found to be superior over the existing methods described for isolation of DNA from mucilaginous hosts. Thus the method described could be used on a wider scale for reliable and consistent detection of begomoviruses from mucilaginous hosts for characterization and variability study. PMID- 19442843 TI - A neutralization assay for HIV-2 based on measurement of provirus integration by duplex real-time PCR. AB - Specific, effective and rapid neutralization assays are crucial for the development of an HIV vaccine based on the stimulation of neutralizing antibodies and the development of such an assay for the human immunodeficiency virus-2 (HIV 2) is described. Virus neutralization was measured as the reduction of provirus integration using a duplex real-time PCR with high efficiency (99.4%). This PCR uses primers and a probe specific for the proviral LTR. Amplification and quantitative analysis of the cellular GAPDH gene was carried out in parallel to control for toxic or growth-inhibitory components in the sera. The neutralization assay was used to screen sera from 23 HIV-2 infected patients. 21 sera were able to neutralize HIV-2(60415K), 20 sera neutralized HIV-2(7312A) and 7 sera cross neutralized HIV-1 IIIB. In contrast, when 14 of these sera were tested in parallel with a conventional neutralization assay based on a p27Gag capture ELISA, only one was found to neutralize HIV-2(60415K) and 11 to neutralize HIV 2(7312A) compared with 12 and 13 sera respectively using the PCR-based assay. PMID- 19442844 TI - A reverse transcription-PCR assay to distinguish the four genogroups of male specific (F+) RNA coliphages. AB - Goals of reducing fecal contamination in recreational, drinking, shellfishing and other waters and accurately assessing risk from exposure can best be attained if tools to distinguish between sources of pollution are available. The male specific RNA coliphage (FRNA) genogroups display a trend of source specificity. Reverse transcription-PCR (RT-PCR) can be effectively used for genotyping if specific primer sets are designed to be capable of identifying all members within each genogroup. In this study genogroup-specific primer sets were designed using a minimum of 5 to a maximum of 10 complete phage genome sequences from strains in each genogroup. With these primers and employing a heat-release procedure that eliminated the need for RNA purification an RT-PCR method for genotype identification of FRNA phages was developed. The four genogroup-specific primer sets generated discrete PCR amplicon sizes from a variety of environmental FRNA phage strains. Limits of detection, cross-reactivity and/or non-specific binding to strains from other genogroups were evaluated. PMID- 19442845 TI - A sensitive direct sequencing assay based on nested PCR for the detection of HBV polymerase and surface glycoprotein mutations. AB - Drug resistance is a crucial problem emerging frequently during treatment of hepatitis B, resulting in treatment failure and progression of liver damage. A direct sequencing method based on a nested PCR was established to detect mutations in samples with low viral load. Primers were designed to obtain an amplicon encompassing the A, B, C, D and E functional domains of HBV polymerase. Fifty-five samples were tested, containing HBV DNA ranging from 19 to 1700 IU/mL. Sixteen samples were also tested by the commercially available assay INNO-LiPA HBV DR v2. Sequencing was successful for all samples, and mutations were detected in 24/55 (43.6%). When used in parallel with DR v2, concordant results were found in 8/16 samples. In the eight discordant cases, four were resolved by sequencing and not by DR v2, and four had differences in the mutation patterns. Direct sequencing was able to show pol mutations not revealed by DR v2, such as rtV214A, rtQ215H/S, and rtM250V. Genotype and env variations were also established. This highly sensitive sequencing protocol, providing valuable sequencing data from samples with a low viral load, is suitable for detection of mutations at the very early signs of failure of treatment, thereby allowing to maximize the success of early treatment changes. PMID- 19442846 TI - Detection and quantitation of fowl adenovirus genome by a real-time PCR assay. AB - The purpose of the study was to develop a highly sensitive real-time polymerase chain reaction (PCR) assay to detect and quantitate fowl adenovirus (FAdV) DNA in chicken tissues, using FAdV-9 as a model. The assay had a dynamic range of 7 logs and minimum detection limit of 9.4 viral genome copies. It was shown to be highly specific, as tissues from uninfected chickens and other viral genomes, such as those of Marek's disease virus, fowlpox virus and infectious laryngotracheitis virus did not produce positive signal. The sensitivity of the real-time PCR was comparable with nested PCR and it was 100 times more sensitive than the conventional PCR. The assay was validated by testing DNA from tissues of chickens infected with FAdV-9 collected at different days post-infection. FAdV-9 DNA was detected in liver, bursa of Fabricius and cecal tonsil tissues in a range of 10(2)-10(7) copies per 100 ng of total DNA. High amounts of viral DNA were present in the cecal tonsils for a week after inoculation making this tissue an ideal sample source for the diagnosis of FAdV infection. This assay is an excellent research and diagnostic tool that provides high sensitivity, specificity and rapid post-PCR analyses. PMID- 19442847 TI - Development of SYBR Green real-time RT-PCR for rapid detection, quantitation and diagnosis of unclassified bovine enteric calicivirus. AB - Unclassified bovine enteric calicivirus (BECV) is a newly recognized bovine enteric calicivirus that differs from bovine norovirus, and which causes diarrhea in the small intestines of calves. To date, methods such as real-time reverse transcription-polymerase chain reaction (RT-PCR) have not been developed for the rapid detection, quantitation and diagnosis of BECV. Presently, a BECV-specific SYBR Green real-time RT-PCR assay was evaluated and optimized. Diarrheic specimens (n=118) collected from 2004 to 2005 were subjected to RT-PCR, nested PCR and SYBR Green real-time RT-PCR. By conventional RT-PCR and nested PCR, 9 (7.6%) and 59 (50%) samples tested positive, respectively, whereas the SYBR Green assay detected BECV in 91 (77.1%) samples. Using BECV RNA standards generated by in vitro transcription, the SYBR Green real-time RT-PCR assay sensitively detected BECV RNA to 1.1 x 10(0)copies/microl (correlation coefficiency=0.98). The detection limits of the RT-PCR and nested PCR were 1.1 x 10(5) and 1.1 x 10(2)copies/microl, respectively. These results indicate that the SYBR Green real time RT-PCR assay is more sensitive than conventional RT-PCR and nested PCR assays, and has potential as a reliable, reproducible, specific, sensitive and rapid tool for the detection, quantitation and diagnosis of unclassified BECV. PMID- 19442848 TI - Error assessment in recombinant baculovirus titration: evaluation of different methods. AB - The success of baculovirus/insect cells system in heterologous protein expression depends on the robustness and efficiency of the production workflow. It is essential that process parameters are controlled and include as little variability as possible. The multiplicity of infection (MOI) is the most critical factor since irreproducible MOIs caused by inaccurate estimation of viral titers hinder batch consistency and process optimization. This lack of accuracy is related to intrinsic characteristics of the method such as the inability to distinguish between infectious and non-infectious baculovirus. In this study, several methods for baculovirus titration were compared. The most critical issues identified were the incubation time and cell concentration at the time of infection. These variables influence strongly the accuracy of titers and must be defined for optimal performance of the titration method. Although the standard errors of the methods varied significantly (7-36%), titers were within the same order of magnitude; thus, viral titers can be considered independent of the method of titration. A cost analysis of the baculovirus titration methods used in this study showed that the alamarblue, real time Q-PCR and plaque assays were the most expensive techniques. The remaining methods cost on average 75% less than the former methods. Based on the cost, time and error analysis undertaken in this study, the end-point dilution assay, microculture tetrazolium assay and flow cytometric assay were found to be the techniques that combine all these three main factors better. Nevertheless, it is always recommended to confirm the accuracy of the titration either by comparison with a well characterized baculovirus reference stock or by titration using two different methods and verification of the variability of results. PMID- 19442849 TI - Comparison of immunoassay and real-time PCR methods for the detection of Jembrana disease virus infection in Bali cattle. AB - A sensitive diagnostic assay for the detection of infections with the bovine lentivirus Jembrana disease virus (JDV) is required in Indonesia to control the spread of Jembrana disease. Immunoassays are used routinely but are compromised by cross-reactive epitopes in the capsid (CA) protein of JDV and the genetically related bovine immunodeficiency virus (BIV). JDV gag-specific primers were tested in a real-time PCR assay to detect proviral DNA in peripheral blood mononuclear cells from 165 cattle from the Tabanan district of Bali. JDV-specific amplicons were detected in 9% of the cattle and only 33% of the real-time PCR positive cattle were seropositive. The delayed seroconversion that occurs after infection with JDV could explain the low concordance between these assays but other factors may be responsible. BIV proviral DNA was not detected in any of the PBMC DNA samples. A high concordance value of 98.6% was found between the JDV plasma derived antigen Western blot and the JDV p26-his recombinant protein ELISA. Only 21% of the seropositive cattle had detectable levels of proviral DNA suggesting that the proviral load in recovered cattle is low. A combination of real-time PCR and JDV p26-his ELISA is recommended for the detection of infection with JDV in Indonesia. PMID- 19442850 TI - High-quality virus images obtained by transmission electron microscopy and charge coupled device digital camera technology. AB - The introduction of digital cameras has led to the publication of numerous virus electron micrographs of low magnification, poor contrast, and low resolution. Described herein is the methodology for obtaining highly contrasted virus images in the magnification range of approximately 250,000-300,000x. Based on recent advances in charged couple device (CCD) digital camera technology, methodology is described for optimal imaging parameters for using CCD cameras mounted in side- and bottom-mount position of electron microscopes and the recommendation of higher accelerating voltages, larger objective apertures, and small spot size. The authors are concerned with the principles of image formation and modulation, advocate a better use of imaging software to improve image quality, and recommend either pre- or post-acquisition adjustment for distributing pixel intensities of compressed histograms over the entire range of tonal values. PMID- 19442851 TI - Quantitation of human immunodeficiency virus type 1 viral load in plasma using reverse transcriptase activity assay at a district hospital laboratory in Botswana: a decentralization pilot study. AB - Roche COBAS Amplicor monitor version 1.5 assay is considered gold standard for viral load monitoring in Botswana. Due to its demand for elaborate infrastructure, viral load testing has been confined to the national HIV reference laboratories. Cavidi ExaVir Load version 2 assay was considered as a potential alternative to decentralize viral load testing to the rural/remote hospital laboratories and thus increase access to therapy. This study compared the performance of ExaVir Load v2 assay at a district hospital laboratory in Serowe and COBAS Amplicor monitor v1.5 assay at the Botswana Harvard HIV Reference Laboratory using quality assessment samples and plasma from HIV positive individuals. ExaVir Load v2 and COBAS Amplicor monitor v1.5 assays had very good agreement; Kappa statistic 0.951. The COBAS Amplicor monitor v1.5 and ExaVir Load v2 assays detected HIV-1 RNA in 84 and 86 samples but did not detect HIV-1 RNA in 221 and 219 samples, respectively. The two assays detected HIV-1 RNA concordantly in 82 samples and were strongly correlated (r=0.8554, P<0.0001). ExaVir Load v2 assay provided a simple and reliable alternative viral load system that is adaptable to district hospital laboratories. The cost per test is less than RT-PCR. The ExaVir Load v2 systems have since been placed in four more district and primary hospital laboratories. PMID- 19442852 TI - A quantitative, real-time polymerase chain reaction assay for beak and feather disease virus. AB - PCR-based assays for the detection of BFDV DNA are in widespread use throughout the world. Quantitative real-time PCR assays are extremely sensitive and have the advantages over standard PCR assays that they do not require post-reaction processing to visualise PCR products and can quantify the amount of DNA present in a sample. This study describes a quantitative real-time PCR assay for the detection of BFDV DNA, using primers designed to amplify a conserved 81 bp fragment of ORFV1 and SYTO9, a fluorescent intercalating dye. A synthetic oligonucleotide was used to make standard curves for the quantitation of viral load in blood and feather preparations. The assay was very sensitive, with a detection limit of 50 copies/microL. The assay was developed using DNA extracts from the feathers of 10 different species of birds which had tested BFDV-positive previously and was validated with blood and feather samples from corellas vaccinated with an experimental BFDV vaccine, then challenged with live virus. Viral DNA was detected consistently in the blood of all control (non-vaccinated) birds and in some vaccinated birds. Contamination of the environment with feather dander from BFDV-infected birds meant that feather preparations used for the haemagglutination assay were unreliable for the detection and quantitation of viral excretion. Nonetheless, the assay should prove to be a useful and sensitive test for the detection of viral DNA in a range of samples. PMID- 19442853 TI - Human single chain monoclonal antibody that recognizes matrix protein of heterologous influenza A virus subtypes. AB - Matrix protein (M1) is predominant and has pivotal role in the influenza A virus replication and assembly. It is therefore an attractive target for antiviral drugs, siRNA studies, and therapeutic antibodies. Nevertheless, therapeutic antibody that interferes with the M1 multiplex function has never been developed. In this study, human single monoclonal antibody fragments (HuScFvs) to M1 were generated. Full length recombinant M1 (rM1) was produced from cDNA prepared from genome of highly pathogenic avian influenza virus, A/H5N1. The rM1 was used as an antigen in phage bio-panning to select phage clones displaying HuScFv from a human antibody phage display library. Several phage clones displaying HuScFv bound to the rM1 and harboring the respective huscfv gene inserts were isolated. RFLP experiments revealed multiple DNA banding patterns which indicated epitope/affinity diversity of the HuScFv. The HuScFv were tested for their binding to native M1 of homologous and heterologous influenza A viruses using ELISA as well as incorporating immunostaining and immunofluorescence studies with infected MDCK cells. One such protein produced from a selected phage clone blocked binding of M1 to viral RNA. The HuScFv in their in vivo functional format, e.g. cell-penetrating molecules, should be developed and tested as a broad spectrum anti-A/influenza. PMID- 19442854 TI - A recombinant protein-based ELISA for detecting antibodies to foot-and-mouth disease virus serotype Asia 1. AB - A recombinant protein-based ELISA was evaluated for detecting antibodies to foot and-mouth disease virus (FMDV) serotype Asia 1. The recombinant protein (rP13C) was derived from the P1 precursor and 3C protease genes that were cloned into a single expression vector and expressed in insect cells. This protein elicited a low titer of FMDV neutralizing antibodies in pigs. Its utility as a diagnostic antigen was explored in a blocking ELISA using monoclonal antibodies. The rP13C ELISA yielded higher endpoint titers than the liquid phase blocking (LPB) ELISA and virus neutralization test performed on sera from goats challenged with FMDV post-vaccination. The rP13C ELISA correctly scored the FMD international reference weak positive serum. The relative sensitivity between the rP13C ELISA and LPB ELISA was equivalent for vaccinated sera. With this comparable sensitivity, the rP13C ELISA exhibited a specificity of 99.7% for domestic naive swine, bovine and caprine sera. This report demonstrates that an ELISA using recombinant proteins has the potential to replace the LPB ELISA using an inactivated FMDV antigen as a simple and robust serological tool for screening antibodies to FMDV serotype Asia 1. PMID- 19442855 TI - Assessment of sensitivity and specificity of first, second, and third generation EIA for the detection of antibodies to HIV-1 in oral fluid. AB - The performances of three blood-based immunoassays test kits were compared with regard to their ability to detect HIV-1 antibody in oral fluid. It was found that these three kits differ in their ability to detect HIV-1 antibody. Notably, a third generation EIA which has been shown to possess superior sensitivity for antibody detection in plasma appears to possess no sensitivity advantage for detecting HIV-1 antibody in oral fluid. PMID- 19442856 TI - Generation and characterization of JCV permissive hybrid cell lines. AB - JC virus (JCV) is a human neurotropic polyomavirus whose replication in the central nervous system induces the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV particles have been detected primarily in oligodendrocytes and astrocytes of the brains of patients with PML and in the laboratory its propagation is limited to primary cultures of human fetal glial cells. In this short communication, the development of a new cell culture system is described through the fusion of primary human fetal astrocytes with the human glioblastoma cell line, U-87MG. The new hybrid cell line obtained from this fusion has the capacity to support efficiently expression of JCV and replication of viral DNA in vitro up to 16 passages. This cell line can serve as a reliable culture system to study the biology of JCV host-cell interaction, determine the mechanisms involved in cell type specific replication of JCV, and provide a convenient cell culture system for high throughput screening of anti-viral agents. PMID- 19442857 TI - Length variability of telomeric repeat sequences of human herpesvirus 6 DNA. AB - The telomeric repeat sequences (TRS) located near both ends of human herpesvirus 6 (HHV-6) genome are unique structures of unknown function among human herpesviruses. The goal of the present study was to investigate the variability of TRS copy number among different laboratory strains and HHV-6-infected clinical specimens regarding the two variants A and B of HHV-6. DNA obtained from infected cells was submitted to a PCR assay designed to amplify the part of genome containing TRS specifically either for HHV-6A or HHV-6B. Amplicons were analyzed by electrophoresis on agarose gel with ethidium bromide staining and nucleotide sequencing. The number of TRS copies was highly variable among the distinct laboratory strains and clinical specimens studied, ranging from 15 up to more than 180. However, this number was constant for a given strain after serial propagation in cell cultures as well as in different samples from the same subject. This permitted to detect a mixed infection with two distinct strains of HHV-6A within the same patient. The PCR-based analysis of HHV-6 TRS has a limited sensitivity but is highly specific, which provides the opportunity to include it in the set of molecular tools dedicated to the study of HHV-6 epidemiology. PMID- 19442858 TI - Two real-time RT-PCR assays of classical swine fever virus, developed for the genetic differentiation of naturally infected from vaccinated wild boars. AB - Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), a disease notifiable to the Office International des Epizooties (OIE). A live marker vaccine would be the ultimate choice for controlling CSF, which enables serological and genetic differentiation of vaccine from wild type CSFV. Recently, a marker vaccine CP7_E2alf has been reported [Koenig, P., Lange, E., Reimann, I., Beer, M., 2007. CP7_E2alf: a safe and efficient marker vaccine strain for oral immunisation of wild boar against classical swine fever virus (CSFV). Vaccine 25, 3391-3399]. A vaccine-specific TaqMan real-time RT-PCR assay was developed and evaluated, and a second, wild type-specific assay was modified from an established one in such a way that both can be performed in two wells side-by-side in a microplate in a single run. The detection limit is 50 viral RNA copies per reaction for the vaccine-specific assay, and 20 copies per reaction for the wild type assay. The two assays have been shown to be highly specific and reproducible, with potential application for genetic differentiation of wild type CSFV from the marker vaccine CP7_E2alf in wild boar vaccination programs. PMID- 19442859 TI - Prevalence and risk factors for type 2 diabetes mellitus in the Chinese adult population: the InterASIA Study. AB - AIMS: To estimate the prevalence of impaired fasting glucose and type 2 diabetes mellitus (T2DM) and identify the potential risk factors of T2DM in Chinese adults. METHODS: A nationally representative sample of 15,236 Chinese adults aged 35-74 years was selected by 4-stage random stratified sampling in 2000-2001 for present study. RESULTS: The prevalence of T2DM in Chinese adults aged 35-74 years was 5.49% (it was 2.51% in China, 1994). The odds ratios (ORs) (95% confidence interval [CI]) for developing T2DM were 2.14 (1.08-4.22) for family history of diabetes, 3.90 (1.39-10.94) for waist-to-hip ratio (WHR) (0.83-0.91 vs. <0.83), 4.82 (1.43-16.28) for WHR (>or=0.92 vs. <0.83), and 3.14 (1.42-6.92) for triglycerides (TG) level (>or=200mg/dl vs. <150 mg/dl) among men but 2.74 (1.14 6.62) for family history of diabetes, 1.92 (1.04-3.56) for hypertension, 3.37 (1.67-6.77) for TG level (150-199 mg/dl vs. <150 mg/dl), and 3.79 (1.62-8.91) for TG level (>or=200mg/dl vs. <150mg/dl) among women. CONCLUSIONS: The prevalence of T2DM in Chinese adults has increased as compared with previous data for China. An effective intervention program regarding T2DM should focus on lifestyle modification and weight reduction. PMID- 19442860 TI - Community-based population data indicates the significant alterations of insulin resistance, chronic inflammation and urine ACR in IFG combined IGT group among prediabetic population. AB - AIMS: To investigate alterations of insulin resistance (IR), chronic inflammation and urine albumin-to-creatinine ratio (ACR) in Chinese community-based prediabetic population. MATERIALS AND METHODS: 252 prediabetics [prediabetes (PD), including impaired fasting glucose (IFG), 91; impaired glucose tolerance (IGT), 123; IFG+IGT, 38] and 38 newly diagnosed-diabetics (NDDM) aged over 35 years older were screened from 2336 community individuals. 123 age and gender matched individuals with normal glucose tolerance (NGT) were selected as controls. Serum adiponectin, interleukin-6 (IL-6) levels and urine ACR were determined, HOMA-IR and Gutt's index were calculated to evaluate IR and insulin sensitivity, respectively. RESULTS: The data displayed significant difference of serum adiponectin, IL-6, ACR and Gutt's index among PD, NDDM and NGT groups. Adiponectin level and Gutt's index decreased, but IL-6 level and ACR increased gradually among NGT, PD and NDDM groups (P<0.01). Unlike adiponectin and IL-6, ACR analysis indicates a gradual increase from NGT, IFG, IGT, IFG+IGT to NDDM individuals (P<0.01). Gutt's index showed significant difference between IFG and NDDM, IFG+IGT and NDDM (P<0.01), but HOMA-IR index did not. CONCLUSIONS: IR, chronic inflammation and endothelial dysfunction dose exist in prediabetic individuals, especially in IFG+IGT population. Gutt's index and ACR might seem to be more sensitive than adiponectin and HOMA-IR index as IR and chronic inflammation maker in prediabetic population. PMID- 19442861 TI - [Occupational health of immigrant workers in Spain [ITSAL Project]: key informants survey]. AB - OBJECTIVE: To describe the characteristics, working conditions, and occupational health situation of immigrant workers in Spain through key informants. METHOD: We performed a qualitative, exploratory and descriptive study using indepth interviews carried out in 2006. Organizations and associations working with immigrant collectives in Alicante, Barcelona, Huelva, Madrid and Valencia were identified and the most representative and accessible entities in each location were selected. Fortythree interviews were performed with key informants from 34 different organisms. A narrative content analysis was performed. RESULTS: Informants described difficulties in having health problems recognized as workrelated, due to irregular and precarious employment, employers' and insurance companies' reluctance, and immigrants' lack of knowledge. Informants coincided in reporting that the occupational risks for immigrant workers did not differ from those affecting Spanish workers in the same occupations and circumstances. However, exposure to occupational risks was exacerbated in immigrants because of their greater presence in unqualified jobs and their economic need to prolong working hours. Immigrants had little knowledge of their occupational health and safetyrelated rights, although some informants detected an increase in empowerment in this area, mostly through greater participation in trade unions. CONCLUSIONS: This first step allowed us to identify some of the general factors influencing the health and safety of immigrant workers in Spain. This information will be used in a longterm, ongoing research project [Project Immigration, Work and Health (Proyecto Inmigracion, Trabajo y Salud [ITSAL]), which aims to evaluate occupational health problems in inmigrants working in Spain through both qualitative and quantitative methods. PMID- 19442862 TI - [Changes in the use of hormone replacement therapy after an educational intervention aimed at women and prescribers]. AB - OBJECTIVE: To describe changes in prescription of hormone replacement therapy (HRT) in Asturias (Spain) after the publication of the results of the Women's Health Initiative and the Million Women Study and following the recommendations of the Spanish Drugs Agency to women and prescribers (2004-2005). METHODS: We performed a quasiexperimental study with no control group. The data used consisted of sales of HRT products from 1996 to 2003 (preintervention period). In 2004 and 2005, annual sales of HRT products and the percentage of women using HRT among the population aged 50-59 years were analyzed. To analyze trends in costs, we used the price of each product in pesetas until 2001 and in euros thereafter. RESULTS: Sales of HRT increased until 2001. Total sales declined by 73.6% between 2001 and 2005. The decrease between 2004 and 2005 (49.1%) was twice that observed between 2002 and 2003 (24.5%). An estimated 17.2% of women aged 50-59 years old were using HRT in 1996 compared with 4.1% in 2005. The total pharmaceutical cost related to HRT showed a similar decrease, although sales of Boltin (tibolone) increased by two-fold. CONCLUSIONS: Systematic and independent educational interventions aimed at women in the general population and prescribers are both effective and necessary. The HRT epidemic and its health costs, as well as the shift to tibolone prescription and the adverse effects of this drug, should be investigated nationwide. PMID- 19442863 TI - [Use of European Quality of Life-5 Dimensions (EQ-5D) questionnary to value the health related quality of life variation because of influenza]. AB - OBJECTIVE: To describe self-perceived health status and health-related quality of life (HRQoL) in healthy individuals of working age, to measure changes due to influenza infection, and to evaluate the effect of influenza infection on HRQoL in monetary terms. METHOD: We performed a descriptive observational study through questionnaires administered to 50 patients of working age infected with the influenza virus during the epidemiologic year 2004-2005 and living in private homes of the city of Logrono (Spain). The patients completed the questionnaires twice: with and without influenza. The dimensions and HRQoL indicators of the European Quality of Life-5 Dimensions (EQ-5D) questionnaire were evaluated. HRQoL utility indices were used to calculate lost quality-adjusted life years (QALYs). RESULTS: On average, the reduction in the HRQoL utility index caused by influenza infection was between 0.37 and 0.65, on a scale from 0 (death) to 1 (perfect health). An influenza epidemic in 100,000 individuals could imply a loss of 137 QALYs, which in monetary terms could represent 2,722,609euro. CONCLUSIONS: The EQ 5D dimension most negatively affected by influenza was <> while the least affected dimension was <>. Influenza causes substantial losses in HRQoL among the population of working age. The results of the sensitivity analysis of the monetary effects of influenza infection yielded intervals showing a range of more than 5 times the mean value. PMID- 19442864 TI - [Indoor air and bathing water pollution in indoor swimming pools in Guipuzcoa (Spain)]. AB - OBJECTIVE: To describe levels of pollutants found in indoor swimming pools in Guipuzcoa (Basque Country, Spain), both in the bathing water and in the air, and to study the association between these pollutants and other variables related to ventilation systems and the use of installations. METHODS: Of the 35 indoor swimming pools registered in Guipuzcoa, the 20 most frequently used by swimmers were studied. Each installation was sampled on two nonconsecutive days. Free and combined chlorine and trihalomethane levels were measured in the water, while total chlorine and chloroform levels were measured in the air. Carbon dioxide (CO(2)) was measured as an indicator of air renewal. RESULTS: The average chlorine level in the air was 0.4 mg/m(3) and that of chloroform was 22 microg/m(3). In all the swimming pools, free and combined chlorine levels were within the permitted values. The average chloroform level in bathing water was 13.7 microg/l. Chloroform levels in the air could be reasonably predicted (R(2) = 0.85), the predictive factors being chloroform levels in the water, CO(2) concentrations, and the number of bathers on the day of measurement. CONCLUSIONS: Levels of pollutants in the water and in the air of swimming pools in Guipuzcoa were lower than those reported in other studies. However, 20% of the installations exceeded the concentration of total chlorine in the air proposed as a reference value to protect swimmers carrying out intense activities (0.5 mg/m(3)). PMID- 19442865 TI - [Use and evaluation of the health care services and the antirretroviral medication in HIV diagnosed people]. AB - AIM: To analyze the use or not of antirretrovirals (ART) human inmunodeficiency virus (HIV) diagnosed people in relation to the utilization and evaluation of the health care services and sociodemographic profiles. METHODS: The data was collected with a questionnaire to 108 HIV people, in the city of Granada (Spain) between July and September 2005. Participants were contacted from three sources: infectious diseases service, HIV's nongovernmental association and from the street through peers. RESULTS: The mean age was 40 years, and the participants knew that they were seropositives since a mean of 12 years ago. At the moment of the interview, 55.6% consumed illegal drugs (cannabis not included), and 63.9% were former injecting drug users. In relation to ART, 25% did not take it, 15.7% were totally adherent, and 59.3% were in treatment but failed in the intake of the medication as prescribed. In general, participants have a positive and accurate perception of ART. The group of the adherents showed the best scores and those who do not take ART the lowest, in almost the totality of the studied variables. CONCLUSION: The present study suggests that is important continuing to improve the access to the health and social resources, to implement strategies of motivation for patients who have been many years in HIV treatment and to integrate in the health care system social excluded HIV positive people. PMID- 19442866 TI - [On the ultimate goal of management in Spanish hospitals]. AB - The European Foundation for Quality Management (EFQM) is the most introduced model in Spanish hospitals. The main target of this model is the internal and external client's satisfaction. The model of strategic management Balanced Scorecard (BSC) facilitates the alignment between management and the mission and vision of hospitals. For this reason, we propose a model of integrated management: EFQM-BSC. In order to obtain the items of this research, a survey was conducted among managers of Spanish hospitals on a battery of 46 indicators, selected from the EFQM model, and prioritised and included in the four perspectives of the BSC model. The research shows two possible models of hypothesis: the client model, where the final effect would be the client perspective (patient, staff and society's satisfaction), or the financial model, where the final effect would be the economic and financial results. After a reliability, dimension analysis and a discriminant analysis, it was obtained more consistent indicators which better explain each perspective. The relationship among these perspectives are determined by structural equations based on methods of partial least squares. The research confirms that the client model reflects a better consistency in its hypothesis. PMID- 19442867 TI - Dopamine modulates default mode network deactivation in elderly individuals during the Tower of London task. AB - Task-induced deactivation is frequently reported in the ventro-medial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC), regions considered to belong to the default mode network. To investigate the effect of dopamine on task induced deactivation, we used positron emission tomography to measure cerebral blood flow during performance of the Tower of London task before and after administration of the dopamine receptor agonist apomorphine in six healthy volunteers (49-66 years old) and six Parkinson disease patients (52-69 years old). Although task-induced deactivation was observed in the vmPFC and PCC in both groups and in both conditions, an inverse correlation between activation and problem complexity was observed in the vmPFC only in the apomorphine condition. PMID- 19442868 TI - Comparison of visual cortical activations induced by electro-acupuncture at vision and nonvision-related acupoints. AB - In the current study, we investigated whether or not stimulation at vision and nonvision-related acupoints was able to induce similarity in the time domain, although stimulation at different acupoints could produce similar spatial distributions. This phenomenon still remains uncertain and contradictory. We introduced a novel experimental paradigm using a modified non-repeated event related (NRER) design, and utilized the methods of independent component analysis (ICA) combined with seed correlated functional connectivity analysis to locate visual cortical activations and to study their temporal characteristics during electro-acupuncture (EAS) at vision-related acupoint GB 37 and nonvision-related acupoint KI 8. Results showed that strong activations were present in the visual cortical areas (BA 17/18/19) at both acupoints, but temporal correlation analysis indicated that they were modulated in opposite directions during the resting state after acupuncture. Our results revealed that acupuncture at vision and nonvision-related acupoints can induce similar activations in spatial distribution but different modulation effects temporally. PMID- 19442869 TI - Age-related differences of saccade induced cortical activation. AB - Recent functional MRI (fMRI) studies have described the increased task-related brain activation in older subjects during motor, cognitive and perceptual tasks. Age affects the ability to control saccadic eye movements. To investigate the age related changes of oculomotor control, we studied the representation of saccades in 11 young (median age 29 years) and 11 older (median age 62 years) healthy individuals using fMRI. Brain activation was measured during a visually guided prosaccade trial. Differences in activation between rest and saccades as well as between younger and older subjects were assessed with statistical parametric mapping (SPM). In both age groups, activation of a frontoparietal network was observed. Older subjects showed increased activation compared to younger subjects with overactivation in bilateral parietal eye fields, the right frontal eye field, as well as in the right extrastriate cortex. We conclude that older adults increase activation in an extended oculomotor and visual network to maintain performance during simple prosaccades. This observation also underlines the importance of using appropriate age-matched control groups in fMRI studies after brain lesions. PMID- 19442870 TI - Axonal release of glutamate analog, d-2,3-3H-Aspartic acid and l-14C-proline from segments of sciatic nerve following electrical and magnetic stimulation. AB - Segments of the mouse sciatic nerve were preloaded with either d-2,3-(3)H Aspartic acid [nonmetabolizable analog of glutamate] or l-(14)C-proline and the release of these exogenous molecules was evaluated in the fractions of the perfusate following electrical or magnetic stimulation. The electrical stimulation (10Hz, 10Am, 20s) induced an instantaneous increase in the release of both molecules, although the release of d-2,3-(3)H-Aspartic acid was much greater. Moreover, contrary to l-(14)C-proline, the release of d-2,3-(3)H Aspartic acid was Ca(2+)-dependent. While magnetic stimulation (15mT, 0.16Hz, 30min) also induced the release of d-2,3-(3)H-Aspartic acid in a Ca(2+)-dependent way, the release of l-(14)C-proline was negligible. These results indicate that axons can release glutamate in a specific, calcium-dependent way. This release may contribute to interaxonal interactions. PMID- 19442871 TI - Age-related changes in the center of mass velocity control during walking. AB - During walking, the body center of mass oscillates along the vertical plane. Its displacement is highest at mid-swing and lowest at terminal swing during the transition to double support. Its vertical velocity (CoMv) has been observed to increase as the center of mass falls between mid- and late swing but is reduced just before double support. This suggests that braking of the center of mass is achieved with active neural control. We tested whether this active control deteriorates with aging (Experiment 1) and during a concurrent cognitive task (Experiment 2). At short steps of <0.4m, CoMv control was low and similar among all age groups. All groups braked the CoMv at longer steps of >0.4m but older subjects did so to a lesser extent. During the cognitive task, young subjects increased CoMv control (i.e. increase in CoMv braking) while maintaining step length and walking speed. Older subjects on the other hand, did not increase CoMv control but rather maintain it by reducing both step length and walking speed. These results suggest that active braking of the CoM during the transition to double support predominates in steps >0.4m. It could be a manifestation of the balance control system, since the braking occurs at late stance where body weight is being shifted to the contralateral side. The active braking mechanism also appears to require some attentional resource. In aging, reducing step length and speed are strategic to maintaining effective center of mass control during the transition to double support. However, the lesser degree of control in older adults indicates a true age-related deficit. PMID- 19442872 TI - P2X receptors are expressed on neurons containing luteinizing hormone-releasing hormone in the mouse hypothalamus. AB - Expression of P2X(1), P2X(2), P2X(3), P2X(4), P2X(5) and P2X(6) receptors, members of a family of ATP-gated cation channels, on neurons containing luteinizing hormone-releasing hormone (LHRH) in the mouse hypothalamus was studied with double-labeling fluorescence immunohistochemistry. This study demonstrated that different combinations of P2X receptor subunits were expressed on the perikarya and axon terminals of LHRH-producing neurons. It was shown for the first time that P2X(2), P2X(4), P2X(5) and P2X(6) receptor subunits were expressed on the perikarya of LHRH-producing neurons and P2X(2) and P2X(6) on their axon terminals. These results suggest that activation of P2X receptors by ATP via different homomeric or heteromeric P2X receptors at both presynaptic and postsynaptic sites could be involved in the regulation of LHRH secretion at the forebrain level. PMID- 19442873 TI - First detection of neuropeptide Y (NPY)-like immunoreactivity in the lateral line: presence and distribution in the neuromasts of the Antarctic notothenioid fish Trematomus bernacchii. AB - The mechanosensory lateral line (LL) is involved in many fish and amphibian behaviors, however little is known about the molecules involved in the signal transmission. Neuropeptide Y (NPY) has a number of functions in vertebrate physiology and also plays important roles in different sensory systems. The Antarctic nototheniods are a monophyletic radiation of fishes that have evolved under the extreme environmental conditions of low light and cold, where non visual sensory structures, such as LL, are of importance. In this study we describe the presence of NPY-like immunoreactivity (IR) in LL of the Antarctic nototheniod fish, Trematomus bernacchii Boulenger. Differences in size and cellular composition between the two neuromasts were in compliance with previous descriptions of these sensory organs. Despite structural and functional differences between canal and superficial neuromasts, the distribution of NPY like IR was similar within both the receptors classes. In particular, NPY IR was observed in all three cell types which constitute these sensory organs, allowing us to hypothesize the involvement of this molecule in the processing of the sensory information. PMID- 19442874 TI - Low-frequency tuning in the human vestibular-ocular projection is determined by both peripheral and central mechanisms. AB - We recently reported that a major contribution to the low-frequency tuning and sensitivity of the human vestibular system is the biomechanical properties of the vestibular end-organs. In the current paper, we investigate the contribution of additional mechanisms to low-frequency tuning. We compared the response properties of the vestibular system in 6 human volunteers to trains of 2 ms pulses of sound and transmastoid vibration using pulse repetition frequencies of 12.5, 25, 50, 100, 200 and 400 Hz. Measurements were made using two separate pathways arising from the vestibular apparatus: to the neck using vestibular evoked myogenic potentials (VEMPs), and to the eyes using ocular vestibular evoked myogenic potentials (OVEMPs). For both sound and vibration the two response pathways produced different tuning to pulse trains. The vestibulo-ocular pathway was characterised by a band-pass tuning with best frequency of 100 Hz whereas the vestibulo-collic pathway showed a peak at 400 Hz with sound only. These results suggest that properties of the vestibulo-ocular pathway also contribute to the low-frequency tuning that occurs for the OVEMP, in addition to previously reported end-organ effects. PMID- 19442875 TI - Pigment epithelium derived factor (PEDF) is neuroprotective in two in vitro models of Parkinson's disease. AB - Transplantation of retinal pigment epithelial (RPE) cells in the basal ganglia has been proposed as a novel cell-based therapy for Parkinson's disease (PD), by providing a constant source of dopamine replacement via the melanin synthetic pathway enzyme tyrosinase. We have demonstrated previously that human RPE cells also produce a neurotrophic effect on primary cultures of rat striata mesencephalic (dopaminergic) neurons and showed that pigment epithelium derived factor (PEDF) accounted for a major portion of the neurotrophic effect. We now have also begun studies that demonstrate that the neurotrophic effect of PEDF corresponds to neuroprotection against toxins used to produce experimental PD. This was shown in (1) rotenone and (2) 6-hydroxydopamine (6-OHDA) in vitro models. The toxins were added at day 10 in culture, PEDF was added 1h prior. The cultures were fixed and analyzed after tyrosine hydroxylase (TH) immunocytochemical staining. Cell count of TH+ neurons clearly shows the neuroprotective potential of PEDF in both neurotoxin models. The neurotoxic effect of rotenone (25nM) on dopaminergic neurons is reversed by addition of PEDF. At a concentration of 1ng/ml PEDF the neurotoxic effect of rotenone is completely counteracted. PEDF (1ng/ml) has also a neuroprotective effect in the 6 OHDA midbrain in vitro model. The effect is most pronounced at concentrations of 25microM and 50microM 6-OHDA. We conclude that the neurotrophic factor PEDF, produced from RPE cells, can improve neuronal survival in models of PD, and plan to test if this effect can be observed using in vivo models of PD following RPE transplantation. PMID- 19442876 TI - 18-Methoxycoronaridine blocks acquisition but enhances reinstatement of a cocaine place preference. AB - The iboga alkaloid congener, 18-methoxycoronaridine (18-MC), decreases self administration of multiple drugs of abuse. Here, in a biased procedure, we investigated whether 18-MC would have a similar effect on the acquisition, expression and reinstatement of a cocaine conditioned place preference (CPP) in male Sprague-Dawley rats. While 18-MC attenuated acquisition of a cocaine CPP, it had no effect on CPP expression, and enhanced the reinstatement of cocaine CPP following extinction. Our results are consistent with those obtained using ibogaine, but reinforce the notion that acquisition, expression and reinstatement of a CPP likely involve separate mechanisms. PMID- 19442877 TI - Neopterin and the risk of dementia in persons with Down syndrome. AB - Persons with Down syndrome show an altered immune response and an increased susceptibility to Alzheimer's disease. In a prospective study, we examined whether the plasma neopterin level, a marker for cell-mediated immune activation and inflammation, is associated with an increased risk of dementia in persons with Down syndrome. Plasma concentrations of neopterin were determined in a population-based study of 394 persons with Down syndrome, who were screened annually for dementia. We used Cox proportional hazards model to determine risk of dementia. Demented persons with Down syndrome have a significantly (p=0.05) higher plasma neopterin concentration than the non-demented. In the non-demented without autoimmune disorders, in those with a plasma level of neopterin above median, the risk to develop dementia increased to 1.83 (95% confidence interval: 1.04-3.20). High plasma neopterin level is an independent determinant of the risk of dementia in persons with Down syndrome. PMID- 19442878 TI - Chronic nicotine exposure inhibits 17beta-estradiol-mediated protection of the hippocampal CA1 region against cerebral ischemia in female rats. AB - Nicotine addiction in women increases the risk of ischemic stroke. Importantly, women who smoke and use hormone replacement therapy/oral contraceptives greatly increase their risk of coronary heart disease and ischemic stroke as compared to nonsmoking women who use occasionally oral contraceptives. Nicotine addiction disturbs the normal periodicity of the menstrual cycle and induces early onset of menopause in women; however, the mechanism of the synergistic effects of nicotine and sex hormones on cerebrovascular health is not clearly understood. In the current study based on a rat model of global cerebral ischemia, our goals are (1) to determine whether chronic nicotine exposure abrogates beneficial effects of estrogen on hippocampal neurons subjected to ischemia, and (2) to determine whether nicotine exposure antagonizes estrogen signaling by reducing the availability of estrogen receptor(s). To test the effects of chronic nicotine exposure, normally cycling or ovariectomized rats were injected with nicotine daily for 15 days. To investigate the efficacy of estrogen treatment, nicotine exposed ovariectomized rats were injected with a bolus of 17beta-estradiol and 48h later ischemia was induced. Our results demonstrated that chronic nicotine exposure followed by ischemic insult at the proestrus stage of the estrous cycle showed that only 14% of normal neurons remained compared to the non-nicotine treated group (p<0.05). Similarly, a bolus of 17beta-estradiol to nicotine treated ovariectomized rats showed only 26% of normal neurons remaining as against 47% in the non-nicotine-treated group. Nicotine exposure decreased ERbeta but not ERalpha protein levels in the hippocampus, suggesting a role for ERbeta in increased post-ischemic neurodegeneration from nicotine exposure. PMID- 19442879 TI - beta1-Adrenoceptor distribution in the rat brain: an immunohistochemical study. AB - Current knowledge of the central nervous system distribution of the beta(1) adrenergic receptors (beta(1)-AR) is incomplete. Here we present a general map of the beta(1)-AR distribution in the rat brain. beta(1)-AR-immunoreactivity was detected throughout the entire rat brain, but particularly dense staining was observed in the cerebellar cortex and basal ganglia. Brainstem areas displaying significant beta(1)-AR-immunoreactivity include the ventrolateral medulla, nucleus ambiguus and the nucleus of the solitary tract. Within the hypothalamus, only the paraventricular nucleus and the median eminence (ME) showed beta(1)-AR immunostaining. Numerous beta(1)-AR-immunoreactive cells were also found in the hippocampus, basal ganglia and cerebral cortex. These results extend our knowledge of the expression profile of beta(1)-AR in the central nervous system. The identification of several distinct beta(1)-AR immunoreactive substrates linked with neuropathophysiological roles in cardiovascular disease supports the hypothesis that the therapeutic benefit of beta(1)-AR blockade may be conferred at least in part through central nervous system mechanisms. PMID- 19442880 TI - Acrylamide decreased dopamine levels and increased 3-nitrotyrosine (3-NT) levels in PC 12 cells. AB - Acrylamide is a chemical known to produce neurotoxicity in animals, as well as in humans. The mechanism of acrylamide-induced neurotoxicity is not fully known. However, recent studies have revealed that acrylamide affects the dopaminergic system. Therefore, the aim of this study was to investigate the effect of acrylamide on dopamine (DA) and the metabolites, 3,4-dihydroxy phenylacetic acid (DOPAC) and homovanillicacid (HVA), levels in Pheochromocytoma (PC 12) cells. In addition, the generation of peroxynitrite (ONOO(-)), measured by 3-nitrotyrosine (3-NT), was investigated as a possible mechanism in acrylamide-induced neurotoxicity. HPLC-coupled to electrochemical detection (ECD) was used to determine DA, DOPAC, HVA and 3-NT levels. Acrylamide (0.01-5mM) exposure produced a dose- and time (1-42h)-dependent decrease in DA levels. The decrease (P<0.05) in DA levels was noted at 24h after exposure to acrylamide. The study also revealed that 3-NT levels in PC 12 increased as a result of treatment with acrylamide. Thus, these data suggest that acrylamide-induced decrease in DA levels in PC 12 cells may be associated with peroxynitrite formation, measured as 3-NT levels. PMID- 19442881 TI - Outcomes and safety of percutaneous aortic valve replacement. AB - The concept of transcatheter aortic valve replacement was developed with the goal of offering a therapeutic solution to patients with severe symptomatic aortic stenosis who are not considered good candidates for surgical valve replacement. Initial attempts were complicated by vascular access problems and lack of appropriate tools. With time and experience, early problems were solved and the concepts of valve sizing, valve positioning, and patient selection were defined. Technological improvements allowed the use of smaller arterial sheaths to decrease vascular trauma, special catheters to facilitate valve delivery, and treatments on the valve prostheses that would ensure longer durability. After 5 years, the number of transcatheter aortic valve replacements has grown significantly, and will likely continue as this technology becomes increasingly available. Currently, 2 valve models, the Edwards SAPIEN valve (Edwards Lifescience, Irvine, California) and the CoreValve ReValving system (CoreValve Inc., Irvine, California), have been used in over 4,000 cases worldwide for the treatment of symptomatic aortic stenosis. Midterm follow-up shows no evidence of restenosis or prosthetic valve dysfunction. Transfemoral and transapical delivery routes can be selected depending on the quality of vascular access and the type of prosthesis used. Randomized trials that are currently underway will confirm procedural safety and guide the applicability of this technology. PMID- 19442882 TI - Transcatheter mitral and pulmonary valve therapy. AB - As the percentage of seniors continues to rise in many populations around the world, the already challenging burden of valvular heart disease will become even greater. Unfortunately, a significant proportion of patients with moderate-to severe valve disease are refused or denied valve surgery based on age and/or accompanying comorbidities. Furthermore, because of advances in pediatric cardiology, the number of adult patients with congenital heart disease is on the rise and over time, these patients will likely require repeat high-risk surgical procedures. The aim of transcatheter valve therapies is to provide a minimally invasive treatment that is at least as effective as conventional valve surgery and is associated with less morbidity and mortality. The objective of this review was to provide an update on the clinical status, applicability, and limitations of transcatheter mitral and pulmonary valve therapies. PMID- 19442883 TI - Perspectives on the American College of Cardiology/American Heart Association guidelines for the prevention of infective endocarditis. AB - In 2007, the American Heart Association published a guideline statement dramatically changing its previous position on the use of antibiotic prophylaxis in patients at risk of infective endocarditis (IE). This year, these views were incorporated in an update of the 2006 American College of Cardiology/American Heart Association Guidelines for the Management of Patients With Valvular Heart Disease. The new recommendations represent a dramatic shift with regard to which patients should receive antibiotic prophylaxis for prevention of IE and for what procedures. The shift in recommendations is striking in that the recommendations are based not on new data, but on no data. (There are no large, prospective, randomized double-blind trials testing the efficacy of IE prophylaxis.) However, available data suggest that there may be no real risk associated with IE prophylaxis. Even if few cases of IE are successfully prevented using antibiotic prophylaxis, those few cases may represent a favorable risk-benefit ratio. On an individual basis, patients with organic heart valve disease who are trying to delay or avoid surgical intervention have something very real to risk if they develop IE, and a very real benefit if they avoid it. Pending data from prospective randomized trials, a strategy of individual decision-making by informed patients may be best. PMID- 19442884 TI - A new transcatheter aortic valve and percutaneous valve delivery system. AB - OBJECTIVES: We describe procedural and clinical outcomes in a high-risk cohort undergoing transcatheter aortic valve replacement with early next-generation transcatheter valve and delivery systems. BACKGROUND: Percutaneous aortic valve replacement is gaining acceptance as a viable option in patients at high surgical risk. Broader application will require further advances in valve and delivery system technology. METHODS: Transarterial aortic valve replacement was attempted in 25 patients (mean age 85 years) determined to be at high surgical risk due to comorbidities. A new delivery catheter system (RetroFlex 2, Edwards Lifesciences, Irving, California) was utilized in combination with either a balloon-expandable SAPIEN (Edwards Lifesciences) valve or a next-generation low-profile cobalt chromium bovine pericardial SAPIEN XT (Edwards Lifesciences) valve. RESULTS: Percutaneous valve replacement was successful in all 25 high-risk patients. Aortic valve area increased from 0.59 +/- 0.15 cm(2) to 1.60 +/- 0.27 cm(2). In this high-risk cohort (Society of Thoracic Surgeons and logistic EuroSCORE estimates of surgical mortality were 8.9% and 21.0%, respectively), 30-day mortality was 0%. CONCLUSIONS: Technical and procedural advances in catheter systems and prosthetic valves designed for percutaneous aortic valve delivery may contribute to increased procedural success and improved clinical outcomes. PMID- 19442885 TI - Extended application of percutaneous pulmonary valve implantation. AB - OBJECTIVES: This study was designed to report a novel indication for percutaneous pulmonary valve implantation in patients with previous right ventricular outflow tract (RVOT) patch. BACKGROUND: Current indications for percutaneous pulmonary valve implantation are limited to patients who had pulmonary valve stenosis and/or regurgitation in a right ventricle-to-pulmonary artery conduit. Percutaneous pulmonary valve implantation has not been previously reported in patients with severe pulmonary valve regurgitation following repair of tetralogy of Fallot (TOF) using RVOT patch. METHODS: After assessment of the RVOT patch in multiple projections, a catheter was placed in a distal pulmonary artery branch. In patients with an RVOT patch, sizing of the narrowest diameter of the RVOT patch by manual inflation of a sizing balloon was performed; a stent was placed into the RVOT patch at the level of the narrowest area to anchor the stent and to create an artificial conduit to place the Melody valve. The percutaneous valve was then implanted. RESULTS: Seven females and 6 males with a mean age of 14.3 years and mean body weight 45 kg had successful percutaneous implantation of the Melody valve. Four patients had previous repair of TOF using RVOT patch. All patients were discharged within 2 days after the procedure without complications. After a mean of 4 months follow-up all patients were alive and well. Transthoracic echocardiography showed competent pulmonary valve. Chest X-ray showed no stent migration or fracture. CONCLUSIONS: Percutaneous pulmonary valve implantation can be performed in patients with pulmonary valve regurgitation, including those with previous RVOT patch using pre-stenting techniques, with satisfactory results. PMID- 19442886 TI - Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography. AB - OBJECTIVES: This study investigated whether aortic valve replacement (AVR) is associated with improved survival in patients with severe low-flow/low-gradient aortic stenosis (LF/LGAS) without contractile reserve (CR) on dobutamine stress echocardiography (DSE). BACKGROUND: Patients with LF/LGAS without CR have a high mortality rate with conservative therapy. The benefit of AVR in this subset of patients remains controversial. METHODS: Eighty-one consecutive patients with symptomatic calcified LF/LGAS (valve area or=20% compared with the baseline value. Multivariable analysis and propensity scores were used to compare survival according to whether or not AVR was performed (n = 55). RESULTS: Five-year survival was higher in AVR patients compared with medically managed patients (54 +/- 7% vs. 13 +/- 7%, p = 0.001) despite a high operative mortality of 22% (n = 12). An AVR was independently associated with lower 5-year mortality (adjusted hazard ratio from 0.16 to 5.21 varying with time [95% confidence interval: 0.12-3.16 to 0.21-8.50], p = 0.00026). In 42 propensity-matched patients, 5-year survival was markedly improved by AVR (65 +/- 11% vs. 11 +/- 7%, p = 0.019). Associated bypass surgery (p = 0.007) and MPG or=1.5 m/s and at least 2 echocardiographic studies >or=2 years apart. Exclusion criteria were: severe aortic regurgitation, bicuspid aortic valve, and left ventricular ejection fraction <40%. RESULTS: The study population consisted of 164 patients (30 treated with statins) followed up for 8.5 +/- 4.2 years. Peak aortic velocity at baseline was not different in patients treated with statins versus untreated patients (2.3 +/- 0.8 m/s vs. 2.3 +/- 0.7 m/s, p = 0.84). There were no significant differences in sex, age, or follow-up duration between the 2 groups. Progression of AS severity was slower in patients receiving statins compared with untreated patients (annual change of peak aortic velocity: 0.05 +/- 0.07 m/s/year vs. 0.12 +/- 0.11 m/s/year, p = 0.001). An annual rate of peak velocity progression >or=0.1 m/s was found in 10% of statin-treated patients and in 49% of untreated patients (p < 0.0001). CONCLUSIONS: This is the first observation of a positive effect of statin treatment in reducing the progression of rheumatic AS. The underlying mechanisms remain to be clarified. PMID- 19442888 TI - Statins in rheumatic heart disease: taking the bite out? PMID- 19442889 TI - Comparison of the hemodynamic performance of percutaneous and surgical bioprostheses for the treatment of severe aortic stenosis. AB - OBJECTIVES: This study was undertaken to compare the hemodynamic performance of a percutaneous bioprosthesis to that of surgically implanted (stented and stentless) bioprostheses for the treatment of severe aortic stenosis. METHODS: Fifty patients who underwent percutaneous aortic valve implantation (PAVI) with the Cribier-Edwards or Edwards SAPIEN bioprosthetic valve (Edwards Lifesciences, Inc., Irvine, California) were matched 1:1 for sex, aortic annulus diameter, left ventricular ejection fraction, body surface area, and body mass index, with 2 groups of 50 patients who underwent surgical aortic valve replacement (SAVR) with a stented valve (Edwards Perimount Magna [SAVR-ST group]), or a stentless valve (Medtronic Freestyle, Medtronic, Minneapolis, Minnesota [SAVR-SL group]). Doppler echocardiographic data were prospectively obtained before the intervention, at discharge, and at 6- to 12-month follow-up. RESULTS: Mean transprosthetic gradient at discharge was lower (p < 0.001) in the PAVI group (10 +/- 4 mm Hg) compared with the SAVR-ST (13 +/- 5 mm Hg) and SAVR-SL (14 +/- 6 mm Hg) groups. Aortic regurgitation (AR) occurred more frequently in the PAVI group (mild: 42%, moderate: 8%) compared with the SAVR-ST (mild: 10%, moderate: 0%) and SAVR-SL (mild: 12%, moderate: 0%) groups (p < 0.0001). At follow-up, the mean gradient in the PAVI group remained lower (p < 0.001) than that of the SAVR-ST group, but was similar to that of the SAVR-SL group. The incidence of severe prosthesis-patient mismatch was significantly lower (p = 0.007) in the PAVI group (6%) compared with the SAVR-ST (28%) and SAVR-SL (20%) groups. However, the incidence of AR remained higher (p < 0.0001) in the PAVI group compared with the 2 other groups. CONCLUSIONS: PAVI provided superior hemodynamic performance compared with the surgical bioprostheses in terms of transprosthetic gradient and prevention of severe prosthesis-patient mismatch, but was associated with a higher incidence of AR. PMID- 19442890 TI - Hemodynamic evaluation of heart valve prostheses paradigm shift for transcatheter valves? PMID- 19442891 TI - The year in valvular heart disease. PMID- 19442892 TI - Recipient genotype is a predictor of allograft cytokine expression and outcomes after pediatric cardiac transplantation. AB - OBJECTIVES: This study sought to investigate the influence of recipient renin angiotensin-aldosterone system (RAAS) genotype on cardiac function, rejection, and outcomes after heart transplantation. BACKGROUND: The RAAS influences cardiac function and up-regulates inflammatory/immune pathways. Little is known about the effect of recipient RAAS polymorphisms in pediatric cardiac transplantation. METHODS: Patients <25 years of age, after cardiac transplantation, were enrolled (2003 to 2008) and genotyped for polymorphisms in genes associated with RAAS upregulation: AGT-G, ACE-D, AGTR1-C, CYP11B2-G, and CMA-A. Presence of at least 1 high-risk allele was defined as a high-risk genotype. Univariable and multivariable associations between genotypes and outcomes were assessed in time dependent models using survival, logistic, or linear regression models. Biopsy samples were immunostained for interleukin (IL)-6, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha during rejection and quiescence. RESULTS: A total of 145 patients were studied, 103 primary cohort and 42 replication cohort; 81% had rejection, 51% had graft dysfunction, and 13% had vasculopathy, 7% died and 8% underwent re-transplantation. A higher number of homozygous high-risk RAAS genotypes was associated with a higher risk of graft dysfunction (hazard ratio [HR]: 1.5, p = 0.02) and a higher probability of death (HR: 2.5, p = 0.04). The number of heterozygous high-risk RAAS genotypes was associated with frequency of rejection (+0.096 events/year, p < 0.001) and rejection-associated graft dysfunction (+0.37 events/year, p = 0.002). IL-6 and TGF-beta were markedly upregulated during rejection in patients with >/=2 high risk RAAS genotypes. CONCLUSIONS: Recipient RAAS polymorphisms are associated with a higher risk of rejection, graft cytokine expression, graft dysfunction, and a higher mortality after cardiac transplantation. This may have implications for use of RAAS inhibitors in high-risk patients after transplantation. PMID- 19442893 TI - Saphenous vein graft pseudoaneurysm. PMID- 19442894 TI - The exportation of clinical research. PMID- 19442895 TI - Exclusive antiplatelet therapy for percutaneous coronary intervention. PMID- 19442898 TI - Zinc and diabetes--clinical links and molecular mechanisms. AB - Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options. PMID- 19442899 TI - Tissue ablation techniques are emerging as minimally invasive alternatives in the treatment of advanced head and neck tumors. Foreword. PMID- 19442900 TI - Minimally invasive, interventional techniques are rapidly evolving and finding an increasing number of applications in the head and neck. Preface. PMID- 19442901 TI - State of the art head and neck imaging for the endovascular specialist. AB - Recent technologic advances including multidetector CT, dynamic CT angiography, high-field MR imaging, four-dimensional MR angiography, and physiologic studies, such as perfusion imaging, have revolutionized the imaging work-up of head, neck, and skull base lesions. These techniques not only provide accurate diagnostic information, but also help plan endovascular therapy. The future holds great promise for interventional neuroradiologists because excellent imaging tools are becoming available that are capable of providing morphologic, hemodynamic, and physiologic information. Furthermore, availability of faster, real-time guidance systems and hybrid systems improves the ability to perform procedures not only in a rapid and safe manner but also with great precision. PMID- 19442902 TI - Approaches for percutaneous needle placement for various head and neck procedures. AB - Use of image-guidance allows safe and precise percutaneous placement of needles for various diagnostic and therapeutic procedures in the head and neck region. This review describes the anatomy relevant to safe-access route planning and the techniques, advantages, and limitations associated with various approaches used for percutaneous needle placement in different head and neck regions. Subzygomatic, retromandibular, paramaxillary, submastoid, transoral, and posterior approaches can be used for percutaneous access in the suprahyoid head and neck region, including skull base and upper cervical vertebrae. In the infrahyoid portion of the neck and for lower cervical vertebrae, access can be achieved via the anterolateral (between the airways and the carotid sheath), posterolateral (posterior to the carotid sheath), and direct posterior approaches. PMID- 19442903 TI - Percutaneous thermal ablation in the head and neck: current role and future applications. AB - Patients with recurrent head and neck cancer have poor quality of life and suffer dismally from debilitating symptoms. Ablative techniques offer patients an alternative, minimally invasive treatment option. As a palliative treatment, they improve quality of life with decreased pain, improved function and appearance. In addition, there is a reduction in tumor bulk and analgesia requirements. Advantages include a reduction in procedural cost, avoidance of complex repetitive surgeries, and an ability to visualize the treated area at the time of the procedure. Ablation therapies are an evolving and exciting treatment option in the head and neck, but a consensus on appropriate indications is currently unclear. PMID- 19442904 TI - Developmental anatomy, angiography, and clinical implications of orbital arterial variations involving the stapedial artery. AB - Classical anatomists have provided detailed description of the arterial collateral pathways found in the head and neck. The small branches building this intricate network are difficult to access. The arterial map inherited from the anatomists has been put to the test with detailed high-resolution vascular imaging. Superselective angiography has helped rediscover the complexity of the craniocervical arterial network. The concept of dangerous collaterals or dangerous anastomoses was born with the advent of endovascular therapy. Although dangerous anastomoses of the skull base are described in the literature, variations and collateral pathways have been overlooked or misunderstood. This article reviews normal orbital arterial vascularization and its principal variations. PMID- 19442905 TI - Embolization of vascular tumors of the head and neck. AB - Juvenile nasopharyngeal angiofibromas and paragangliomas are the most common hypervascular tumors of the head and neck that require embolization as an adjunct to surgery. A detailed understanding of the functional vascular anatomy of the external carotid artery is necessary for safe and effective endovascular therapy. Embolization, using a transarterial technique and particulate agents, a direct puncture technique and liquid embolic agents, or both techniques may allow for complete devascularization of hypervascular tumors of the head and neck. Effective embolization of these tumors results in a significant reduction of blood loss during surgery and allows for complete resection of the tumors. Use of meticulous technique and a thorough knowledge of functional anatomy of the head and neck vasculature are essential. PMID- 19442906 TI - Neurointerventional management of low-flow vascular malformations of the head and neck. AB - Mulliken and Glowacki's seminal classification of vascular anomalies into vascular tumors (with infantile hemangiomas being paradigmatic) versus nontumorous vascular malformations has been as important in the head and neck region as elsewhere. These latter are congenital, have an equal gender incidence, virtually always grow in size with the patient during childhood, and virtually never involute spontaneously. The vascular malformations can in turn be subclassified into high-flow and low-flow. Our focus is on the low-flow malformations, which include those with venous, lymphatic, and, to a lesser extent, capillary components. We address diagnostic and clinical characteristics, particularly insofar as they relate to the structures of the head and neck, and discuss neurointerventional management in some detail. PMID- 19442907 TI - Neurointerventional management of high-flow vascular malformations of the head and neck. AB - Head and neck high-flow vascular malformations are uncommon lesions whose management presents a clinical challenge. Although in some rare cases a complete cure is possible, in the vast majority the primary objective is symptom control, cosmesis improvement, and preservation of vital functions. Striving for "complete" treatment in most cases results in potentially devastating clinical and cosmetic outcome. Collateral supply via intracranial vessels is not uncommon, and scrupulous efforts to avoid complications related to inadvertent intracranial embolization or venous thrombosis are mandatory. Regardless of therapeutic goal, close long-term follow-up for lesion recurrence is necessary. Recent demonstration of syndromic associations for some subsets of HFVMs holds out the promise of the future development of medical therapy for these difficult lesions. PMID- 19442908 TI - Endovascular treatment of carotid cavernous fistulas. AB - Carotid cavernous fistulas (CCFs) are abnormal communications between the carotid arterial system and the cavernous sinus. CCFs are broadly classified as either direct or indirect. Surgical treatment of CCFs is technically difficult and is associated with significant morbidity. Endovascular techniques from either an arterial or a venous approach have become the mainstay of treatment given the recent advances in endovascular technology. This article provides an overview of various endovascular approaches available for the treatment of CCFs. PMID- 19442909 TI - Cervical dissections: diagnosis, management, and endovascular treatment. AB - Cervical arterial dissections and dissecting aneurysms are relatively rare pathologies, but can be associated with significant morbidity from ischemic complications. We review the challenges in diagnosing cervical arterial dissections, their unique clinical presentations and imaging characteristics. Although the majority of cervical dissections heal spontaneously with medical management, we discuss the specific indications for surgical or endovascular treatment to prevent thromboembolic complications. Furthermore, we provide a detailed technical review on endovascular stent reconstruction, the primary interventional option for symptomatic cervical dissections and dissecting aneurysms refractory to medical management. PMID- 19442910 TI - Update on endovascular management of the carotid blowout syndrome. AB - Carotid blowout syndrome can be a life-threatening late complication of surgical and radiation therapy for head and neck tumors in the vicinity of the cervical carotid artery. The syndrome spans a spectrum of pathology from impending to acute rupture of the artery. These cases are uncommon, can be dramatic in terms of blood loss, and are often true emergencies. The optimal management of these patients requires quick recognition, and often advanced trauma life-support skills and creative endovascular solutions. Definitive endovascular treatment is the therapy of choice in this condition; open surgical options are very limited. In this article, we present some background information regarding the clinical and pathologic aspects of the syndrome and our experience in endovascular management. PMID- 19442911 TI - Key consultations in hepatology. Preface. PMID- 19442912 TI - The asymptomatic outpatient with abnormal liver function tests. AB - Traditionally, the constellation of biochemistry tests including liver enzymes, total bilirubin, and hepatic synthetic measures (prothrombin time (PT) and serum albumin level) are referred to as liver function tests (LFTs). Abnormal LFTs can be encountered during primary health care visits, routine blood donation, and insurance screening. A reported 1% to 4% of asymptomatic patients exhibit abnormal LFTs, leading to a sizeable number of annual consultations to a gastroenterology and/or hepatology practice. A cost-effective and systematic approach is essential to the interpretation of abnormal LFTs. A review of pattern of abnormal LFTs, detailed medical history, and a comprehensive physical examination help establish a foundation for further individualized testing. Further investigation often involves biochemical testing for disease-specific markers, radiographic imaging, and even consideration of a liver biopsy. In the following account, markers of hepatic injury are reviewed followed by a discussion on an approach to various patterns of abnormal LFTs in an asymptomatic patient. PMID- 19442913 TI - The hospitalized patient with abnormal liver function tests. AB - Evaluation of abnormal liver function tests (LFTs) in the hospitalized patient is typically more urgent than the outpatient setting. This process is best organized into four steps. The first step is to determine whether the abnormal LFTs are associated with the illness resulting in the admission to the hospital or preceded the present illness. The second is to determine the etiology of the underlying liver disease. The third step is to evaluate the severity of the liver dysfunction and determine if acute liver failure (ALF) or acute decompensation of chronic liver failure is present. The final step is to look for the presence of associated complications-either those of ALF or chronic liver failure as appropriate. PMID- 19442914 TI - Approach to a liver mass. AB - Incidentally discovered liver masses are becoming more common with the increasing application and power of imaging techniques for the evaluation of abdominal conditions. Although such masses are often benign, conclusive diagnoses must be established in order to provide appropriate patient care. Various imaging modalities can be utilized to accurately diagnose such masses without resort to more invasive diagnostic measures. PMID- 19442915 TI - Surgery in the patient with liver disease. AB - The advent of liver transplantation has greatly improved the long-term survival of patients with decompensated cirrhosis, and surgery is now performed more frequently in patients with advanced liver disease. The estimation of perioperative mortality is limited by the retrospective nature of and biased patient selection in the available clinical studies. The overall experience is that, in patients with cirrhosis, use of the Child classification and Model for End-Stage Liver Disease (MELD) score provides a reasonably precise estimation of perioperative mortality. Careful preoperative preparation and monitoring to detect complications early in the postoperative course are essential to improve outcomes. PMID- 19442916 TI - Modern diagnosis and management of hepatocellular carcinoma. AB - The incidence of hepatocellular carcinoma (HCC) is rising, and the number of patients with HCC is expected to more than double over the next 1 to 2 decades. HCC meets the criteria for establishment of a surveillance program. Patients with cirrhosis, regardless of the cause, are at the highest risk for developing HCC and this is the population in which surveillance should be performed. (Alpha fetoprotein and hepatic ultrasonography are the currently recommended surveillance tests. If a surveillance test is abnormal, there is a need for a recall test for diagnostic evaluation of HCC. Triple-phase imaging is recommended for evaluation at recall, with MRI being more sensitive and specific. Novel genetic markers can improve the histologic diagnosis of early HCC. The Barcelona staging classification is the best system for determining the prognosis of patients and it is linked to an evidence-based treatment algorithm. Resection, transplantation, and percutaneous ablation are considered curative interventions and are currently applied to about 30% of all patients with HCC. PMID- 19442917 TI - Nonalcoholic fatty liver disease: a practical approach to evaluation and management. AB - Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease in the Western world. The rise in NAFLD is thought to be associated with the prevalence of metabolic syndrome. NASH is a subtype of NAFLD that may progress to cirrhosis and end stage liver disease. Although there are no approved treatment regimens for NAFLD or NASH, a number of different interventions are being tested. Meanwhile, most experts advocate that components of metabolic syndrome should be effectively treated. PMID- 19442918 TI - Management of alcoholic liver disease. AB - Understanding alcohol addiction and abstinence is key to treating alcoholic liver disease, since abstinence leads to improvement in all forms of alcoholic liver damage. Although pharmacotherapy for alcoholism, using agents such as naltrexone, acamprosate, topiramate, and baclofen, is an exciting field, few studies have included patients with liver disease or cirrhosis. To treat alcoholic liver injury, corticosteroids have become the standard of care in patients with severe alcoholic hepatitis. In contrast, the role of pharmacotherapy to treat alcoholic fibrosis is unclear, with failure to observe a benefit in randomized, placebo controlled clinical trials of colchicine, S-adenosylmethionine (SAMe), or phosphatidylcholine. Liver transplantation remains an option in selected patients with life-threatening alcoholic liver disease. PMID- 19442919 TI - Drug-induced hepatotoxicity or drug-induced liver injury. AB - Drug-induced hepatotoxicity is underreported and underestimated in the United States. It is an important cause of acute liver failure. Common classes of drugs causing drug-induced hepatotoxicity include antibiotics, lipid lowering agents, oral hypoglycemics, psychotropics, antiretrovirals, acetaminophen, and complementary and alternative medications. Hepatotoxic drugs often have a signature or pattern of liver injury including patterns of liver test abnormalities, latency of symptom onset, presence or absence of immune hypersensitivity, and the course of the reaction after drug withdrawal. PMID- 19442920 TI - Management of autoimmune and cholestatic liver disorders. AB - The management of autoimmune and cholestatic liver disorders is a challenging area of hepatology. Autoimmune and cholestatic liver diseases represent a comparatively small proportion of hepatobiliary disorders, yet their appropriate management is of critical importance for patient survival. In this article, management strategies are discussed, including the indications and expectations of pharmacologic therapy, endoscopic approaches, and the role of liver transplantation. PMID- 19442921 TI - Hepatitis vaccination and prophylaxis. AB - The three most commonly identified causes of viral hepatitis in the United States are hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Hundreds of millions of people worldwide are infected by these viruses; many experience illness as a result. This article discusses current recommendations for vaccination and other forms of prophylaxis aimed at minimizing the clinical effects of these viruses. PMID- 19442922 TI - Care of the cirrhotic patient. AB - Timely surveillance for varices and hepatocellular carcinoma, prophylaxis against spontaneous bacterial peritonitis (SBP) improve survival in patients awaiting transplantation. Early diagnosis of minimal or overt hepatic encephalopathy can delay life threatening complications, reduce need for hospitalization, and potentially improve survival pending liver transplantation. PMID- 19442923 TI - The construction of a scientific model: Otto Warburg and the building block strategy. AB - In the years 1919 to 1923, Otto Warburg published four papers that were to revolutionise the field of photosynthesis. In these articles, he introduced a number of new techniques to measure the rate of photosynthesis, put forward a new model of the mechanism and added a completely new perspective to the topic by attempting to establish the process's efficiency in terms of the light quantum requirement. In this paper I trace the roots of Warburg's series of contributions to photosynthesis research by exploring three different contexts of inspiration: Warburg's own research into cell respiration, his father's work on the quantum yield of photochemical reactions in general and the photosynthesis work carried out by Richard Willstatter and Arthur Stoll. When these influences are considered together, it becomes clear that Warburg implemented a Building Block Strategy in his research: rather than inventing his photosynthesis model from scratch, he availed himself of fragments from other contexts, which he then recombined in a new and innovative way. This way of working is considered to be standard practice in scientific research. PMID- 19442924 TI - Off with your heads: isolated organs in early Soviet science and fiction. AB - In the summer of 1925, a debutant writer, Aleksandr Beliaev, published a 'scientific-fantastic story', which depicted the travails of a severed human head living in a laboratory, supported by special machinery. Just a few months later, a young medical researcher, Sergei Briukhonenko, succeeded in reviving the severed head of a dog, using a special apparatus he had devised to keep the head alive. This paper examines the relationship between the literary and the scientific experiments with severed heads in post-revolutionary Russia, which reflected the anxieties about death, revival, and survival in the aftermath of the 1914-1923 'reign of death' in that country. It contrasts the anguished ethical questions raised by the story with the public fascination for 'science that conquers death'. PMID- 19442925 TI - The costs of being a restless intellect: Julian Huxley's popular and scientific career in the 1920s. AB - Julian Huxley's (1887-1975) contribution to twentieth-century biology and science popularisation is well documented. What has not been appreciated so far is that despite Huxley's eminence as a public scientific figure and the part that he played in the rise of experimental zoology in Britain in the 1920s, his own research was often heavily criticised in this period by his colleagues. This resulted in numerous difficulties in getting his scientific research published in the early 1920s. At this time, Huxley started his popular science career. Huxley's friends criticised him for engaging in this actively and attributed the publication difficulties to the time that he allocated to popular science. The cause might also have its roots in his self-professed inability to delve deeply into the particularities of research. This affected Huxley's standing in the scientific community and seems to have contributed to the fact that Huxley failed twice in the late 1920s to be elected to the Royal Society. This picture undermines to some extent Peter J. Bowler's recent portrayal of Huxley as a science populariser. PMID- 19442926 TI - Rethinking 'style' for historians and philosophers of science: converging lessons from sexuality, translation, and East Asian studies. AB - Historians and philosophers of science have furnished a wide array of theoretical historiographical terms to emphasize the discontinuities among different systems of knowledge. Some of the most famous include Thomas Kuhn's "paradigm", Michel Foucault's "episteme", and the notion of "styles of reasoning" more recently developed by Ian Hacking and Arnold Davidson. This paper takes up this theoretical-historiographical thread by assessing the values and limitations of the notion of "style" for the historical and philosophical study of science. Specifically, reflecting on various methodological and theoretical concerns prompted by sexuality, translation, and East Asian studies, this paper argues that the heretofore ways in which historians and philosophers of science have used the notion of "style" are severely restricted in terms of its mere applicability to the intellectual history of Western science. The particular example of the translation of "homosexuality" into Chinese during the May Fourth era reveals that the notion of "style" has the potential of carrying a much more dynamic conceptual weight, as when used in "styles of argumentation". The paper also engages briefly with the historiography of scientific "national styles" and ends with some concluding remarks on the limitations of "social histories from below" and the under appreciated importance of "epistemological histories of possibilities". PMID- 19442927 TI - The uncertain foundation of neo-Darwinism: metaphysical and epistemological pluralism in the evolutionary synthesis. AB - The Evolutionary Synthesis is often seen as a unification process in evolutionary biology, one which provided this research area with a solid common theoretical foundation. As such, neo-Darwinism is believed to constitute from this time onward a single, coherent, and unified movement offering research guidelines for investigations. While this may be true if evolutionary biology is solely understood as centred around evolutionary mechanisms, an entirely different picture emerges once other aspects of the founding neo-Darwinists' views are taken into consideration, aspects potentially relevant to the elaboration of an evolutionary worldview: the tree of life, the ontological distinctions of the main cosmic entities (inert matter, biological organisms, mind), the inherent properties of self-organizing matter, evolutionary ethics, and so on. Profound tensions and inconsistencies are immediately revealed in the neo-Darwinian movement once this broader perspective is adopted. This pluralism is such that it is possible to identify at least three distinct and quasi-incommensurable epistemological/metaphysical frameworks as providing a proper foundation for neo Darwinism. The analysis of the views of Theodosius Dobzhansky, Bernhard Rensch, and Ernst Mayr will illustrate this untenable pluralism, one which requires us to conceive of the neo-Darwinian research agenda as being conducted in more than one research programme or research tradition at the same time. PMID- 19442928 TI - On our best behavior: optimality models in human behavioral ecology. AB - This paper discusses problems associated with the use of optimality models in human behavioral ecology. Optimality models are used in both human and non-human animal behavioral ecology to test hypotheses about the conditions generating and maintaining behavioral strategies in populations via natural selection. The way optimality models are currently used in behavioral ecology faces significant problems, which are exacerbated by employing the so-called 'phenotypic gambit': that is, the bet that the psychological and inheritance mechanisms responsible for behavioral strategies will be straightforward. I argue that each of several different possible ways we might interpret how optimality models are being used for humans face similar and additional problems. I suggest some ways in which human behavioral ecologists might adjust how they employ optimality models; in particular, I urge the abandonment of the phenotypic gambit in the human case. PMID- 19442929 TI - Pulmonary function and spinal cord injury. AB - Injury to the cervical and upper thoracic spinal cord disrupts function of inspiratory and expiratory muscles, as reflected by reduction in spirometric and lung volume parameters and static mouth pressures. In association, subjects with tetraplegia have decreased chest wall and lung compliance, increased abdominal wall compliance, and rib cage stiffness with paradoxical chest wall movements, all of which contribute to an increase in the work of breathing. Expiratory muscle function is more compromised than inspiratory muscle function among subjects with tetraplegia and high paraplegia, which can result in ineffective cough and propensity to mucus retention and atelectasis. Subjects with tetraplegia also demonstrate heightened vagal activity with reduction in baseline airway caliber, findings attributed to loss of sympathetic innervation to the lungs. Significant increase in airway caliber following inhalation of ipratropium bromide, an anticholinergic agent, suggests that reduction in airway caliber is not due to acquired airway fibrosis stemming from repeated infections or to abnormal hysteresis secondary to chronic inability of subjects to inhale to predicted total lung capacity. Reduced baseline airway caliber possibly explains why subjects with tetraplegia exhibit airway hyperresponsiveness to methacholine and ultrasonically nebulized distilled water. While it has been well demonstrated that bilateral phrenic nerve pacing or stimulation through intramuscular diaphragmatic electrodes improves inspiratory muscle function, it remains unclear if inspiratory muscle training improves pulmonary function. Recent findings suggest that expiratory muscle training, electrical stimulation of expiratory muscles and administration of a long-acting beta(2)-agonist (salmeterol) improve physiological parameters and cough. It is unknown if baseline bronchoconstriction in tetraplegia contributes to respiratory symptoms, of if the chronic administration of a bronchodilator reduces the work of breathing and/or improves respiratory symptoms. Less is known regarding the benefits of treatment of obstructive sleep apnea, despite evidence indicating that the prevalence of this condition in persons with tetraplegia is far greater than that encountered in able-bodied individuals. PMID- 19442930 TI - Comparison of micron- and nanoparticle deposition patterns in a realistic human nasal cavity. AB - Knowledge regarding particle deposition processes in the nasal cavity is important in aerosol therapy and inhalation toxicology applications. This paper presents a comparative study of the deposition of micron and submicron particles under different steady laminar flow rates using a Lagrangian approach. A computational model of a nasal cavity geometry was developed from CT scans and the simulation of the fluid and particle flow within the airway was performed using the commercial software GAMBIT and FLUENT. The air flow patterns in the nasal cavities and the detailed local deposition patterns of micron and submicron particles were presented and discussed. It was found that the majority of micron particles are deposited near the nasal valve region and some micron particles are deposited on the septum wall in the turbinate region. The deposition patterns of micron particles in the left cavity are different compared with that in the right one especially in the turbinate regions. In contrast, the deposition for nanoparticles shows a moderately even distribution of particles throughout the airway. Furthermore the particles releasing position obviously influences the local deposition patterns. The influence of the particle releasing position is mainly shown near the nasal valve region for micron particle deposition, while for submicron particles deposition, both the nasal valve and turbinate region are influenced. The results of the paper are valuable in aerosol therapy and inhalation toxicology. PMID- 19442931 TI - Effects of indomethacin on cerebrovascular response to hypercapnea and hypocapnea in breath-hold diving and obstructive sleep apnea. AB - We tested whether breath hold divers (BHD) and obstructive sleep apnea (OSA) subjects had similar middle cerebral artery velocity (MCAV) responses to hypercapnea and hypocapnea. We analyzed changes in MCAV (cm/s) in response to hypocapnea and hyperoxic hypercapnea during placebo or after 90 min of oral indomethacin (100 mg) in BHD (N=7) and OSA (N=7). During control hypercapnea MCAV increased for 54.4% in BHD and 48.4% in OSA. Indomethacin blunted the MCAV increase in response to hypercapnea in BHD (P=0.02), but not in OSA. Indomethacin attenuated the mean arterial pressure response in BHD, but not in OSA. The blunted MCAV responses to hypercapnea with indomethacin in BHD, but not in OSA patients suggests that (a) the normal contribution of local vasodilating mechanisms to the cerebrovascular responses to hypercapnea is absent in OSA patients and (b) exposure to chronic/repeated apneas is not causal per se in limiting the contribution of vasodilating mechanisms to the cerebrovascular responses to hypercapnea in OSA. PMID- 19442932 TI - Acute effects of inspiratory pressure threshold loading upon airway resistance in people with asthma. AB - Large inspiratory pressures may impart stretch to airway smooth muscle and modify the response to deep inspiration (DI) in asthmatics. Respiratory system resistance (Rrs) was assessed in response to 5 inspiratory manoeuvres using the forced oscillation technique: (a) single unloaded DI; (b) single DI at 25 cmH(2)O; (c) single DI at 50% maximum inspiratory mouth pressure [MIP]; (d) 30 DIs at 50% MIP; and (e) 30 DIs at 50% MIP with maintenance of normocapnia. Rrs increased after the unloaded DI and the DI at 25 cmH(2)O but not after a DI at 50% MIP (3.6+/-1.6 hPa Ls(-1) vs. 3.6+/-1.5 hPa Ls(-1); p=0.95), 30 DIs at 50% MIP (3.9+/-1.5 hPa Ls(-1) vs. 4.2+/-2.0 hPa Ls(-1); p=0.16) or 30 DIs at 50% MIP under normocapnic conditions (3.9+/-1.5 hPa Ls(-1) vs. 3.9+/-1.5 hPa Ls(-1); p=0.55). Increases in Rrs in response to DI were attenuated after single and multiple loaded breaths at 50% MIP. PMID- 19442933 TI - Effect of expiratory resistive loading on inspiratory and expiratory muscle fatigue. AB - Inspiratory and expiratory pressures are increased during expiratory resistive loading (ERL). We asked whether ERL elicits inspiratory as well as expiratory muscle fatigue. On four separate days, seven male subjects underwent ERL to task failure. Subjects maintained respiratory frequency at 15 breaths min(-1), expiratory gastric pressure at 40% or 60% of maximum, and expiratory duty cycle at 0.4 or 0.7 (ERL(40%0.4), ERL(40%0.7), ERL(60%0.4), ERL(60%0.7)). Inspiratory and abdominal muscle contractility was assessed before and up to 30 min after ERL by measuring transdiaphragmatic twitch pressure (P(di,tw)) and gastric twitch pressure (P(ga,tw)) in response to magnetic nerve stimulation. After each trial, P(di,tw) and P(ga,tw) were reduced below baseline values (-9 to -15% for P(di,tw) and -15 to -22% for P(ga,tw); P<0.05). The severity of diaphragm fatigue was unaffected by expiratory pressure production or expiratory duty cycle, whereas extending the expiratory duty cycle increased the severity of abdominal muscle fatigue. In conclusion, ERL elicits contractile fatigue of the diaphragm and the abdominal muscles. PMID- 19442934 TI - Riluzole disrupts autoresuscitation from hypothermic respiratory arrest in neonatal hamsters but not rats. AB - We examined the effect of riluzole on expression of the central respiratory rhythm and the ability of neonates to autoresuscitate from hypothermic respiratory arrest using in vitro brainstem-spinal cord preparations of rats and hamsters. At a constant temperature of 27 degrees C, riluzole (5-200 microM) decreased the burst amplitude of respiratory-related motor discharge, but had little effect on the fictive respiratory frequency in rat preparations. In contrast, in hamster preparations, riluzole reduced fictive respiratory frequency, but had little effect on burst amplitude. Hamster preparations were more cold-tolerant than rat preparations, with respiratory arrest and autoresuscitation occurring at lower temperatures during cooling of the preparation. This difference was removed by incubation with riluzole (5 microM); riluzole significantly increased the temperature at which fictive respiration arrested and restarted in hamster preparations, but had no effect in rat preparations. The species differences observed in this study may reflect fundamental differences in the relative role of riluzole-sensitive mechanisms in the expression of the respiratory rhythm in early development of an altricial vs. a more precocial species. PMID- 19442935 TI - CO2 activates orexin-containing neurons in mice. AB - Accumulating evidence shows possible participation of orexin, a hypothalamic neuropeptide also known as hypocretin, in regulation of breathing. In this study we examined whether hypercapnic stimulation in vivo activates orexin-containing neurons in the hypothalamus. A hypercapnic gas mixture of 10% CO(2), 21% O(2), and residual N(2) or room air was inhaled to awake and freely moving mice for 3h. Their brains were examined by double immunohistochemical staining for orexin and c-Fos. We found that inhalation of CO(2) significantly increased c-Fos expression in the orexin-containing cells that were located in the perifornical region and the dorsomedial hypothalamus (15.8+/-1.6% for room air vs. 28.4+/-2.7% for CO(2), p=0.011) but not in the lateral hypothalamic area (12.3+/-1.2% for room air vs. 12.4+/-3.0% for CO(2)). Although current methodology cannot differentiate between direct effect of CO(2) on the orexin-containing neurons and indirect one through other neurons, this is the first report showing that inhalation of CO(2) did activate the orexin-containing neurons in vivo. PMID- 19442936 TI - Right atrial volume index in chronic systolic heart failure and prognosis. AB - OBJECTIVES: The aim of this study was to determine the relationship between right atrial volume index (RAVI) and right ventricular (RV) systolic and diastolic function, as well as long-term prognosis in patients with chronic systolic heart failure (HF). BACKGROUND: RV dysfunction is associated with poor prognosis in patients with HF, although echocardiographic assessment of RV systolic and diastolic dysfunction is challenging. The ability to visualize the RA allows a quantitative, highly reproducible assessment of the RA volume that can be indexed to body surface area. METHODS: The ADEPT (Assessment of Doppler Echocardiography for Prognosis and Therapy) trial enrolled 192 subjects with chronic systolic HF (left ventricular ejection fraction [LVEF] 130 ms, and ejection fraction <35%) before and 6 to 8 months after CRT. Left ventricular (LV) dyssynchrony was estimated by calculating the SD of time to peak velocities (Ts-SD) by conventional tissue Doppler imaging (TDI), and the mean phase index (mean EPI-Index) was calculated by EPI in 12 mid-ventricular and basal segments. Patients who were alive and had significant relative decrease in end-systolic LV volume of Delta ESV >or=15% at 6 to 8 months of follow-up were defined as responders. All others were classified as nonresponders. RESULTS: The Ts-SD and the mean EPI-Index were related to Delta ESV (r = 0.43 for Ts-SD and r = 0.67 for mean EPI-Index, p < 0.01 for both), and both parameters yielded similar accuracy for the prediction of LV remodeling (area under the curve of 0.87 for TDI vs. 0.90 for EPI, difference between areas = 0.03, p = NS) and ejection fraction (EF) improvement (area under the curve of 0.87 for TDI vs. 0.93 for EPI, difference between areas = 0.06, p = NS). Furthermore, patients classified as responders by EPI (mean EPI-Index or=3 years showed adipose tissue in MI. Conversely, none of 9 patients with infarct age <10 months showed fatty replacement. CONCLUSIONS: Myocardial adipose tissue is common in patients with infarct age >or=3 years. CT evaluation of myocardial adipose tissue may be important for accurate interpretation of CT perfusion and infarct imaging of the heart. PMID- 19442940 TI - Assessment of mitral valve anatomy and geometry with multislice computed tomography. AB - OBJECTIVES: The purpose of the present study was to assess the anatomy and geometry of the mitral valve by using 64-slice multislice computed tomography (MSCT). BACKGROUND: Because it yields detailed anatomic information, MSCT may provide more insight into the underlying mechanisms of functional mitral regurgitation (FMR). METHODS: In 151 patients, including 67 patients with heart failure (HF) and 29 patients with moderate to severe FMR, 64-slice MSCT coronary angiography was performed. The anatomy of the subvalvular apparatus of the mitral valve was assessed; mitral valve geometry, comprising the mitral valve tenting height and leaflet tethering, was evaluated at the anterolateral, central, and posteromedial levels. RESULTS: In the majority of patients, the anatomy of the subvalvular apparatus was highly variable because of multiple anatomic variations in the posterior papillary muscle (PM): the anterior PM had a single insertion, whereas the posterior PM showed multiple heads and insertions (n = 114; 83%). The assessment of mitral valve geometry demonstrated that patients with HF with moderate to severe FMR had significantly increased posterior leaflet angles and mitral valve tenting heights at the central (44.4 degrees +/- 11.9 degrees vs. 37.1 degrees +/- 9.0 degrees, p = 0.008; 6.6 +/- 1.4 mm/m(2) vs. 5.3 +/- 1.3 mm/m(2), p < 0.0001, respectively) and posteromedial levels (35.9 degrees +/- 10.6 degrees vs. 26.8 degrees +/- 10.1 degrees, p = 0.04; 5.4 +/- 1.6 mm/m(2) vs. 4.1 +/- 1.2 mm/m(2), p < 0.0001, respectively), as compared with patients with HF without FMR. In addition, a more outward displacement of the PMs, reflected by a higher mitral valve sphericity index, was observed in patients with HF with FMR (1.4 +/- 0.3 vs. 1.2 +/- 0.3, p = 0.004). Mitral valve tenting height at the central level and mitral valve sphericity index were the strongest determinants of FMR severity. CONCLUSIONS: MSCT provides anatomic and geometric information on the mitral valve apparatus. In patients with HF with moderate to severe FMR, a more pronounced tethering of the mitral leaflets at the central and posteromedial levels was demonstrated using MSCT. PMID- 19442941 TI - Computed tomography to analyze mitral valve: an answer in search of a question. PMID- 19442942 TI - Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and validation with single photon emission computed tomography. AB - OBJECTIVES: Our goal was to validate myocardium at risk on T2-weighted short tau inversion recovery (T2-STIR) cardiac magnetic resonance (CMR) over time, compared with that seen with perfusion single-photon emission computed tomography (SPECT) in patients with ST-segment elevation myocardial infarction, and to assess the amount of salvaged myocardium after 1 week. BACKGROUND: To assess reperfusion therapy, it is necessary to determine how much myocardium is salvaged by measuring the final infarct size in relation to the initial myocardium at risk of the left ventricle (LV). METHODS: Sixteen patients with first-time ST-segment elevation myocardial infarction received (99m)Tc tetrofosmin before primary percutaneous coronary intervention. SPECT was performed within 4 h and T2-STIR CMR within 1 day, 1 week, 6 weeks, and 6 months. At 1 week, patients were injected with a gadolinium-based contrast agent for quantification of infarct size. RESULTS: Myocardium at risk at occlusion on SPECT was 33 +/- 10% of the LV. Myocardium at risk on T2-STIR did not differ from SPECT, at day 1 (29 +/- 7%, p = 0.49) or week 1 (31 +/- 6%, p = 0.16) but declined at week 6 (10 +/- 12%, p = 0.0096 vs. 1 week) and month 6 (4 +/- 11%, p = 0.0013 vs. 1 week). There was a correlation between myocardium at risk demonstrated by T2-STIR at week 1 and myocardium at risk by SPECT (r(2) = 0.70, p < 0.001), and the difference between the methods on Bland-Altman analysis was not significant (-2.3 +/- 5.7%, p = 0.16). Both modalities identified myocardium at risk in the same perfusion territory and in concordance with angiography. Final infarct size was 8 +/- 7%, and salvage was 75 +/- 19% of myocardium at risk. CONCLUSIONS: This study demonstrates that T2-STIR performed up to 1 week after reperfusion can accurately determine myocardium at risk as it was before opening of the occluded artery. CMR can also quantify salvaged myocardium as myocardium at risk minus final infarct size. PMID- 19442943 TI - A closer look on the battlefield: the salvaged area at risk as an outcome marker for myocardial reperfusion. PMID- 19442944 TI - Serial contrast-enhanced cardiac magnetic resonance imaging demonstrates regression of hyperenhancement within the coronary artery wall in patients after acute myocardial infarction. AB - OBJECTIVES: Our aim was to determine whether serial contrast-enhanced cardiac magnetic resonance (CE-CMR) is useful for the characterization of tissue signal changes within the coronary vessel wall in patients after acute myocardial infarction (AMI). BACKGROUND: Inflammation plays a key role in the development of AMI. CE-CMR of the vessel wall has been found useful for the characterization of inflammatory tissue signal changes in patients with carotid artery stenosis, giant cell arteritis, or Takayasu's arteritis; however, it has never been serially performed in the coronary artery wall in patients with acute and chronic myocardial infarction using a gadolinium-based contrast medium and compared with systemic markers of inflammation. METHODS: CE-CMR using a T1-weighted 3 dimensional gradient echo inversion recovery sequence of the coronary artery wall and 0.2 mmol/kg of gadolinium-diethylenetriaminepentaacetic acid was performed in 10 patients with AMI 6 days and 3 months after coronary intervention and in 9 subjects without coronary artery disease on invasive coronary angiography. Contrast-to-noise ratio (CNR) within the coronary artery wall was quantified in comparison with blood signal. RESULTS: Patients with AMI demonstrated a significantly increased coronary vessel wall enhancement 6 days after infarction compared with normal subjects (CNR 7.8 +/- 4.4 vs. 5.3 +/- 3.2, p < 0.001). Three months after infarction, CNR decreased to 6.5 +/- 4.7 (p < 0.03). This decrease paralleled declines in C-reactive protein. Angiographically normal segments showed no contrast changes, but CNR significantly decreased in stenotic segments, from 10.9 +/- 3.8 to 6.8 +/- 5.0 (p < 0.002), resulting in a reduction of enhanced segments from 70% to 25% (p < 0.01). CONCLUSIONS: Serial CE-CMR identified changes in spatial extent and intensity of coronary contrast enhancement in patients after AMI. This technique may be useful for the characterization of transient coronary tissue signal changes, which may represent edema or inflammation during the post-infarction phase. In addition, CE-CMR may offer the potential for visualization of inflammatory activity in atherosclerosis associated with acute coronary syndromes. PMID- 19442945 TI - Can contrast-enhanced cardiac magnetic resonance assess inflammation of the coronary wall? PMID- 19442946 TI - Abnormal glucose metabolism in acute myocardial infarction: influence on left ventricular function and prognosis. AB - OBJECTIVES: We studied the influence of abnormal glucose metabolism on left ventricular (LV) function and prognosis in 203 patients with acute myocardial infarction. BACKGROUND: Abnormal glucose metabolism is associated with increased mortality after acute myocardial infarction. This appears to be particularly attributable to an increased incidence of post-infarction congestive heart failure. A relationship between glucose metabolism and LV function could potentially explain this excess mortality. METHODS: In patients without known diabetes, glucose metabolism was determined using an oral glucose tolerance test before discharge. LV function was assessed using echocardiographic measurements (LV end-diastolic volume, LV end-systolic volume, LV ejection fraction, restrictive diastolic filling pattern, early transmitral flow velocity to early diastolic mitral annular velocity ratio [E/e'], and left atrial volume index) and by measuring plasma N-terminal pro-B-type natriuretic peptide levels. RESULTS: After adjustment for age and gender, a linear relationship between the degree of abnormal glucose metabolism was observed for each marker of LV dysfunction (p(trend) < 0.05) with the exception of left atrial volume index (p = 0.10). During a median follow-up of 21 months, 32 patients died, and 39 patients met the secondary end point of death or hospitalization for heart failure. After adjustment for differences in LV function, as well as other relevant characteristics, newly detected, as well as known diabetes were independent predictors of both all-cause mortality (hazard ratios [HR]: 4.2 [95% confidence interval (CI): 1.1 to 17.1] and HR: 5.7 [95% CI: 1.3 to 25.2], respectively), and the composite of death or hospitalization for heart failure (HR: 4.3 [95% CI: 1.2 to 15.6] and HR: 5.8 [95% CI: 1.5 to 22.3], respectively). Comparable nonsignificant trends were observed for patients with impaired glucose tolerance. CONCLUSIONS: Although perturbations in glucose metabolism were linearly associated with impairment of LV function in the early phase of acute myocardial infarction, this relationship alone did not explain the excess mortality in patients with newly detected or known diabetes. PMID- 19442947 TI - Dysglycemia and acute myocardial infarction: the role of echocardiography. PMID- 19442948 TI - Intraoperative fluorescence imaging system for on-site assessment of off-pump coronary artery bypass graft. AB - OBJECTIVES: The aim of this study was to evaluate the intraoperative fluorescence imaging (IFI) system in the real-time assessment of graft patency during off-pump coronary artery bypass graft. BACKGROUND: Intraoperative fluorescence imaging is an intraoperative angiography-like imaging modality using fluorescent indocyanine green excited with laser light. Recently, assessment of graft patency using the IFI system was introduced into clinical use. The feasibility and efficacy of IFI technology in off-pump coronary artery bypass graft has not been systematically compared with other conventional diagnostic modalities. METHODS: Patients undergoing off-pump coronary artery bypass graft received IFI analysis, intraoperative transit time flowmetry, and postoperative X-ray angiography. In off-line IFI analysis, the graft washout was classified based on the number of heartbeats required for indocyanine green washout: fast washout (15 beats). RESULTS: A total of 507 grafts in 137 patients received IFI analysis. Of all the IFI analyses, 379 (75%) grafts were visualized clearly up to the distal anastomosis. With regard to anastomosis location, anterior location was associated with a higher percentage of fully analyzable images (90%). More than 80% of images were analyzable, irrespective of graft type. Six grafts with acceptable transit time flowmetry results were diagnosed with graft failure by IFI, which required on-site graft revision. All revised grafts' patency was confirmed by post-operative X-ray angiography. Conversely, 21 grafts with unsatisfactory transit time flowmetry results demonstrated acceptable patency with IFI. Graft revision was considered unnecessary in these grafts, and 20 grafts (95%) were patent by post-operative X-ray angiography. Compared with slow washout, fast washout was associated with a higher preoperative ejection fraction, use of internal mammary artery grafts, and anterior anastomosis location. CONCLUSIONS: The IFI system enables on-site assessment of graft patency, providing both morphologic and functional information. This technique may help reduce procedure-related, early graft failures in off-pump bypass patients. PMID- 19442949 TI - Assessment of graft patency during coronary artery bypass graft surgery: mitigating the risk. PMID- 19442950 TI - Atherosclerotic and thrombogenic neointima formed over sirolimus drug-eluting stent: an angioscopic study. AB - OBJECTIVES: We sought to examine by angioscopy the neointima formation and thrombogenic potential of the neointima after deployment of a drug-eluting stent (DES). BACKGROUND: Late stent thrombosis after DES implantation, a major safety concern, has been associated with poor strut coverage by neointima. Intracoronary angioscopy provides a method for visual evaluation of stent coverage by neointima and detection of thrombus in the stented coronary segment. METHODS: Patients undergoing implantation of a sirolimus DES (n = 57) were serially examined by angioscopy immediately after (baseline) and again at 10 months (follow-up) after implantation. The angioscopic color grade of the neointima from white to yellow was assessed in a semiquantitative manner. Stent coverage was classified into not covered (Grade 0), covered by a thin layer (Grade 1), or buried under neointima (Grade 2). The thrombogenic potential of the neointima was evaluated by the prevalence of thrombus on the neointima. RESULTS: The maximum yellow color grade of the neointima within DES-implanted lesions increased significantly from baseline to follow-up (1.4 +/- 1.1 vs. 1.9 +/- 0.6, p = 0.0008). Even among lesions without yellow color at baseline, yellow color was detected in 94% (17 of 18) of lesions at follow-up. The prevalence of thrombus was significantly higher on the yellow than on the white neointimal areas. Thrombus was detected on yellow and/or Grade-0/1 neointima, but never on the white Grade-2 neointima. CONCLUSIONS: Sirolimus DES promoted formation of atherosclerotic yellow neointima in the stent-implanted lesion at 10-month follow-up. Thrombus was detected more often on the yellow area than on the white area and was never detected where a stent was buried under white neointima. These data suggest that the increased potential risk of late stent thrombosis in DES lesions may be due to the newly formed yellow neotima and cholesterol-laden plaque. PMID- 19442951 TI - One step forward and two steps back with drug-eluting-stents: from preventing restenosis to causing late thrombosis and nouveau atherosclerosis. PMID- 19442952 TI - Synergistic effect of cardiovascular risk factors on necrotic core in coronary arteries: a report from the global intravascular radiofrequency data analysis registry. AB - OBJECTIVES: This study explored whether an individual or a cluster of risk factors affects the extent of necrotic core (NC) assessed by intravascular ultrasound (IVUS) radiofrequency data (RFD) analysis. BACKGROUND: Several systemic diseases contribute to the development of coronary artery disease. METHODS: The Global Intravascular Radiofrequency Data Analysis Registry was a prospective, multicenter, nonrandomized database that enrolled 990 patients with coronary artery disease in whom 1 major coronary artery was imaged by IVUS-RFD. For the multivariable analysis, the population was divided into 4 classes: young women, young men (both 62 years). Mean NC area was categorized as 1: top quartile (>or=0.62 mm(2)) or as 0: lower 3 quartiles. RESULTS: Young patients had less NC compared with older patients (0.40 +/- 0.36 mm(2) of NC vs. 0.50 +/- 0.46 mm(2) in old patients, p = 0.0007). Nondiabetic patients had less NC than diabetic patients (0.43 +/- 0.41 mm(2) of NC vs. 0.51 +/- 0.44 mm(2) in diabetic patients, p = 0.02). The NC area was lower in normotensive patients (0.40 +/- 0.36 mm(2)) than in hypertensive patients (0.48 +/- 0.44 mm(2)) (p = 0.02). In the bivariate analysis, age, hypertension, diabetes, and prior coronary artery bypass graft were statistically significant, however in logistic regression analysis, only age (odds ratio [OR]: 1.023, 95% confidence interval [CI]: 1.009 to 1.037, p = 0.001) and diabetes (OR: 1.636, 95% CI: 1.174 to 2.279, p = 0.004) remained statistically significant. In a per-class logistic regression analyses including only diabetes as covariate, the OR in young women was 2.1 (95% CI: 0.77 to 6.0, p = 0.14), in young men the OR was 1.6 (95% CI: 0.90 to 2.7, p = 0.11), in old women the OR was 2.3 (95% CI: 1.09 to 4.9, p = 0.03), and in old men the OR was 1.6 (95% CI: 0.96 to 2.7, p = 0.07). Further, when only patients with diabetes and hypertension were included, young men (OR: 2.0, p = 0.041), old women (OR: 3.04, p = 0.046), and old men (OR: 2.2, p = 0.025) were significant. CONCLUSIONS: Individually and collectively, age and diabetes mellitus are associated with an increase in NC by IVUS-RFD analysis. PMID- 19442954 TI - Left ventricular torsion: an expanding role in the analysis of myocardial dysfunction. AB - During left ventricular (LV) torsion, the base rotates in an overall clockwise direction and the apex rotates in a counterclockwise direction when viewed from apex to base. LV torsion is followed by rapid untwisting, which contributes to ventricular filling. Because LV torsion is directly related to fiber orientation, it might depict subclinical abnormalities in heart function. Recently, ultrasound speckle tracking was introduced for quantification of LV torsion. This fast, widely available technique may contribute to a more rapid introduction of LV torsion as a clinical tool for detection of myocardial dysfunction. However, knowledge of the exact function and structure of the heart is fundamental for understanding the value of LV torsion. LV torsion has been investigated with different measurement methods during the past 2 decades, using cardiac magnetic resonance as the gold standard. The results obtained over the years are helpful for developing a standardized method to quantify LV torsion and have facilitated the interpretation and value of LV torsion before it can be used as a clinical tool. PMID- 19442955 TI - Newer methods for noninvasive assessment of myocardial perfusion: cardiac magnetic resonance or cardiac computed tomography? PMID- 19442953 TI - Macrophage-specific lipid-based nanoparticles improve cardiac magnetic resonance detection and characterization of human atherosclerosis. AB - OBJECTIVES: We sought to determine whether gadolinium (Gd)-containing lipid-based nanoparticles (NPs) targeting the macrophage scavenger receptor-B (CD36) improve cardiac magnetic resonance (CMR) detection and characterization of human atherosclerosis. BACKGROUND: Gd-containing lipid-based NPs targeting macrophages have improved MR detection of murine atherosclerosis. METHODS: Gadolinium containing untargeted NPs, anti-CD36 NPs, and nonspecific Fc-NPs were created. Macrophages were incubated with fluorescent targeted and nontargeted NPs to determine uptake via confocal microscopy and inductively coupled plasma mass spectroscopy (ICP-MS) quantified Gd uptake. Human aortic specimens were harvested at autopsy. With a 1.5-T scanner, T1, T2, and PDW 3-dimensional scans were performed along with post-contrast scans after 24 h incubation. The T1 and cluster analyses were performed and compared with immunohistopathology. RESULTS: The NPs had a mean diameter of 125 nm and 14,900 Gd-ions, and relaxivity was 37 mmol/l(-1)s(-1) at 1.5-T and 37 degrees C. Confocal microscopy and ICP-MS demonstrated significant in vitro macrophage uptake of targeted NPs, whereas non targeted NPs had minimal uptake. On T1 imaging, targeted NPs increased contrast to-noise ratio (CNR) by 52.5%, which was significantly greater than Fc-NPs (CNR increased 17.2%) and nontargeted NPs (CNR increased 18.7%) (p = 0.001). Confocal fluorescent microscopy showed that NPs target resident macrophages, whereas the untargeted NPs and Fc-NPs are found diffusely throughout the plaque. Targeted NPs had a greater signal intensity increase in the fibrous cap compared with non targeted NPs. CONCLUSIONS: Macrophage-specific (CD36) NPs bind human macrophages and improve CMR detection and characterization of human aortic atherosclerosis. Thus, macrophage-specific NPs could help identify high-risk human plaque before the development of an atherothrombotic event. PMID- 19442956 TI - Effects of left bundle branch block and right ventricular pacing on assessing myocardial viability by positron emission tomography. PMID- 19442957 TI - Coronary flow reserve and pharmacologic stress perfusion imaging: beginnings and evolution. PMID- 19442958 TI - Devices, biology, imaging, and the regulatory processes... PMID- 19442959 TI - Evaluation of the wash resistance of three types of manufactured insecticidal nets in comparison to conventionally treated nets. AB - The present study evaluated the efficacy and wash resistance of several commercial deltamethrin-treated nets (PermaNet, from factory (PN-F) and market (PN-M), Yorkool (Y) and AZ net) that were claimed by the manufacturers to be Long Lasting Insecticide Treated Nets (LLITNs), compared to ITNs conventionally treated with deltamethrin (23-27 mg/m(2), using one K-O Tab tablet (KO) per net). Montpellier washing technique was used for washing the pieces of the nets. Insecticidal activity was assessed on dried pieces of nets after 0, 2, 5, 8, 11, 15, 18 and 21 washes, using two types of bioassay (mean median knock down times and mortality 24 h after a 3-min exposure) and reared female Anopheles stephensi. To evaluate the effect of heat on diffusion of insecticide from inside of the nets to the surface of them, some Permanet nets were heated. For all the types of nets tested the median knock down time (MKDT) increased approximately linearly with number of washes. The slopes of the lines (increase of MKDT per wash) were low with the PN-F and PN-M, intermediate with Y and equally high with KO and AZ. No significant differences can be claimed with the 3-min exposure tests. The slopes of the regression lines did not differ significantly between the heated and unheated samples. It is concluded that diffusion at ambient temperature is fast enough to rapidly compensate for the loss of insecticide on the surface with no need to artificially stimulate diffusion by heating. PMID- 19442960 TI - Understanding dynamics of myoglobin in heterogeneous aqueous environments using coupled water fractions. AB - This work presents an analysis of near environment of myoglobin (Mb) in different aqueous solutions (in the presence of NaCl, sucrose, trehalose, urea, and glycerol) using the coupled water fractions measured using a quartz crystal microbalance (QCM). The secondary structural features of the protein from circular dichroic (CD) spectroscopy and the coupled water fractions give important clues to the overall dynamics of the protein. Using time resolved fluorescence, these leads have been applied to understand the observed lifetime relaxations of Mb. Though the time scales of observation of coupled water and the lifetimes are very different, our study suggests that the trends in coupled water fraction seem to be good indicators for regulation of the relaxation dynamics of the protein. The relaxations generally show a triphasic distribution of time scales. The initial relaxation in the picoseconds time scale represents the local motions of coupled water followed by a slightly slower decay in hundreds of picoseconds attributable to coupled water-'quasi free' water interactions. The third nanosecond lifetime is due to changes in transitions in isomers of hydrated protein. The dynamics of coupled water in Mb with NaCl is the fastest (around 21 ps) and is slowest in glycerol (250 ps). The results strongly indicate that it is the resident times of water molecules that play a dominant role in the overall stability of protein in a particular hydrated isomer and not just always the number of such water molecules in the hydrated protein. PMID- 19442961 TI - Comparison of fourier-domain and time-domain optical coherence tomography for assessment of corneal thickness and intersession repeatability. AB - PURPOSE: To compare Fourier-domain optical coherence tomography (FD-OCT) with time-domain OCT (TD-OCT) for agreement in corneal pachymetry in the central (2 mm) zone and paracentral (2- to 5-mm) zone, minimum corneal thickness, and instrument intersession reliability in candidates with normal cornea. DESIGN: Prospective comparative trial. METHODS: The study was performed at a tertiary care ophthalmic hospital. One hundred normal candidates with no ocular pathology except mild refractive error were included. FD-OCT and TD-OCT were used for pachymetric analysis within 15 minutes of each other. Repeat testing on both machines was done on the next day. One eye from each patient was randomly selected for analysis of both comparison and reliability. RESULTS: The mean thickness was significantly more for FD-OCT (difference being 5.8, 11.1, and 19.2 mum for central, paracentral, and minimal thickness). Highest correlation, best linear fit, and smallest range of 95% limits of agreement (LoA) was seen for central corneal thickness, followed by paracentral and minimum corneal thickness (R(2) values for the 3 best fit lines were 0.93, 0.86, and 0.58, respectively). In terms of intersession reliability, FD-OCT was better (coefficients of reliability <1.5% vs 4.5% of TD-OCT) with smaller 95% LoA range, suggesting its better performance. CONCLUSIONS: The corneal thickness measurements between TD OCT and FD-OCT were highly correlated but not similar. Conversion equations may be used for central and paracentral, but not for minimum, corneal thickness. Even though both the OCT instruments had good reliability, FD-OCT was better. PMID- 19442962 TI - Spontaneous corneal clearance despite graft detachment in descemet membrane endothelial keratoplasty. AB - PURPOSE: To describe spontaneous recovery of corneal transparency in 2 cases with nearly complete graft detachment after Descemet membrane endothelial keratoplasty (DMEK). DESIGN: Case series. METHODS: In 2 patients with Fuchs endothelial dystrophy, DMEK was performed. Through a 3-mm clear corneal tunnel incision, the recipient Descemet membrane and its endothelium was stripped off from the posterior stroma. A 9.5-mm diameter organ-cultured Descemet roll was inserted into a recipient anterior chamber, positioned onto the posterior stroma, and secured by a complete air filling of the anterior chamber for 45 minutes. RESULTS: At 1 month after uneventful DMEK, both transplanted corneas showed decompensation attributable to subtotal graft detachment. Unexpectedly, corneal transparency improved spontaneously, and at 3 months, both transplanted corneas had a normal pachymetry, despite persistent graft detachment. The patients' visual acuities improved to 20/50 (0.4) and 20/25 (0.8) at 3 months to 20/28 (0.7) and 20/20 (1.0), respectively at 9 months. CONCLUSIONS: Corneal clearance in the presence of a detached DMEK graft is not consistent with the current concept of endothelial keratoplasty, which requires an (attached) donor endothelial cell layer at the recipient posterior corneal surface. Endothelial transfer, migration, regeneration, or a combination thereof from either the donor or the recipient may explain the visual recovery. These observations suggest that a review of our approach to endothelial keratoplasty and the management of corneal endothelial disorders may be warranted. PMID- 19442963 TI - Detection of cytotoxin genotypes of Helicobacter pylori in stomach, saliva and dental plaque. AB - BACKGROUND: The aim of this study was to detect the presence of Helicobacter pylori and its virulent cagA genes in the oral cavity of individuals with upper gastric diseases. Sixty-two individuals (42+/-2.3 years) with dispepsy symptoms, referred for gastroscopy and who were H. pylori positive in the gastric biopsy, were recruited and separated in two groups: case group-individuals with gastric disease (n = 30); control group-individuals with no gastric disease (n = 32); saliva, dental plaque and biopsy samples were collected from all individuals. Oral and biopsy samples were analyzed by PCR using specific primers for H. pylori 16S ribosomal and cagA genes. PCR products were sequenced for DNA homology confirmation. H. pylori was detected neither in dental plaque nor in saliva in the control group. In the case group H. pylori DNA was detected in 16/30 (53.3%) saliva samples and in 11/30 (36.6%) dental plaque samples. The cagA gene was detected in 13/30 (43.3%) gastric biopsies, in 7/16 (43.8%) saliva samples, and in 3/11 (27.3%) dental plaque samples. Eighteen (60.0%) individuals in the case group were H. pylori positive both in oral and biopsy samples, and 8 (26.6%) of those were positive for cagA-H. pylori DNA. H. pylori and its virulent clone showed a higher prevalence in the oral cavity of individuals in the case group than in the control group (p < 0.05). Our results suggest that dental plaque and saliva may serve as temporary reservoir for H. pylori and its virulent cagA variant in individuals with gastric disease. PMID- 19442964 TI - Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism. AB - Na,K-ATPase is a ubiquitous transmembrane protein that regulates and maintains the intracellular Na(+) and K(+) gradient necessary for cell homeostasis. Recently, the importance of this pump in external stimuli-induced leukemia cell apoptosis has been increasingly appreciated, however, the exact role of Na,K ATPase in mitochondrial apoptotic pathway still remains little understood. In this study, we found mitochondrial toxin rotenone caused a rapid mitochondrial membrane potential (MMP) collapse in Jurkat cells followed by plasma membrane depolarization (PMP). Similar results were also obtained in human U937 cells and non-cancerous mouse primary T cells. Rotenone-induced PMP depolarization occurred before apoptosis and well correlated with Na,K-ATPase impairment. To understand the mechanisms, Jurkat cells with mtDNA depletion and catalase overexpression were used. The results demonstrated that both PMP depolarization and Na,K-ATPase impairment induced by rotenone were regulated by mitochondrial H(2)O(2) and Bcl 2. Finally, Na,K-ATPase suppression by ouabain greatly accelerated and enhanced mitochondrial toxins-induced cells apoptosis in Jurkat, U937 and primary T cells. In sum, by using leukemia cells and mouse primary T cells, we confirmed that mitochondria-to-Na,K-ATPase and PMP depolarization might represent a novel mechanism for mitochondria to amplify death signals in the initiation stage of cells apoptosis induced by mitochondrial toxins. PMID- 19442965 TI - Isolation and structure elucidation of two different polysaccharides from the lipopolysaccharide of Rahnella aquatilis 33071T. AB - Two different polysaccharides were obtained by mild acid degradation of the lipopolysaccharide of Rahnella aquatilis 33071(T). These were studied by sugar and methylation analyses along with 1D and 2D (1)H and (13)C NMR spectroscopy. The following structures were established for the polysaccharides: -->4)-alpha-D Rhap-(1-->3)-alpha-D-Rhap-(1-->3)beta-D-Galp-(1-->3)-alpha-D-Manp-(1-->2)-alpha-D Manp-(1--> beta-D-Glcp-(1-->3)-alpha-D-galp-(1-->4)-alpha-D-GlcpA-(1-->2). The former structure is new, whereas the latter has been reported earlier as the structure of the O-specific polysaccharide of R. aquatilis 95 U003 (Zdorovenko, E. L.; Varbanets, L. D.; Zatonsky, G. V.; Kachala, V. V.; Zdorovenko, G. M.; Shashkov, A. S.; Knirel, Y. A. Carbohydr. Res.2008, 343, 2494-2497). PMID- 19442966 TI - Simulation of cyclic reprocessing buildup on reused medical devices. AB - A series of discrete models were developed to study the development of cyclic reprocessing buildup (CRB) on medical devices, and to explore the effect of cleaning efficacy and type of disinfection on the removal of this CRB. A cellular automata (CA) model was used to simulate the development of CRB, including microbial replication and production of extracellular matrix (EM). The process of disinfection (microbes being killed, EM being cross-linked or oxidized, etc.) was also described in the CA model. Next, a stochastic model, Ising's model combined with Monte Carlo methods was used to simulate the removal of CRB from a surface by cleaning. These models were developed to simulate the persistent residual CRB that occurs on reused medical devices such as flexible endoscopes, to determine how well the various microbes survive in the CRB during disinfection and cleaning, and to predict the efficiency of disinfectants to kill microbes within the CRB. The CRB model will help evaluate cleaning methods to identify those that will reduce/eliminate the CRB from occurring; thereby reducing the infection transmission potential in clinical procedures involving reprocessed medical devices. PMID- 19442967 TI - Time to pregnancy after a previous miscarriage in subfertile couples. AB - OBJECTIVE: To assess the time to spontaneous ongoing pregnancy after a previous miscarriage in subfertile couples. DESIGN: A prospective cohort study. SETTING: The study was conducted in 38 fertility centers in the Netherlands. PATIENT(S): Subfertile couples who miscarried after completing their basic fertility work-up. INTERVENTION(S): Expectant management after a miscarriage. MAIN OUTCOME MEASURE(S): Spontaneous ongoing pregnancy. RESULT(S): We included 5,663 subfertile couples, of which 1,098 (19%) conceived spontaneously. Among these 1,098 couples, 199 (18%) miscarried and these couples were included in the present study. Follow-up was completed for 171 couples, of which 95 conceived again within 24 months of follow-up. Of these 95 pregnancies, 86 (91%) were ongoing. The cumulative spontaneous ongoing pregnancy rate (PR) after 24 months was 70% (95% confidence interval [CI] 59%-81%). CONCLUSION(S): Subfertile couples, who experience a treatment-independent pregnancy resulting in a miscarriage, have very good prospects of a spontaneous ongoing pregnancy in the near future. This information is useful in counseling couples who had a miscarriage after a previous period of subfertility. PMID- 19442968 TI - Long-term oral contraceptive pills and postoperative pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled trial. AB - OBJECTIVE: To evaluate postoperative long-term cyclic and continuous administration of combined oral contraceptive (OC) pills in preventing endometriosis-related pain recurrence. DESIGN: Prospective, randomized, controlled trial. SETTING: Tertiary care university hospital. PATIENT(S): Three hundred eleven women who underwent laparoscopic excision for symptomatic ovarian endometrioma. INTERVENTION(S): Patients were randomly divided into three groups: nonuser group receiving no therapy, and cyclic user group and continuous user group receiving low-dose, monophasic OC pills for 24 months in either cyclic or continuous administration. MAIN OUTCOME MEASURE(S): Presence and intensity of dysmenorrhea, dyspareunia, and chronic pelvic pain were assessed by a 10-point visual analogue scale (VAS) at 6, 12, 18, and 24 months postoperatively. RESULT(S): A significant reduction in recurrence rate and VAS scores for dysmenorrhea was evident in the continuous users versus the other groups at 6 months, and in cyclic users versus nonusers at 18 months postoperatively. No significant differences in recurrence rate and VAS scores for dyspareunia and chronic pelvic pain were demonstrated among the groups. The increase of VAS scores from 6-24 months during the study period for dysmenorrhea, dyspareunia, and chronic pelvic pain was significantly higher in nonusers than in the other groups. CONCLUSION(S): Long-term postoperative use of OC pills can reduce the frequency and the severity of recurrent endometriosis-related dysmenorrhea. PMID- 19442969 TI - Reproductive consequences of genome-wide paternal uniparental disomy mosaicism: description of two cases with different mechanisms of origin and pregnancy outcomes. AB - OBJECTIVE: To describe the molecular and cytogenetic characterization of two different prenatal cases of androgenetic/biparental mosaicism and review the different possible mechanisms of origin in each case. DESIGN: Case study and literature review. SETTING: Tertiary medical center (prenatal diagnosis unit). PATIENT(S): A 26-year-old pregnant woman referred for suspected partial mole placenta and a 33-year-old pregnant woman referred for polyhydramnios and fetal malformations. INTERVENTION(S): Ultrasound examination, prenatal invasive procedures, molecular and cytogenetic analysis, physical and pathologic evaluation, and genetic counseling. MAIN OUTCOME MEASURE(S): Cytogenetic analysis, fluorescent in situ hybridization, and quantitative fluorescence polymerase chain reaction (QF-PCR) analysis. RESULT(S): The finding of a normal karyotype together with a triploidy-like QF-PCR profile led to the diagnosis of two cases of androgenetic (genome-wide paternal uniparental disomy)/biparental mosaicism. The first case showed placental mesenchymal dysplasia and a normal fetus, and the second one presented a fetus showing Beckwith-Wiedemann syndrome features and an apparently normal placenta. CONCLUSION(S): These cases highlight the wide range of possible clinical presentations of androgenetic/biparental mosaicism, the variety of mechanisms of their origin, and the importance of the combination of molecular and cytogenetic analysis to achieve an accurate diagnosis and provide reproductive counseling. PMID- 19442970 TI - Can an educational DVD improve the acceptability of elective single embryo transfer? A randomized controlled study. AB - OBJECTIVE: To assess whether provision of an educational DVD was more effective in increasing the uptake of elective single embryo transfers (eSET) than an educational brochure in an IVF population. DESIGN: Randomized controlled trial. SETTING: Private IVF clinic. PATIENT(S): One hundred thirty-one couples starting their first cycle of IVF were randomized to receive either an educational DVD or brochure. INTERVENTION(S): Sixty-four couples received the DVD and 67 couples received the brochure. Both provided identical factual information on outcomes and risks of twin pregnancies. The DVD also included two short interviews with mothers of twins. MAIN OUTCOME MEASURE(S): Preference for eSET after the intervention. RESULT(S): There were no significant differences in fertility history or demographics. After the interventions, both groups demonstrated significantly improved knowledge. Patients in the DVD group were significantly more likely to prefer eSET compared with patients who read the brochure (82.6% vs. 66.7%). CONCLUSION(S): Patients exposed to the educational DVD were significantly more likely to prefer eSET. Provision of an educational DVD, such as the one used in the present study, may provide an affordable and more effective means of delivering health risk information. PMID- 19442971 TI - U-shaped sacral fractures: surgical treatment and quality of life. AB - BACKGROUND: U-shaped sacral fractures are rare and highly unstable pelvic ring fractures. They are not recognised in the standard classification systems of these fractures. The fracture pattern is associated with significant neurological injury and can lead to progressive deformity and chronic pain if not diagnosed and treated properly. In recent years a variety of surgical strategies have been shown to facilitate early mobilisation and reduce early mortality as compared to non-operative strategies. Poor evidence, however, has hampered the development of a standard treatment algorithm. As for the long-term morbidity, the influence of operative treatment may be difficult to assess due to associated injury. However, evidence exists that there is a significant effect on the long-term morbidity. OBJECTIVE: To assess the injury characteristics, choice of treatment and quality of life of U-shaped sacral fractures. METHODS: Eight polytraumatised patients with U-shaped sacral fractures were identified over a 7-year period and evaluated retrospectively. They were analysed for fracture classification, associated injury, and injury severity. Clinical and Radiological results were evaluated. Neurological outcome was retrospectively classified by Gibbons' criteria. Long term quality of life outcome was evaluated using the EuroQoL-6D questionnaire. RESULTS: The study population consists of five women and three men; with a median age of 29 years. All patients sustained severe associated injury. The Injury Severity Score ranged from 17 to 45 (median 23). The median time between trauma and definitive internal fixation was 4 days (range, 2-22 days). Definitive fixation included either percutaneous iliosacral screws (n=2), transsacral plate osteosynthesis (n=1) or triangular osteosynthesis with (n=4) or without transsacral plating (n=1). Early postoperative mobilisation and early partial weight-bearing were encouraged when possible. Follow-up ranged from 5 to 65 months (median, 36 months). Pain, mood disorders and mobility problems mainly influenced patients' present general health status. CONCLUSION: U-shaped sacral fractures present a rare and heterogeneous injury. Operative treatment depended mainly on fracture type, associated spinal fractures, and the surgeon's preference. Long-term quality of life is dominated by pain, mood disorders and moderate mobility problems. PMID- 19442972 TI - Surgeon versus metalwork--tips to remove a retained intramedullary nail fragment. PMID- 19442973 TI - Penetrating cardiac injury: overcoming the limits set by Nature. AB - Repair of cardiac wounds was considered impossible little over 100 years ago. Despite progress, penetrating cardiac injury remains a highly lethal form of trauma today. Cardiac tamponade and exsanguination are the greatest immediate and life-threatening risks. Clinical presentation is extremely variable and diagnosis may be highly deceptive. Unlike other forms of trauma, resuscitation is of limited value and urgent operative intervention is the only meaningful treatment. Refinements in cardiothoracic surgery and the simultaneous evolution of trauma care systems have both contributed to saving lives. However, mortality rates for this condition have changed little in the last century, due largely to the rising proportion of more lethal injuries caused by gunshot wounds. PMID- 19442975 TI - Lifestyle intervention in obese children is associated with a decrease of the metabolic syndrome prevalence. AB - BACKGROUND: Weight loss is the appropriate approach to reduce the obesity-related health risk. However, the effect of lifestyle interventions on the metabolic syndrome prevalence has been rarely studied in obese children. METHODS: We analyzed changes of weight status, 2h glucose levels from oral glucose tolerance tests (oGTT), fasting glucose, lipids, blood pressure, and the prevalence of metabolic syndrome in relation to a 1-year outpatient lifestyle intervention in 288 obese children (45% male; mean age 12.5 years, mean SDS-BMI 2.48). These data were compared to 186 obese children without intervention with similar distributions of age, gender, and weight status. RESULTS: Lifestyle intervention led to a significant decrease of SDS-BMI (mean -0.22; 95%CI -0.18 to -0.26), while SDS-BMI increased significantly in children without intervention (mean +0.15; 95%CI +0.13 to +0.18). Children with lifestyle intervention had a significant decrease of metabolic syndrome prevalence (from 19% to 9%; definition according to IDF) and an improvement of waist circumference, blood pressure, and 2h glucose values in the oGTT in contrast to obese children without intervention. The degree of weight loss was significantly associated with the amount of improvement of the components of the metabolic syndrome. Particularly, the children with a SDS-BMI reduction >0.5 showed an improvement of all components of the metabolic syndrome. CONCLUSIONS: Lifestyle intervention led to weight loss and an improvement of the metabolic syndrome and its components. Degree of weight loss was associated with the improvement of the prevalence of metabolic syndrome and its components. PMID- 19442974 TI - Gender differences in heart failure self-care: a multinational cross-sectional study. AB - BACKGROUND: Despite a common view that women are better at self-care, there is very little evidence to support or challenge this perspective in the heart failure (HF) population. OBJECTIVE: The purpose of this study was to determine if there are cross-cultural gender differences in self-reported HF self-care and to describe gender differences in the determinants of HF self-care. DESIGN, SETTING, AND PARTICIPANTS: A secondary analysis was completed of cross-sectional study data collected on 2082 adults with chronic HF from the United States, Australia and Thailand. METHODS: Comparisons were made between men and women regarding self care maintenance, management and confidence as assessed by the Self-Care of Heart Failure Index, as well as the proportion of subjects engaged in adequate self care. Multivariate comparisons were made to determine if gender explained sufficient variance in HF self-care and the likelihood of reporting adequate self care, controlling for nine model covariates. RESULTS: The sample was comprised of 1306 men and 776 women. Most (73.5%) had systolic or mixed systolic and diastolic HF and 45% had New York Heart Association class III or IV HF. Although small and clinically insignificant gender differences were found in self-care maintenance, gender was not a determinant of any aspect of HF self-care in multivariate models. Married women were 37% less likely to report adequate self-care maintenance than unmarried women. Comorbidities only influenced the HF self-care of men. Being newly diagnosed with HF also primarily affected men. Patients with diastolic HF (predominantly women) had poorer self-care maintenance and less confidence in self-care. CONCLUSION: Differences in HF self-care are attributable to factors other than gender; however, there are several gender-specific determinants of HF self-care that help identify patients at risk for practicing poor self-care. PMID- 19442976 TI - The mechanical properties of neonatal rat spinal cord in vitro, and comparisons with adult. AB - A number of studies have investigated the mechanical properties of adult spinal cord under tension, however it is not known whether age has an effect on these properties. This is of interest to those aiming to understand the clinical differences between adults and children with spinal cord injury (e.g. severity and recovery), and those developing experimental or computational models for paediatric spinal cord injury. Entire spinal cords were freshly harvested from neonatal rats (14 days) and tested in vitro under uniaxial tension at a range of strain rates (0.2, 0.02, 0.002/s) to a range of strains (2%, 3.5%, 5%), with relaxation responses being recorded for 15 min. These mechanical properties were compared to previously reported data from similar experiments on adult rat spinal cords, and the peak stress and the stress after 15 min of relaxation were found to be significantly higher for spinal cords from adults than neonates (p<0.001). A non-linear viscoelastic model was developed and was observed to adequately predict the mechanical behaviour of this tissue. The model developed in this study may be of use in computational models of paediatric spinal cord. The significant differences between adult and neonatal spinal cord properties may explain the higher initial severity of spinal cord injury in children and may have implications for the development of experimental animal models for paediatric spinal cord injury, specifically for those aiming to match the injury severity with adult experimental models. PMID- 19442977 TI - Does residual force enhancement increase with increasing stretch magnitudes? AB - It is generally accepted that force enhancement in skeletal muscles increases with increasing stretch magnitudes. However, this property has not been tested across supra-physiological stretch magnitudes and different muscle lengths, thus it is not known whether this is a generic property of skeletal muscle, or merely a property that holds for small stretch magnitudes within the physiological range. Six cat soleus muscles were actively stretched with magnitudes varying from 3 to 24 mm at three different parts of the force-length relationship to test the hypothesis that force enhancement increases with increasing stretch magnitude, independent of muscle length. Residual force enhancement increased consistently with stretch amplitudes on the descending limb of the force-length relationship up to a threshold value, after which it reached a plateau. Force enhancement did not increase with stretch amplitude on the ascending limb of the force-length relationship. Passive force enhancement was observed for all test conditions, and paralleled the behavior of the residual force enhancement. Force enhancement increased with stretch magnitude when stretching occurred at lengths where there was natural passive force within the muscle. These results suggest that force enhancement does not increase unconditionally with increasing stretch magnitude, as is generally accepted, and that increasing force enhancement with stretch appears to be tightly linked to that part of the force-length relationship where there is naturally occurring passive force. PMID- 19442978 TI - IMU: inertial sensing of vertical CoM movement. AB - The purpose of this study was to use a quaternion rotation matrix in combination with an integration approach to transform translatory accelerations of the centre of mass (CoM) from an inertial measurement unit (IMU) during walking, from the object system onto the global frame. Second, this paper utilises double integration to determine the relative change in position of the CoM from the vertical acceleration data. Five participants were tested in which an IMU, consisting of accelerometers, gyroscopes and magnetometers was attached on the lower spine estimated centre of mass. Participants were asked to walk three times through a calibrated volume at their self-selected walking speed. Synchronized data were collected by an IMU and an optical motion capture system (OMCS); both measured at 100 Hz. Accelerations of the IMU were transposed onto the global frame using a quaternion rotation matrix. Translatory acceleration, speed and relative change in position from the IMU were compared with the derived data from the OMCS. Peak acceleration in vertical axis showed no significant difference (p> or =0.05). Difference between peak and trough speed showed significant difference (p<0.05) but relative peak-trough position between the IMU and OMCS did not show any significant difference (p> or =0.05). These results indicate that quaternions, in combination with Simpsons rule integration, can be used in transforming translatory acceleration from the object frame to the global frame and therefore obtain relative change in position, thus offering a solution for using accelerometers in accurate global frame kinematic gait analyses. PMID- 19442979 TI - Robot-based methodology for a kinematic and kinetic analysis of unconstrained, but reproducible upper extremity movement. AB - Although arm movements play an important role in everyday life, there is still a lack of procedures for the analysis of upper extremity movement. The main problems for standardizing the procedure are the variety of arm movements and the difficult assessment of external hand forces. The first problem requires the predefinition of motions, and the second one is the prerequisite for calculation of net joint forces and torques arising during motion. A new methodology for measuring external forces during prespecified, reproducible upper extremity movement has been introduced and validated. A robot-arm has been used to define the motion and 6 degrees of freedom (DoF) force sensor has been attached to it for acquiring the external loads acting on the arm. Additionally, force feedback has been used to help keeping external loads constant. Intra-individual reproducibility of joint angles was estimated by using correlation coefficients to compare a goal-directed movement with robot-guided task. Inter-individual reproducibility has been evaluated by using the mean standard deviation of joint angles for both types of movement. The results showed that both inter- and intra individual reproducibility have significantly improved by using the robot. Also, the effectiveness of using force feedback for keeping a constant external load has been shown. This makes it possible to estimate net joint forces and torques which are important biomechanical information in motion analysis. PMID- 19442980 TI - Parametric and subject-specific finite element modelling of the lower cervical spine. Influence of geometrical parameters on the motion patterns. AB - Morphometrical and postural features of the cervical spine are supposed to significantly influence its biomechanical behaviour. However, the effects of these geometrical parameters are quite difficult to evaluate. An original numerical method is proposed in order to automatically generate parametric and subject-specific meshes of the lower cervical spine. Sixteen finite element models have been built from cadaver specimens using low dose biplanar X-rays. All the generated meshes fulfilled the quality criteria. A preliminary evaluation was performed on the C5-C6 functional units using a database of previous experimental tests. The principal and coupled motions were simulated. The responses of the numerical models were within the experimental standard deviation corridors in most cases. Rotation-moment relationships were then compared to assess the influence of geometry on the mechanical response. Geometry was found to play a significant role in the motion patterns. PMID- 19442981 TI - Validation of a multi-residue liquid chromatography-tandem mass spectrometry confirmatory method for 10 anticoccidials in eggs according to Commission Decision 2002/657/EC. AB - A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the simultaneous detection and confirmation of halofuginone, robenidine, diclazuril, nicarbazin, monensin, narasin, lasalocid, salinomycin, maduramicin and semduramicin in whole egg has been developed and validated. The anticoccidial residues were extracted by acetonitrile, evaporated and dissolved in a sodium acetate/acetonitrile mixture. Then, the samples were injected on a C8 column in a gradient mode. Diclazuril-bis, DNC-d8 and nigericin were used as internal standards. The results of the full validation in accordance with the guidelines of the Commission Decision no 2002/657/EC are presented. This rapid and sensitive method was found suitable to confirm the anticoccidials at 1 and at 75 microg kg( 1) for the MRL compound lasalocid. PMID- 19442982 TI - Synthesis of penetrable macroporous silica spheres for high-performance liquid chromatography. AB - Silica microspheres have been synthesized by phase separation and sol-gel transition coupled with emulsion method. The as-obtained material is characterized by scanning electron microscopy, nitrogen sorption, elemental analysis and particle size distribution measurements. The results demonstrated that the material featured with hierarchically porous structure, possessing both mesopores and penetrable macropores. The mesopores provide large surface area while the macropores traverse the silica particles, which may facilitate fast mass transfer as well as guarantee low backpressure when such materials are used for packed high-performance liquid chromatography (HPLC) column. Therefore, their preliminary applications as HPLC packings in fast separation and low-pressure separation have been attempted in the present study. Benzene, benzaldehyde and benzyl alcohol were separated within two minutes on the silica column at a flow rate of 7 mL min(-1). Vitamin E mixtures can also be baseline separated at a high flow rate of 8 mL min(-1). In addition, thirteen aromatic hydrocarbons were well separated on the octadecyl-bonded silica (ODS) column. In comparison with a commercial Kromasil ODS column, the pressure of the proposed column is much lower (<1/2) under the same chromatographic conditions, while comparable separation efficiency can be achieved. PMID- 19442983 TI - Preparation of monodispersed vinylpyridine-divinylbenzene porous copolymer resins and their application to high-performance liquid chromatographic separation of aromatic amines. AB - For the separation of aromatic amines, two types of monodispersed porous polymer resins were prepared by the copolymerization of 2-vinylpyridine and 4 vinylpyridine with divinylbenzene in the presence of template silica gel particles (particle size 5 microm), followed by dissolution of the template silica gel in an alkaline solution. The transmission electron micrographs and the scanning electron micrograph revealed that these templated polymer resins have a spherical morphology with a good monodispersity and porous structure. Using these monodispersed polymer resins, the high-performance liquid chromatographic separation of aromatic amines in the mobile phases of pHs 2.0, 2.9, 4.1, 7.2 and 11.7 were carried out. The 2-vinylpyridine-divinylbenzene copolymer resins showed slightly stronger retentions for aromatic amines than the 4-vinylpyridine divinylbenzene copolymer resins. Under acidic conditions (around pH 2.0), aniline and the toluidines showed no retention on these copolymer resins due to the repulsion between the cationic forms of these amines and pyridinium cations in the stationary phase, whereas less basic aromatic amines or non-basic acetanilide showed slight retentions. Above pH 4.1, the separation of aromatic amines with these polymer resins showed a typical reversed-phase mode separation. Therefore, the separation patterns of aromatic amines are effectively tunable by changing the pH value of the mobile phases. A good separation of eight aromatic amines was achieved at pH 2.9 using the 2-vinylpyridine-divinylbenzene copolymer resins. PMID- 19442984 TI - Comparison of the adsorption kinetics and surface arrangement of "as received" and purified bovine submaxillary gland mucin (BSM) on hydrophilic surfaces. AB - The effect of bovine serum albumin (BSA) as impurity in a commercial bovine submaxillary gland mucin preparation (BSM; Sigma M3895) on the adsorption of BSM to hydrophilic surfaces (mica and silica) has been studied in terms of adsorption kinetics, amount and structure of the formed adlayer. The Surface Force Apparatus (SFA) was used to gain information about the extended and compressed structure of adsorbed "as received" BSM, purified BSM, BSA extracted from the "as received" BSM and mixtures of the latter purified proteins. The adsorbed amount was estimated using a combination of X-ray Photoelectron Spectroscopy (XPS), Enzyme Linked Immuno Sorbent Assay (ELISA), Enzyme-Linked Lectin Assay (ELLA), Dual Polarization Interferometry (DPI) and Quartz Crystal Microbalance (QCM-D) measurements. Under the used conditions, purified BSM showed very low affinity for silica and only small amounts were found to adsorb on mica. Initially, the BSM molecules adopted an extended conformation on the mica surface with tails extending into the bulk phase. These tails were irreversibly compressed into a very thin (10A) layer upon applying a high load. "As received" BSM formed considerably thicker compressed layers (35A); however, the extended layer structure was qualitatively the same. When mixtures of purified BSM and BSA were coadsorbed on mica, a 9wt-% albumin content gave a comparable layer thickness as the "as received" BSM and from XPS data we draw the conclusion that the albumin content in the layer adsorbed from "as received" BSM was approximately 5wt-%. Adsorption from an equal amount of BSM and BSA revealed that even though the amount of BSM is scarce in the mixed layer, the few BSM molecules have a drastic effect on the adsorbed thickness and structure. Clearly, this study shows the importance of characterizing the mucin used since differences in purity give rise to different adsorption behaviours in terms of both adsorbed amount and layer structure. PMID- 19442985 TI - Assembly behavior of double thermo-responsive block copolymers with controlled response temperature in aqueous solution. AB - We reported the synthesis of double thermo-responsive block copolymers comprised of a poly(N-isopropylacrylamide (NIPAAm)) block and a poly(NIPAAm-co-N (hydroxymethyl)acrylamide (HMAAm)) block, which was synthesized using an atom transfer radical polymerization (ATRP) technique. The cloud point of the poly(NIPAAm-co-HMAAm) (NH) block could be easily controlled by altering the HMAAm content. Below the cloud point of polyNIPAAm (N) block, the block copolymers were completely dissolved. Between the cloud points of each block, the block copolymer formed the aggregate structure that could be constructed with the hydrated NH shell and the dehydrated N core. Moreover with increases in temperature, the diameter decreased due to the dehydration of the NH block shell. The response was completely reversible by changes in temperature, as confirmed by (1)H NMR, turbidity, and FE-SEM measurements. PMID- 19442986 TI - Towards a neurocircuitry in anorexia nervosa: evidence from functional neuroimaging studies. AB - Functional neuroimaging is widely used to unravel changes in brain functioning in psychiatric disorders. In the current study, we review single-photon emission tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies in anorexia nervosa (AN), a difficult-to-treat eating disorder with the highest mortality rate among psychiatric disorders. We discuss the role of the parietal cortex, anterior and subgenual cingulate cortex, frontal cortex and temporal lobe in light of the cardinal symptoms of AN. The insights of the current review may ultimately lead to the development of new treatments. PMID- 19442987 TI - Acute bilateral thalamic infarction as a cause of acute dementia and hypophonia after occlusion of the artery of Percheron. AB - The thalami of the human brain obtain their blood supply from many perforating arteries, which exhibit complex distribution and many variations. One rare variation is the artery of Percheron that supplies the paramedian thalami bilaterally. This artery arises from the first segment of the posterior cerebral artery and gives rise to bilateral medial thalamic perforants. Occlusion of the artery of Percheron none rarely results in bilateral thalamic and mesencephalic infarctions. We describe the case of a 38-year-old male patient with a presumed occlusion of this artery in which MR imaging revealed characteristic symmetrical bilateral paramedian thalamic infarctions. The unique characteristics of this case are based on the young age of the patient, the absence of any risk factors or other diseases and even more on the rare clinical manifestations consisted of hypophonia, memory dysfunction, time disorientation and apathy. PMID- 19442988 TI - Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice. AB - Demyelination and neurodegeneration is a major contributor in the progression of disability in multiple sclerosis (MS). Thus, the development of therapies that are neuroprotective has elicited considerable interests. Estrogens and estrogen receptor (ER) ligand treatments are promising treatments to prevent MS-induced neurodegeneration and a multicenter phase II clinical trial of estriol as a beneficial therapy in MS is underway. Here, we discuss studies performed in our laboratory that examined the effects of ER ligands in the inflammatory/demyelinating disorder experimental autoimmune encephalomyelitis (EAE), a model of MS. Administration of estriol or 17beta-estradiol reduced clinical severity and this clinical disease improvement was associated with favorable changes in cytokine production. There was a significant decrease of neuronal pathology in gray matter along with myelin and axon preservation in white matter of spinal cords of mice with EAE. In subsequent experiments, we contrasted the results of ERalpha versus ERbeta ligand treatment. While ERalpha ligand treatment was anti-inflammatory, ERbeta ligand treatment was not. ERbeta ligand treatment nevertheless reduced demyelination and preserved axon numbers in white matter and prevented neuronal abnormalities in gray matter. Clinically, ERalpha ligand treatment abrogated the disease at the onset, while ERbeta ligand treatment had no effect at disease onset, but promoted recovery. Thus, unlike ERalpha ligand treatment, ERbeta ligand treatment was protective at the level of the target organ, independent of anti-inflammatory effects in the peripheral immune system. ERbeta ligand treatment should be considered as a potential neuroprotective agent for MS and other neurodegenerative diseases, particularly since breast and uterine cancer are mediated through ERalpha. PMID- 19442989 TI - Long term survival in anti-Hu associated adult neuroblastoma. AB - We report on a young lady suffering from adult neuroblastoma and anti-Hu associated paraneoplastic encephalomyelitis (PEM) with a tumour free survival of nine years up to now. Treatment included tumour surgery, radiation, high dose chemotherapy, and stem cell transplantation. Serological testing demonstrated a marked decline in anti-Hu antibody titres under therapy, and subsequent disappearance of the antibody 31 months after second tumour resection. PMID- 19442990 TI - Stroke due to septic embolism resulting from Aspergillus aortitis in an immunocompetent patient. AB - INTRODUCTION: Cerebral infarction secondary to Aspergillus arteritis or septic embolism is an exceptional finding. We present a case of multiple systemic embolism and cerebral infarction resulting from Aspergillus aortitis in an immunocompetent patient. PATIENT: A 65-year-old male with hypertension, hyperglycaemia and myocardial infarction with aorto-coronary by-pass surgery three years before admission, that suffered cerebral infarction in middle right cerebral artery territory and right cubital artery embolism. One month later he presented abrupt increase of his left hemiparesia and left central facial palsy associated with fever of unknown origin. Laboratory test, cranial CT and echocardiogram were performed. He died ten days later. RESULTS: Hemogram: leucocytes 34.700/microL (85% N, 4.8%L). Cranial CT: cerebral infarction in middle right cerebral artery territory. Transthoracic and transesophageal echocardiogram: moderate left ventricular hypertrophy and slight inferior hypokinesis. Arteriography: complete thrombosis of the left internal carotid. Necropsy: parietal aortic aspergillosis with generalized septic embolisms (brain, kidney, liver, fingers), cerebral infarction in middle right cerebral artery territory and thrombosis of the left carotid siphon with Aspergillus arteritis. CONCLUSIONS: Aspergillosis is an exceptional cause of cerebral infarction, especially in immunocompetent patients, and their diagnosis is complicated, being usually found at necropsy. PMID- 19442991 TI - Development of a laboratory exposure system using marine fish to carry out realistic effect studies with produced water discharged from offshore oil production. AB - A biotest system for environmentally realistic exposure of fish to produced water (PW) was developed and tested. Authentic PW was collected at an oil production platform in the North Sea and preserved by freezing in multiple aliquots a 25L. After transport to the test laboratory onshore, daily PW aliquots were thawed, homogenised and administered to the test fish, Atlantic cod (Gadus morhua), in two diluted exposure concentrations, 0.1% and 0.5%, during a 15 d period, using a continuous flow-through exposure setup. Positive control groups were exposed to two crude oil treatments for comparison. Chemical analyses showed that alkylphenol (AP) and PAH concentrations in PW exposure waters were very low. Observations of significantly increased AP and PAH metabolite levels in PW exposed fish demonstrated the suitability of the biotest system for its use in biological exposure/effect studies of PW, and it also demonstrated the sensitivity of bile metabolites as PW exposure markers in fish. The relevance of the biotest system for PW effect studies and for validating modelled environmental risk estimates of PW dischargers from offshore oil production is discussed. PMID- 19442993 TI - [Dietetic approach to trimethylaminuria]. PMID- 19442992 TI - Macroalgae blooms and delta 15N in subtropical coastal lagoons from the Southeastern Gulf of California: discrimination among agricultural, shrimp farm and sewage effluents. AB - Macroalgae blooms of Gracilaria vermiculophylla, Hypnea spinella and Spyridia filamentosa have been found in coastal lagoons in the SE Gulf of California. Agriculture, livestock, shrimp and poultry farms and sewage contribute anthropogenic nitrogen to the systems. The delta(15)N of these sources, water column and macroalgae were studied in order to identify the N supply for macroalgae blooms. delta(15)N of three species of macroalgae (4.3-13.6 per thousand) were enriched compared to the water column (delta(15)N-NO(3)(-) 3.7-6.8 per thousand), probably because of fractioning from the macroalgae. delta(15)N of POM (1.4-10.3 per thousand) was similar to the water column but the relationship was unclear. Depending on the site, macroalgae showed different delta(15)N values since some sites receive more or less influence from one given source of the associated watershed, which is reflected in the different delta(15)N values of the macroalgae of the same system and in the relative contributions of the sources. PMID- 19442994 TI - [Current role of angiotensin II receptor antagonists and their combination in the treatment of hypertension]. PMID- 19442995 TI - [Familial hypobetalipoproteinemia: clinical characterization of a new mutation in the APOB gene]. AB - BACKGROUND AND OBJECTIVE: Familial hypobetalipoproteinemia (FHB) is usually due to mutations in the APOB gene. Almost 60 different mutations have been reported. We report a Spanish family with FHB phenotype and a new mutation. PATIENT AND METHODS: We performed an analytical, localizing and molecular study of the APOB gene in the proband and in two relatives phenotypically affected. RESULTS: The proband was a 32-year-old woman with moderate to severe mental retardation, morbid obesity, hypocholesterolemia, hypertransaminasemia, and hepatic steatosis. The familial phenotypic study was positive in other 6 relatives. The genetic study confirmed the presence of a novel mutation (apoB-69.27) in the APOB gene. The proband, her mother and one maternal great aunt were heterozygote for that mutation. CONCLUSIONS: FHB has a variable phenotypic expression that can range from oligosymptomatic disease to severe neurological damage. PMID- 19442996 TI - [Neuropsyquiatric manifestations in systemic lupus erythematosus]. PMID- 19442997 TI - [Clinical and genetic heterogeneity in hypobetalipoproteinemia]. PMID- 19442998 TI - [Predictive models for identification of germline mutation carriers in Lynch syndrome]. PMID- 19442999 TI - [Considerations on a cutaneous manifestation of systemic vasculopathy]. PMID- 19443000 TI - Polyketide synthases of bacterial symbionts in sponges--evolution-based applications in natural products research. AB - Marine sponges are an unusually rich source of bioactive natural products with clinical potential. They also often harbor rich communities of symbiotic bacteria that have often been suspected as the true producers of sponge-derived compounds. To date, these bacteria can in most cases not be cultivated, but culture independent methods, such as isolating and analyzing biosynthetic gene clusters using metagenomic strategies, have recently provided first insights into their chemical potential. This review summarizes recent work of our laboratory on the study of polyketide synthases (PKSs). These studies revealed two evolutionarily distinct, unusual PKS types that are commonly found in sponge metagenomes and were shown to be of bacterial origin. One, the sup PKS, dominates sponge metagenomic DNA libraries, occurs widespread in bacteriosponges and is to date exclusively known from such animals. Data suggest that it is a type of synthase that generates methyl-branched fatty acids, which are commonly present in sponges. The other PKS type, termed trans-acyltransferase (AT) PKS, is responsible for the biosynthesis of complex, bioactive polyketides, such as the onnamides, and also occurs in free-living bacteria. The diversity of PKS genes present in a single sponge metagenome can be enormous. However, the phylogenetic approaches outlined in this review can provide valuable insights into the PKS function and structures of polyketides and can assist in the targeted isolation of gene clusters. PMID- 19443001 TI - Physico-chemical and antifungal properties of protease inhibitors from Acacia plumosa. AB - This study was aimed at investigating the purification, biological activity, and some structural properties of three serine protease inhibitors isoforms, denoted ApTIA, ApTIB, and ApTIC from Acacia plumosa Lowe seeds. They were purified from the saline extract of the seeds, using Superdex-75 gel filtration and Mono-S ion exchange chromatography. They were further investigated by mass spectrometry, spectroscopic measurements, surface plasmon resonance, and inhibition assays with proteases and phytopathogenic fungi. The molecular mass of each isoform was estimated at ca. 20 kDa. Each contained two polypeptide chains linked by a disulfide bridge, with different isoelectric points that are acidic in nature. The N-terminal sequences of both chains indicated that they were Kunitz-type inhibitors. Circular dichroism (CD) analyses suggested the predominance of both disordered and beta-strands on ApTI isoforms secondary structure, as expected for beta-II proteins. In addition, it was observed that the proteins were very stable, even at either extreme pH values or at high temperature, with denaturation midpoints close to 75 degrees C. The isoinhibitors could delay, up to 10 times, the blood coagulation time in vitro and inhibited action of trypsin (Ki 1.8 nM), alpha-chymotrypsin (Ki 10.3 nM) and kallikrein (Ki 0.58 microM). The binding of ApTIA, ApTIB, and ApTIC to trypsin and alpha-chymotrypsin, was investigated by surface plasmon resonance (SPR), this giving dissociation constants of 0.39, 0.56 and 0.56 nM with trypsin and 7.5, 6.9 and 3.5 nM with alpha-chymotrypsin, respectively. The growth profiles of Aspergillus niger, Thielaviopsis paradoxa and Colletotrichum sp. P10 were also inhibited by each isoforms. These three potent inhibitors from A. plumosa may therefore be of great interest as specific inhibitors to regulate proteolytic processes. PMID- 19443002 TI - ACE inhibitory tetrapeptides from Amaranthus hypochondriacus 11S globulin. AB - Amaranth seed is a valuable source of dietary protein with very high nutritional quality, and recently its potential as a nutraceutical has been proposed. The aim of this work was to provide experimental evidence for the presence of anti hypertensive peptides in globulin 11S, one of the major constituents of the seed, by means of an in-silico based peptide library screening method. A three dimensional model of globulin 11S was built, upon which anti-hypertensive peptides were mapped via a database-driven method. Solvent accessibility was evaluated for each potential peptide, and two potent and exposed tripeptides were detected: IKP and LEP. An N-terminal extension of these two peptides was built using the globulin 11S primary sequence information, and ACE inhibitory behaviour was simulated by automated ligand-protein docking. The occurrence of two inhibitory tetrapeptides, ALEP and VIKP, was predicted and experimentally validated by an in vitro ACE inhibition assay that showed IC50 values of 6.32 mM and 175 microM, respectively. This study is the first to provide experimental proof of the anti-hypertensive value of Amaranth. Furthermore, this is the first time that a peptide docking approach is used to find ACE-inhibitory peptides from a food protein source. PMID- 19443003 TI - Analysis using life tables of the major causes of death and the differences between country of birth groups in New South Wales, Australia. AB - OBJECTIVES: This study used life table methods to evaluate the potential effects of reduction in major disease mortality on life expectancy in New South Wales (NSW), and the differences in cause-specific mortality between country of birth groups. The total and partial elimination of major causes of death were examined to identify the high-risk groups for community-level health planning. STUDY DESIGN: Life tables were used to combine the mortality rates of the NSW population at different ages into a single statistical model. METHODS: Using abridged, multiple decrement and cause-elimination life tables with the mortality data for NSW in 2000-2002, broader disease groups were examined. Multiple decrement tables were generated by country of birth. The effect of the partial elimination of ischaemic heart disease (IHD) was also studied. RESULTS: This study found that Pacific-born men and women who reach their 30th birthday and eventually die from IHD are expected to live, on average, 10.8 and 5.8 years less, respectively, than average men and women in NSW. If IHD is eliminated as a cause of death, 7.5 years for males and 6.7 years for females would be added to life expectancy at birth. CONCLUSIONS: Life expectancy at birth is likely to be further increased by reducing deaths caused by diseases of the cardiovascular system, particularly among people aged over 65 years, by reducing malignant neoplasm deaths among those aged below 65 years, and by reducing deaths due to accidents, injury and poisoning, mainly among men aged 15-29 years. Further gains in life expectancy could be achieved with community-level educational programmes on lifestyle management and disease prevention. PMID- 19443004 TI - Distinct human papillomavirus type 16 methylomes in cervical cells at different stages of premalignancy. AB - Human papillomavirus (HPV) gene expression is dramatically altered during cervical carcinogenesis. Because dysregulated genes frequently show abnormal patterns of DNA methylation, we hypothesized that comprehensive mapping of the HPV methylomes in cervical samples at different stages of progression would reveal patterns of clinical significance. To test this hypothesis, thirteen HPV16 positive samples were obtained from women undergoing routine cervical cancer screening. Complete methylation data were obtained for 98.7% of the HPV16 CpGs in all samples by bisulfite-sequencing. Most HPV16 CpGs were unmethylated or methylated in only one sample. The other CpGs were methylated at levels ranging from 11% to 100% of the HPV16 copies per sample. The results showed three major patterns and two variants of one pattern. The patterns showed minimal or no methylation (A), low level methylation in the E1 and E6 genes (B), and high level methylation at many CpGs in the E5/L2/L1 region (C). Generally, pattern A was associated with negative cytology, pattern B with low-grade lesions, and pattern C with high-grade lesions. The severity of the cervical lesions was then ranked by the HPV16 DNA methylation patterns and, independently, by the pathologic diagnoses. Statistical analysis of the two rating methods showed highly significant agreement. In conclusion, analysis of the HPV16 DNA methylomes in clinical samples of cervical cells led to the identification of distinct methylation patterns which, after validation in larger studies, could have potential utility as biomarkers of neoplastic cervical progression. PMID- 19443005 TI - Identification and functional characterization of regions that can be crosslinked to RNA in the helicase-like domain of BaMV replicase. AB - The helicase-like domain of the Bamboo mosaic virus replicase catalyzes the release of 5'-gamma-phosphate from both ATP and 5'-triphosphated RNA by an identical set of catalytic residues with a presumably larger binding pocket for RNA. In this study, the peptidyl regions involved in RNA binding were mapped by reversible formaldehyde crosslinking and mass spectrometry. Eleven residues within these regions were examined by mutational analysis. H636A, Y704A, and K706A greatly diminished the enzymatic activities and were unable to support the viral replication in Nicotiana benthamiana protoplasts. K843A decreased activity toward the RNA substrate to 17% of WT, and approximately 20% replication efficiency was retained in protoplasts. R597A and K610A retained approximately 50 and approximately 90% of the enzymatic activities, respectively. However, replication in protoplasts of these mutants was extremely limited. Proteins with the mutations K603A, R628A, R645A, H794A, and R799A were present at levels 30-69% of WT in protoplasts. However, the fates of these mutations in plants were different. Viral cell-to-cell movement was limited by the K603A and R628A mutations, while systemic movement was restricted by R645A and H794A. The implications of the helicase-like domain in the viral replication and movement are discussed. PMID- 19443006 TI - Enhanced removal of 1,2-dichloroethane by anodophilic microbial consortia. AB - 1,2-Dichloroethane (1,2-DCA) is a well-known recalcitrant groundwater contaminant. New environment-friendly approaches for the removal of 1,2-DCA that does not bring about volatilization of the compound are required. In this study, different anodophilic consortia enriched in microbial fuel cells (MFCs) operated under airtight conditions were shown to effectively degrade 1,2-DCA (up to 102mg per liter reactor volume per day), while concomitantly generating a current. An anodophilic consortium previously enriched with acetate as the electron donor changed its composition at the rate of 48% per week and increased its richness (Rr) 3-fold, upon adapting to 1,2-DCA as the new electron donor. After being stable, during 1month of operation, it removed up to 95% of the 1,2-DCA amount in the medium in the first 2weeks, while converting 43+/-4% of electrons available from the removal to electricity. A natural consortium from a 1,2-DCA contaminated site changed its composition at the rate of 9% per week and increased its Rr 2 fold, upon adapting to the MFC anode conditions with 1,2-DCA as the electron donor. After being stable, during 1month of operation, it removed up to 85% of the 1,2-DCA amount in the medium in the first 2weeks and the coulombic efficiency was 25+/-4%. The operation of the MFCs under closed circuit conditions resulted in higher 1,2-DCA removal rates than the operation under open circuit conditions, indicating that bioelectrochemical activities enhanced the removal of 1,2-DCA in the MFC anode. The production of ethylene glycol, acetate and carbon dioxide indicated that the anodophilic bacteria oxidatively metabolized 1,2-DCA, probably by means of a hydrolysis-based pathway. The results show that MFCs can be potentially used as a practically convenient technology for the biological removal of 1,2-DCA. PMID- 19443007 TI - Recovery of nitrogen and phosphorus from alkaline fermentation liquid of waste activated sludge and application of the fermentation liquid to promote biological municipal wastewater treatment. AB - In previous publications we reported that by controlling the pH at 10.0 the accumulation of short-chain fatty acids (SCFA) during waste activated sludge (WAS) fermentation was remarkably improved [Yuan, H., Chen, Y., Zhang, H., Jiang, S., Zhou, Q., Gu, G., 2006. Improved bioproduction of short-chain fatty acids (SCFAs) from excess sludge under alkaline conditions. Environ. Sci. Technol. 40, 2025-2029], but significant ammonium nitrogen (NH(4)-N) and soluble ortho phosphorus (SOP) were released [Chen, Y., Jiang, S., Yuan, H., Zhou, Q., Gu, G., 2007. Hydrolysis and acidification of waste activated sludge at different pHs. Water Res. 41, 683-689]. This paper investigated the simultaneous recovery of NH(4)-N and SOP from WAS alkaline fermentation liquid and the application of the fermentation liquid as an additional carbon source for municipal wastewater biological nitrogen and phosphorus removal. The central composite design (CCD) of the response surface methodology (RSM) was employed to optimize and model the simultaneous NH(4)-N and SOP recovery from WAS alkaline fermentation liquid. Under the optimum conditions, the predicted and experimental recovery efficiency was respectively 73.4 and 75.7% with NH(4)-N, and 82.0 and 83.2% with SOP, which suggested that the developed models described the experiments well. After NH(4)-N and SOP recovery, the alkaline fermentation liquid was added to municipal wastewater, and the influence of volume ratio of fermentation liquid to municipal wastewater (FL/MW) on biological nitrogen and phosphorus removal was investigated. The addition of fermentation liquid didn't significantly affect nitrification. Both SOP and total nitrogen (TN) removal were increased with fermentation liquid, but there was no significant increase at FL/MW greater than 1/35. Compared to the blank test, the removal efficiency of SOP and TN at FL/MW=1/35 was improved from 44.0 to 92.9%, and 63.3 to 83.2%, respectively. The enhancement of phosphorus and nitrogen removal was mainly attributed to the increase of influent SCFA, or rather, the increase of intracellular polyhydroxyalkanoates (PHA) which served as the carbon and energy sources for denitrification and phosphorus uptake. The addition of alkaline fermentation liquid to municipal wastewater, however, increased the effluent COD, which was caused mainly by the increase of influent humic acid, not protein or carbohydrate. PMID- 19443008 TI - Control of DMSO in wastewater to prevent DMS nuisance odors. AB - A "canned corn-like" odor was periodically detected at Philadelphia's Northeast Water Pollution Control Plant (NEWPCP) for more than two decades. Previous research concluded that it was caused by dimethyl sulfide (DMS), from the reduction of dimethyl sulfoxide (DMSO) discharged by a local industrial customer. Several process modifications were implemented at the industrial site to eliminate the "canned corn-like" odor. Results showed that enhancing DMSO recovery by 25% and equalizing the aqueous wash discharge over a longer period of time reduced the DMSO source peak discharge from 1124 to 49 kg/h, and the peak concentrations of DMSO and DMS at the NEWPCP by 81 and 88%. Reduction of DMSO discharge by segregating the first wash for off-site disposal further reduced the peak discharge of DMSO from 49 to 18 kg/h at the source, and DMSO and DMS concentrations at the NEWPCP by 48 and 92%. Segregation of the dehydration distillate for off-site disposal reduced DMSO discharge by 3 kg/h. Modifications by concentrating a higher percentage of the DMSO into the first wash and increasing the DMSO solvent recovery by an additional 33% reduced the total DMSO discharge from 522 to 200 kg and peak discharge rate from 15 to 6 kg/h. All of these process modifications collectively reduced the DMSO source discharge by 92% and the DMSO concentration received at NEWPCP by 97%, from 12 mg/L to approximately 500 microg/L. At this reduced concentration, the company's wastewater discharge was no longer found to cause the "canned corn" odor at the fence line of NEWPCP, thereby mitigating any further need for odor control. PMID- 19443009 TI - Degradation of sulfamethoxazole in water by solar photo-Fenton. Chemical and toxicological evaluation. AB - In this work, the photocatalytic degradation of the antibiotic sulfamethoxazole (SMX) by solar photo-Fenton at pilot plant scale was evaluated in distilled water (DW) and in seawater (SW). Degradation and mineralization of SMX were strongly hindered in SW compared to DW. The influence of H(2)O(2) and iron concentration on the efficiency of the photocatalytic process was evaluated. An increase in iron concentration from 2.6 to 10.4 mg L(-1) showed only a slight improvement in SMX degradation and mineralization. However, an increase in H(2)O(2) concentration up to 120 mg L(-1) during photo-Fenton in DW decreased SMX solution toxicity from 85% to 20%, according to results of Daphnia magna bioassays. The same behaviour was not observed after photo-Fenton treatment in SW. Despite 45% mineralization in SW, toxicity increased from 16% to 86% as shown by Vibrio fischeri bioassays, which suggests that the intermediates generated in SW are different from those in DW. A SMX degradation pathway during the photo-Fenton treatment in DW is proposed. PMID- 19443010 TI - Efficient decomposition of perfluorocarboxylic acids in aqueous solution using microwave-induced persulfate. AB - The microwave-hydrothermal decomposition of persistent and bioaccumulative perfluorooctanoic acid (PFOA) in water with persulfate (S(2)O(8)(2-)) at 60, 90, and 130 degrees C was examined to develop an effective technology for treating PFOA pollution. S(2)O(8)(2-) is an efficient oxidant for degrading PFOA even at the room temperature of 27 degrees C. Higher temperature accelerates the PFOA decomposition rate, but an extremely high temperature (130 degrees C) will lead to the formation of significant amounts of radical oxidants that are released rapidly to consume most remaining persulfate thus causing a lower mineralization efficiency. The solution pH value is another important factor to influence the degradation rate; there is almost no PFOA decomposition reaction under alkaline conditions. The decomposition rate in acidic conditions is 1.1-7.4 times faster than in alkaline condition. Additionally, the proposed method is also effective in decomposing other PFCA species such as the C2-C7 perfluoroalkyl groups. PMID- 19443011 TI - Lemna minor L. as a model organism for ecotoxicological studies performing 1H NMR fingerprinting. AB - A validated method applying (1)H NMR fingerprinting for the study of metabolic changes caused in Lemna minor L. by various phytotoxic substances is presented. (1)H NMR spectra of crude extracts from untreated and treated colonies with the herbicides glyphosate, mesotrione, norflurazon, paraquat and the phytotoxin pyrenophorol were subjected to multivariate analyses for detecting differences between groups of treatments. Partial least squares-discriminant analysis (PLS DA) and hierarchical cluster analysis (HCA) were carried out in order to discriminate and classify treatments according to the observed changes in the metabolome of the plant. Although the compounds at the concentrations used did not cause macroscopically observable symptoms of phytotoxicity, characteristic metabolic changes were detectable by analyzing (1)H NMR spectra. Analyses results revealed that metabonomics applying (1)H NMR fingerprinting is a potential method for the investigation of toxicological effects of xenobiotics on L. minor, and possibly on other duckweed species, helping in the understanding of such interactions. PMID- 19443012 TI - Biodegradation of brominated aromatics by cultures and laccase of Trametes versicolor. AB - 2-Bromophenol (1), 4-bromophenol (2), 2,4-dibromophenol (3), 2,6-dibromophenol (4), 2,4,6-tribromophenol (5) and tetrabromobisphenol A (6) (1 mM each) added to growing submerged cultures of Trametes versicolor CCBAS 612 were eliminated by 65 85% from the culture medium within 4d. Extracellular laccase activity in the culture medium was influenced by the type of brominated compound added. Maximum level of laccase (63 U L(-1)) was found in the culture with 2-bromophenol. Tetrabromobisphenol A was degraded by a commercial laccase from Trametes versicolor in absence of any oxidation mediator, hydroxylated dibrominated compounds being detected as soluble reaction products by LC/MS. A significant degradation of brominated phenols by laccase was achieved only in the presence of ABTS structural characterization of major products suggesting reaction between bromophenol and ABTS radicals. PMID- 19443013 TI - Environmental aging of polycyclic aromatic hydrocarbons on soot and its effect on source identification. AB - Soot-associated PAHs were exposed to simulated sunlight to investigate disappearance rates under environmental aging conditions and to examine the robustness of diagnostic ratios for PAH source apportionment. Naphthalene, acenaphthylene, acenaphthene, and fluorene showed an obvious two-phase disappearance in all experiments while phenanthrene and anthracene exhibited this behavior for all but the highest soot loading. The first phase loss is 5-40 times faster than the second phase loss and occurred within 3h for naphthalene, acenaphthylene, acenaphthene, and fluorene and within 10h for phenanthrene and anthracene. Two-phase disappearance was not observed for any of the higher molecular weight PAHs with 4-6 rings. Each PAH has a unique loss rate via photodegradation and volatilization and these rates of some PAHs were affected by soot loadings; phenanthrene and anthracene showed similar rates in the first phase and increased loss rates in the second phase as soot loading increased. In the absence of light, the loss of PAHs was related to both temperature and molecular characteristics. Due to differences in disappearance rates of individual PAHs under illumination over extended times, prolonged exposure to sunlight could change the interpretation of some diagnostic ratios used previously for PAH source identification. This result indicates that more consistent and accurate methods that take into consideration the longevity of particulate PAHs are needed for reliable source apportionment. PMID- 19443015 TI - Comparison of receptor models for source apportionment of the PM10 in Zaragoza (Spain). AB - Receptor models are useful to understand the chemical and physical characteristics of air pollutants by identifying their sources and by estimating contributions of each source to receptor concentrations. In this work, three receptor models based on principal component analysis with absolute principal component scores (PCA-APCS), Unmix and positive matrix factorization (PMF) were applied to study for the first time the apportionment of the airborne particulate matter less or equal than 10microm (PM10) in Zaragoza, Spain, during 1year sampling campaign (2003-2004). The PM10 samples were characterized regarding their concentrations in inorganic components: trace elements and ions and also organic components: polycyclic aromatic hydrocarbons (PAH) not only in the solid phase but also in the gas phase. A comparison of the three receptor models was carried out in order to do a more robust characterization of the PM10. The three models predicted that the major sources of PM10 in Zaragoza were related to natural sources (60%, 75% and 47%, respectively, for PCA-APCS, Unmix and PMF) although anthropogenic sources also contributed to PM10 (28%, 25% and 39%). With regard to the anthropogenic sources, while PCA and PMF allowed high discrimination in the sources identification associated with different combustion sources such as traffic and industry, fossil fuel, biomass and fuel-oil combustion, heavy traffic and evaporative emissions, the Unmix model only allowed the identification of industry and traffic emissions, evaporative emissions and heavy-duty vehicles. The three models provided good correlations between the experimental and modelled PM10 concentrations with major precision and the closest agreement between the PMF and PCA models. PMID- 19443014 TI - Assessment of azaarenes and azaarones (oxidized azaarene derivatives) in the Dutch coastal zone of the North Sea. AB - Azaarones (oxidized derivatives of azaarenes) is a group of newly emerging chemical compounds. Little is known about their occurrence in the aquatic environment. Azaarenes are polycyclic aromatic heterocyclic compounds containing one nitrogen atom in one of the aromatic rings. The (photo) oxidized metabolites of the azaarenes are often more toxic than the parent compound. For the first time the concentration of seven azaarenes and seven primary metabolites have been measured in the surface sediments (fraction<63microm) of the Dutch coastal zone of the North Sea. Samples collected in 2000 and 2001 were analyzed using a newly developed method to determine the contents of azaarenes and azaarones simultaneously in a single GC-MS run. The concentrations of acridine, benz[a]acridine, benz[c]acridine and 5,6-benzoquinoline varied between 10-63, 3.9 25, 3.3-11 and 3.98-10.84ngg(-1), respectively. Concentrations of 7,8 benzoquinoline and phenanthridine were below the limit of detection. 2 Hydroxyquinoline and 5-hydroxyquinoline, probably metabolites of quinoline, were present in relatively high concentrations: 7.4-949 and 11-188ngg(-1). A gradient was observed with highest concentrations of the sum of azaarenes and the sum of the concentration of their metabolites close to the coast and lower concentrations further offshore. The concentrations of azaarenes and their metabolites are in the same order of magnitude as those found to induce phototoxicity to algae. The concentrations of mineral oil and PAHs in the surface sediments of the Dutch coastal zone of the North Sea were, at most locations, above the Dutch chemical targets for environmental protection. Spatial distribution of PAHs and mineral oil were slightly different from those of azaarenes and transformation products. Simultaneous GC-MS for azaarenes and their degradation products is possible but extraction/clean up can be further improved. Azaarenes as well as their primary metabolic products are present in the marine environment. In sediments the cumulative concentrations of transformation products amount to about four times the cumulative concentrations of the azaarenes. In conclusion, azaarenes and their metabolites constitute a new group of emerging polycyclic aromatic compounds which need more attention in the future. PMID- 19443016 TI - Mass loading and partitioning of dioxins in irrigation runoff from Japanese paddy fields: combination usage of the CALUX assay with HRGC/HRMS. AB - Lack of understanding of dioxins mass loading into the aquatic environment motivated the quantitative investigation of dioxins runoff from paddy fields during one entire irrigation period in the Minakuchi region, Japan. Combination use of the chemically activated luciferase gene expression (CALUX) bioassay together with high resolution gas chromatography and high resolution mass spectrometry (HRGC/HRMS) enabled efficient investigation of dioxins contamination. The result shows that the congener profile in irrigation runoff is quite similar to those in paddy soil samples and that 1,3,6,8-/1,3,7,9-TeCDD and OCDD derived from pesticides (i.e., pentachlorophenol (PCP) and chloronitrophen (CNP)) are predominant congeners in irrigation runoff. Although it is not surprising that dioxins concentration was strongly dependent on the suspended solids (SS) and the particulate organic carbon (POC) concentration, the dioxins toxic equivalency (TEQ) concentration was extremely high in irrigation runoff (max: 16,380 pg/L, corresponding to 12 pg WHO-TEQ/L) due to runoff of highly contaminated paddy soils. The results imply that dioxins concentration in a river must be monitored considering soil contamination level, land use, and soil runoff events. Using experimental data and a theoretical model, the mass loading of dioxins from the paddy fields by irrigation runoff was estimated to be 1.50 x 10( 2)% of total amount of dioxins accumulated in the paddy fields. Given the results of other researches, it is implied the following: 1) large portion of paddy soils released into the river appear to be settled on the riverbed due to small water flux, and, then, washed out and transported by rainfall runoff after irrigation period, 2) rainfall runoff itself also wash out paddy soils directly from paddy fields. Combination use of the CALUX bioassay with HRGC/HRMS is demonstrated as an alternative strategy to assess dioxins contamination in the environment. PMID- 19443017 TI - New Australopithecus robustus fossils and associated U-Pb dates from Cooper's Cave (Gauteng, South Africa). AB - Australopithecus robustus is one of the best represented hominin taxa in Africa, with hundreds of specimens recovered from six fossil localities in the Bloubank Valley area of Gauteng Province, South Africa. However, precise geochronological ages are presently lacking for these fossil cave infills. In this paper, we provide a detailed geological background to a series of hominin fossils retrieved from the newly investigated deposit of Cooper's D (located partway between Sterkfontein and Kromdraai in the Bloubank Valley), including uranium-lead (U-Pb) ages for speleothem material associated with A. robustus. U-Pb dating of a basal speleothem underlying the entire deposit results in a maximum age of 1.526 (+/ 0.088) Ma for Cooper's D. A second U-Pb date of ca. 1.4 Ma is produced from a flowstone layer above this basal speleothem; since this upper flowstone is not a capping flowstone, and fossiliferous sediments are preserved above this layer, some of the hominins might be slightly younger than the calculated age. As a result, we can broadly constrain the age of the hominins from Cooper's D to between 1.5 and approximately 1.4 Ma. Extinct fauna recorded in this comparatively young deposit raise the possibility that the Bloubank Valley region of South Africa represented a more stable environmental refugium for taxa relative to tectonically more active East Africa. The sediments of the deposit likely infilled rapidly during periods when arid conditions prevailed in the paleoenvironment, although it is unclear whether sediment deposition and bone deposition were necessarily contemporaneous occurrences. We reconstruct the paleoenvironment of Cooper's D as predominantly grassland, with nearby woodlands and a permanent water source. The hominin teeth recovered from Cooper's D are all from juveniles and can be confidently assigned to A. robustus. In addition, two juvenile mandibular fragments and an adult thoracic vertebra are tentatively attributed to A. robustus. PMID- 19443018 TI - Evidence guided antiplatelet treatment: time to move from bench to bedside. PMID- 19443019 TI - Platelet reactivity on aspirin, clopidogrel and abciximab in patients with acute coronary syndromes and reduced estimated glomerular filtration rate. PMID- 19443020 TI - PLAUR polymorphisms are associated with asthma, PLAUR levels, and lung function decline. AB - BACKGROUND: Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes. OBJECTIVE: Linkage and association analyses using 587 United Kingdom and Dutch asthma families (n = 2819 subjects) were used to investigate this region. METHODS: A 3-phase procedure was used: (1) linkage and association analyses using 15 microsatellite markers spanning 14.4 mega base pairs (Mbps) on 19q13, (2) fine mapping of the refined region using 26 haplotype tagging single nucleotide polymorphisms (SNPs), and (3) dense gene analyses using 18 SNPs evaluated for association with asthma, bronchial hyperresponsiveness (BHR), FEV1, plasma urokinase plasminogen activator receptor (PLAUR), and rate of annual FEV1 decline in subjects with asthma. RESULTS: The microsatellite analyses provided tentative support for an asthma/lung function susceptibility locus (48.9 49.1Mbps), and fine mapping localized modest association to the PLAUR gene. PLAUR SNPs in the 5' region, intron 3, and 3' region are associated with asthma and BHR susceptibility and predict FEV1 and plasma PLAUR levels. SNPs in the 5' region showed association for asthma (2 populations), FEV1 (2 populations), and BHR (2 populations) phenotypes. SNPs in intron 3 showed association with asthma (2 populations) and BHR (3 populations). Importantly, the same 5' region and intron 3 SNPs were associated with plasma PLAUR levels. The same 5' region and 3' region SNPs were found to be determinants of FEV1 decline in subjects with asthma. CONCLUSION: This study represents the first report to identify PLAUR as a potential asthma susceptibility gene and determine PLAUR regions underlying this association, including a role in influencing plasma PLAUR levels. Finally, the association of PLAUR with lung function decline supports a role for PLAUR in airway remodeling in asthma. PMID- 19443021 TI - Intravenous immunoglobulin contains a broad repertoire of anticarbohydrate antibodies that is not restricted to the IgG2 subclass. AB - BACKGROUND: Specificities for carbohydrate IgG antibodies, thought to be predominantly of the IgG2 subclass, have never been broadly examined in healthy human subjects. OBJECTIVE: To examine commercial intravenous immunoglobulin (IVIG) preparations for their ability to recognize a wide range of glycans and to determine the contribution of IgG2 to the binding pattern observed. METHODS: We used a glycan microarray to evaluate IVIG preparations and a control mix of similar proportions of human myeloma IgG1 and IgG2 for binding to 377 glycans, courtesy of the Consortium for Functional Glycomics Core H. Glycans recognized were categorized using public databases for their likely cellular sources. IgG2 was depleted from IVIG by using immunoaffinity chromatography, and depletion was confirmed by using nephelometry and surface plasmon resonance. RESULTS: Nearly half of the glycans bound IgG. Some of the glycans with the greatest antibody binding can be found in structures of human pathogenic bacteria (eg, Streptococcus pneumoniae, Mycobacterium tuberculosis, Vibrio cholera) and nonpathogenic bacteria, including LPS and lipoteichoic acid, capsular polysaccharides, and exopolysaccharides. Surprisingly, depletion of IgG2 had only a modest effect on anticarbohydrate recognition patterns compared with the starting IVIG preparation. Little to no binding activity was detected to human endogenous glycans, including tumor-associated antigens. CONCLUSIONS: This novel, comprehensive analysis provides evidence that IVIG contains a much wider range than previously appreciated of anticarbohydrate IgG antibodies, including those recognizing both pathogenic and non-pathogen-associated prokaryotic glycans. PMID- 19443022 TI - Venom immunotherapy reduces large local reactions to insect stings. AB - BACKGROUND: Large local reactions to insect stings cause significant morbidity and impair quality of life. Venom immunotherapy is not recommended because of a low risk for future systemic reaction and unproven efficacy in preventing large local reactions. OBJECTIVE: To determine the feasibility of performing a controlled trial to examine the efficacy of venom immunotherapy in reducing the size and duration of large local reactions. METHODS: Sting challenge in 41 patients with previous large local reactions and positive venom skin tests caused large local reactions 16 cm or larger in 34 patients, and 29 consented to treatment. Venom immunotherapy was initiated in 19, and 10 were untreated controls. Sting challenge was repeated after 7 to 11 weeks (control patients then began venom immunotherapy), and annually for as long as 4 years. RESULTS: After 7 to 11 weeks of treatment, the size and duration of large local reactions decreased 42% and 53%, respectively, in treated patients and 18% in controls (P < .01 for both). The response was similar after 1 year, and improved after 2 to 4 years to 60% and 70%, respectively. CONCLUSIONS: Venom immunotherapy significantly reduced the size and duration of the large local reactions, and the efficacy improved over a period of 2 to 4 years of treatment. Further studies are needed to establish the safety and efficacy of venom immunotherapy for large local reactions, the optimal duration of treatment, and the mechanism for the differences in degree and rate of clinical response compared with venom immunotherapy in systemic reactors. PMID- 19443023 TI - Up-regulation of hepatic ABCC2, ABCG2, CYP1A1 and GST in multixenobiotic resistant killifish (Fundulus heteroclitus) from the Sydney Tar Ponds, Nova Scotia, Canada. AB - Cellular defence against accumulation of toxic xenobiotics includes metabolism by phase I and II enzymes and export of toxicants and their metabolites via ATP binding cassette (ABC) transporters. Liver gene expression of representatives of these three protein groups was examined in a population of multixenobiotic resistant killifish (Fundulus heteroclitus) from the Sydney Tar Ponds, Nova Scotia, Canada. The Tar Ponds are heavily polluted with polycyclic aromatic hydrocarbons, polychlorinated biphenyls and heavy metals. The relationship among ABC transporters ABCB1, ABCB11, ABCC2, ABCG2, phase I enzyme cytochrome P4501A1 (CYP1A1) and phase II enzyme glutathione-S-transferase (GST-mu) was investigated by quantifying hepatic transcript abundance. In Tar Pond killifish, hepatic mRNA expression levels of ABCC2, ABCG2, CYP1A1 and GST-mu were elevated compared to reference sites, suggesting that hydrophobic contaminants undergo phase I and II metabolism and are then excreted into the bile of these fish. Hepatic ABCB1 and ABCB11 mRNA were not up-regulated in Tar Pond fish compared to two reference sites, indicating that these two proteins are not involved in conferring multixenobiotic resistance to Tar Pond killifish. The results suggest instead that liver up-regulation of phase I and II enzymes and complementary ABC transporters ABCC2 and ABCG2 may confer contaminant resistance to Tar Pond fish. PMID- 19443024 TI - The use of a kinetic biomarker approach for in situ monitoring of littoral sediments using the crab Carcinus maenas. AB - Caged, transplanted, intermoult, female shore crabs (Carcinus maenas) were exposed to sediments from the Port of Cadiz (SW, Spain); the Port of Huelva (SW, Spain), the Port of Pasajes (NE, Spain) and the Port of Bilbao (NW, Spain) for a period of 28 days. Organisms were sampled on days 0, 7, 14, 21 and 28 allowing examination of different biomarkers to exposure to metals and organic compounds; metallothioneins (MTs), ethoxyresorufin O-deethylase (EROD), glutathione-S transferase (GST) and glutathione peroxidase (GPX). Sediment samples were also analyzed to determine chemical concentration of metals (As, Cd, Cr, Cu, Hg, Mn, Ni, Pb and Zn), PAHs and PCBs. Metals such as As, Cu and Zn associated with mining activities (Port of Huelva), and contaminants such as Ni, Pb, Hg and PCBs, associated with oil spills and industrial activities (Ports of Cadiz, Pasajes and Bilbao), were found to interfere in detoxification and/or anti-stress oxidative defenses in C. maenas. Positive, significant (p<0.05) induction of MTs concentration was associated with increasing sediment As, Cu, Zn and Hg concentrations. EROD activity was associated with PCBs, GST activity with Hg and GPX activity with As, Cu, Ni, Pb and Zn. The use of the parameter AR, which involves the kinetic patterns of the battery of biomarkers tested, was found to be a powerful and sensitive tool for evaluating the bioavailability and adverse effects of contaminants bound to sediments, enabling polluted and nonpolluted sites to be easily distinguished. PMID- 19443026 TI - The influence of ascorbic acid, TGF-beta1, and cell-mediated remodeling on the bulk mechanical properties of 3-D PEG-fibrinogen constructs. AB - Two-dimensional cell culture studies have shown that matrix rigidity can influence cell function, but little is known about how matrix physical properties, and their changes with time, influence cell function in 3-D. Biosynthetic hydrogels based on PEGylated fibrinogen permit the initial decoupling of matrix chemical and mechanical properties, and are thus potentially attractive for addressing this question. However, the mechanical stability of these gels due to passive hydrolysis and cell-mediated remodeling has not previously been addressed. Here, we show that the bulk mechanical properties of acellular PEG-fibrinogen hydrogels significantly decrease over time in PBS regardless of matrix cross-linking density in 7 days. To compensate, smooth muscle cells (SMCs) were encapsulated and stimulated to produce their own matrix using ascorbic acid or TGF-beta1. Ascorbic acid treatment improved the mechanical properties of the constructs after 14 days in less cross-linked matrices, but TGF beta1 did not. The increase in matrix modulus of the constructs was not due to an increase in type I collagen deposition, which remained low and pericellular regardless of cross-link density or the soluble factor applied. Instead, ascorbic acid, but not TGF-beta1, preferentially enhanced the contractile SMC phenotype in the less cross-linked gels. Inhibition of contractility reduced cell spreading and the expression of contractile markers, and eliminated any beneficial increase in matrix modulus induced by cell-generated contraction of the gels. Together, these data show that PEG-fibrinogen hydrogels are susceptible to both hydrolysis and proteolysis, and suggest that some soluble factors may stimulate matrix remodeling by modulating SMC phenotype instead of inducing ECM synthesis in a 3-D matrix. PMID- 19443025 TI - Identification of regulatory Hck and PAI-2 proteins in the monocyte response to PEG-containing matrices. AB - Mass spectrometry is a powerful proteomic tool enabling researchers to survey the global proteome of a cell. This technique has only recently been employed to investigate cell-material interactions. We had previously identified material scarcity and limited adherent cells as challenges facing mass spectrometric analysis of cell-material interactions. U937 adherent to tissue culture poly(styrene) was used as a model system for identifying proteins expressed by adherent monocytes and analyzed by HPLC coupled offline to MALDI-ToF/ToF (LC MALDI). We identified 645 proteins from two cation fractions of crude U937 monocyte cell lysate. Forty three proteins of interest from the 645 were chosen based on literature searches for relevance to monocyte-material inflammation and wound healing. Proteins such as 40S ribosomal protein S19 and tyrosyl tRNA synthetase highlight the ability of LC-MALDI to identify proteins relevant to monocyte-material interactions that are currently unexplored. We used PEG-based semi-interpenetrating polymer networks and PEG-only hydrogels to investigate surface dependent effects on the Src family kinase Hck and plasminogen activator inhibitor-2 (PAI-2) using the pyrazolo pyrimidine small molecule inhibitor PP2 and exogenous urokinase plasminogen activator addition, respectively. Hck is well researched in cell adhesion while PAI-2 is virtually unknown in cell-material interactions. U937 on TCPS and PEG-only hydrogels secreted similar levels of inflammatory cytokines and gelatinase MMP-9. MCP-1 secretion from monocytes on PEG-only hydrogels was Hck independent in contrast to Hck-dependent MCP-1 secretion in U937 on TCPS. Overall, U937 adherent to sIPNs secrete low levels of soluble gelatinase MMP-9, IL-1beta, TNF-alpha, IL-6, and MCP-1 independent of Hck and PAI-2. This work demonstrates significant changes in surface dependent expression of proteins from monocytes adherent to PEG-based materials compared to TCPS. PMID- 19443027 TI - In-vitro osteogenesis of synovium stem cells induced by controlled release of bisphosphate additives from microspherical mesoporous silica composite. AB - In this study, in-vitro osteogenesis was successfully induced in the highly chondrogenic synovium mesenchymal stem cells (SMSCs) by controlled release of a nitrogenous bisphosphonate additive--alendronate (AL) from a mesoporous silica (MS)-hydroxyapatite (HA) composite that was mediated in poly(lactic-co-glycolic acid) (PLGA) microspheres. This microspherical based controlled release system is constructed with three levels of degradable structures: (1) the AL drug was first hybridized with HA nanoparticles; (2) the HA-AL complexes were filled into the mesopores of MS particles by self-assembly in situ; and (3) the HA-AL-laden MS constructs (MSH-AL) were built in the bulk of PLGA microspheres. In comparison with any mono-component construct, the superiority of this multi-component system comes from two aspects of functionalities: (1) significantly greater loading capacity of the extremely hydrophilic drug-AL; and (2) better controlled profile of AL release. Based on this newly developed PLGA/MSH-AL releasing system, as recipients the SMSCs, which usually exhibit exclusively high chondrogenesis, demonstrated a strong osteogenic commitment. The results were verified by alkaline phosphatase (ALP) activity assay, calcium secretion assay, real time PCR and immunohistochemistry analysis. Considering the renewable source and high proliferative profile of SMSCs, the achievement of engineered SMSC osteogenesis with this PLGA/MSH-AL controlled release system would open a new door to major bony reparation and regeneration. PMID- 19443028 TI - Self-assembly of pH-responsive fluorinated dendrimer-based particulates for drug delivery and noninvasive imaging. AB - Dendrimers are nanoscale macromolecules with well-defined branching chemical structures. Control over the architecture and function of these structures has enabled many advances in materials science and biomedical applications. Though dendrimers are directly synthesized by iteration of simple repetitive steps, generation of the larger, more complex structures required for many biomedical applications by covalent synthetic methods has been challenging. Here we demonstrate a spontaneous self-assembly of poly(amidoamine) dendrimers into complex nanoscopic and microscopic particulates following partial fluorination of the constituent dendrimer subunits. These dense particulates exhibit a stimulus induced response to low external pH that causes their disassembly over time, enabling controlled release of encapsulated agents. In addition, we show that these assemblies offer a sufficiently high density of fluorine spins to enable detection of their site-specific accumulation in vivo by (19)F magnetic resonance imaging ((19)F MRI). Fluorinated dendrimer-based particulates present new features and capabilities important for a wide variety of emerging biomedical applications. PMID- 19443029 TI - A case of intrauterine growth restriction in association with placental mesenchymal dysplasia with abnormal placental lymphatic development. AB - Placental mesenchymal dysplasia (PMD) is a rare human disorder associated with stillbirth, intrauterine growth restriction (IUGR) and Beckwith-Wiedemann syndrome. Although the morphology of this condition has been described in 86 cases, the underlying cellular origin is unclear. We investigate the placental cell type involved in a case of PMD associated with a live born female infant with IUGR. In PMD intermediate villi contain cisternae, lined by non proliferative cells. Immunostaining reveals they are not of trophoblast or vascular endothelial origin. There is positive immunostaining for lymphatic endothelium; this abnormal lymphangiogenesis is in concordance with current hypotheses regarding the aetiology of PMD. Furthermore, such observations suggest that placental villous mesenchyme may differentiate into various cell types, even those not normally found in the human placenta. PMID- 19443030 TI - A leukemic plasmacytoid dendritic cell line, PMDC05, with the ability to secrete IFN-alpha by stimulation via Toll-like receptors and present antigens to naive T cells. AB - We established a plasmacytoid dendritic cell (pDC) line (PMDC05) from leukemia cells of pDC leukemia. PMDC05 cells were positive for CD4, CD56, CD33, HLA-DR, CD123 (IL-3Ralpha) and CD86 in the absence of lineage markers. mRNA of TLR1, TLR2, TLR4, TLR7 and TLR9 was clearly expressed and among these TLRs, TLR7 was prominent. Production of IFN-alpha and IL-12 in PMDC05 was enhanced by the stimulation with CpG-A and LPS, respectively. PMDC05 possessed a considerable antigen presenting ability, which was enhanced by culturing with IL3, influenza virus or LPS. PMDC05 could be a useful tool for investigating the pathophysiology of pDCL. PMID- 19443031 TI - Myelodysplastic syndrome appearing during imatinib mesylate therapy in a patient with GIST. AB - The introduction of imatinib has been a major advance in the treatment of gastrointestinal stromal tumor (GIST). However, despite its remarkable efficacy and toxicity profile little is known about the potential for long-term toxicity. This may be an important issue because some patients (pts) with chronic myelogenous leukemia (CML) develop, during imatinib treatment, chromosomal abnormalities in philadelphia chromosome (Ph) negative cells with evolution to myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), furthermore a nonrandom association between GIST and myeloid leukemia has been recently reported. We report here a case of refractory cytopenia with mutilineage dysplasia (RAEB-1) with monosomy 7 which rapidly transformed into AML in a patient with GIST during imatinib treatment. PMID- 19443032 TI - Microscopic studies on the Aspergillus flavus infected kernels of commercial peanuts in Georgia. AB - This article describes the use of microscopy to prove the presence of the aflatoxin producing pathogen, Aspergillus flavus Link ex Fries in commercially available edible peanuts in Georgia. Light microscopy in combination with electron microscopy has been used to describe the infection course established by the fungus. The alkali maceration technique used in the study was successful and sufficient to detect the kernel infection of A. flavus and monitor the infection percentage in edible peanuts. Percentage of infected kernel varied from one commercial outlet to another in the region. Briefly, peanut seeds from Cartersville had the highest percentage of A. flavus infection. Electron microscopy confirmed the seed-borne infection of this mold. Mycelium established inside the host tissues both intercellularly and intracellularly aided by active, continuous branching of young hyphae. Establishment of mycelium was also detected in the xylem vessels of roots indicative of systemic infection. Thus, edible peanuts can form an important source of inoculum and facilitate the spread of the fungus from one peanut to another in commercial outlets and elsewhere. Present study provides strong evidence that A. flavus can escape detection at selling points and lands in commercial outlets via edible peanuts. That these contaminated peanuts could pose public health hazards is discussed. PMID- 19443033 TI - Descriptive analysis of the prevalence and the molecular epidemiology of Mycobacterium avium complex-infected pigs that were slaughtered on the main island of Okinawa. AB - Recent genetic studies have revealed that several epidemiological factors affect Mycobacterium avium complex (MAC) infection in pig populations. However, mechanisms underlying the spread of MAC infection among hog farms have not been clarified. In consideration of this situation, we cross-sectionally investigated the mechanisms underlying the spread of MAC on the island of Okinawa. Pigs slaughtered (n=706,763) and 331 hog farms on Okinawa were surveyed during the years 2002-2004. Two outbreaks of MAC infection were occurred in several farms during survey period. Bacteria were isolated from randomly selected pigs and genotype of isolates was determined by using genetic finger printing methods with the insertion sequence (IS) 1245 restriction fragment length polymorphism (RFLP). Most isolates had large numbers of IS1245 copies, while strains with low copy numbers of IS1245 and isolates without IS1245 were seen in few farms. MACs strains were repeatedly isolated from pigs of the affected farms during the survey period. Those farms with an identical pig rearing systems showed synchronic changes in the prevalence of MAC infection. An industrial farm without an outbreak had an independent pig flow, but maintained distinct MAC strains. Multivariate analysis did not reveal independent factors for the prevalence of the MAC infection. These findings suggest that there were three clusters distinguished genetically in the main island of Okinawa, which were potentially spread by common pig flow. However, the outbreaks occurred because of unspecified conditions on each farm environment. PMID- 19443034 TI - History and future of comparative analyses in sleep research. AB - The comparative methods of evolutionary biology are a useful tool for investigating the functions of sleep. These techniques can help determine whether experimental results, derived from a single or few species, apply broadly across a specified group of animals. In this way, comparative analysis is a powerful complement to experimentation. The variation in the time mammalian species spend asleep has been most amenable for use with this approach, given the large number of mammals for which sleep data exist. Here, it is assumed that interspecific variation in the time spent asleep reflects underlying differences in the need for sleep. If true, then significant predictors of sleep times should provide insight into the function of sleep. Many such analyses have sought the evolutionary determinants of mammalian sleep by relating the time spent in the two basic states of sleep, rapid eye movement (REM) and non-REM sleep, to constitutive variables thought to be functionally related to sleep. However, the early analyses had several methodological problems, and recent re-analyses have overturned some widely accepted relationships, such as the idea that species with higher metabolic rates engage in more sleep. These more recent studies also provide evolutionarily broad support for a neurophysiological role for REM sleep. Furthermore, results from comparative analyses suggest that animals are particularly vulnerable to predation during REM sleep, a finding that lends further support to the notion that REM sleep must serve an important function. Here, we review the methodology and results of quantitative comparative studies of sleep. We highlight important developments in our understanding of the evolutionary determinants of sleep and emphasize relationships that address prevailing hypotheses for the functions of sleep. Lastly, we outline a possible future for comparative analyses, focusing on work in non-mammalian groups, the use of more physiologically meaningful variables, and electrophysiological sleep studies conducted in the wild. PMID- 19443035 TI - A multicriteria-based methodology for site prioritisation in sediment management. AB - Decision-making for sediment management is a complex task that incorporates the selections of areas for remediation and the assessment of options for any mitigation required. The application of Multicriteria Analysis (MCA) to rank different areas, according to their need for sediment management, provides a great opportunity for prioritisation, a first step in an integrated methodology that finally aims to assess and select suitable alternatives for managing the identified priority sites. This paper develops a methodology that starts with the delimitation of management units within areas of study, followed by the application of MCA methods that allows ranking of these management units, according to their need for remediation. This proposed process considers not only scientific evidence on sediment quality, but also other relevant aspects such as social and economic criteria associated with such decisions. This methodology is illustrated with its application to the case study area of the Bay of Santander, in northern Spain, highlighting some of the implications of utilising different MCA methods in the process. It also uses site-specific data to assess the subjectivity in the decision-making process, mainly reflected through the assignment of the criteria weights and uncertainties in the criteria scores. Analysis of the sensitivity of the results to these factors is used as a way to assess the stability and robustness of the ranking as a first step of the sediment management decision-making process. PMID- 19443036 TI - Role of the sixth transmembrane segment of domain IV of the cockroach sodium channel in the action of sodium channel blocker insecticides. AB - Sodium channel blocker insecticides (SCBIs), such as indoxacarb and metaflumizone, are a new class of insecticides with a mechanism of action different from those of other insecticides that target sodium channels. SCBIs block sodium channels in a manner similar to local anesthetics (LAs) such as lidocaine. Several residues, particularly F1579 and Y1586, in the sixth transmembrane segment (S6) of domain IV (IV) of rat Na(v)1.4 sodium channels are required for the action of LAs and SCBIs and may form part of overlapping receptor sites. However, the binding site for SCBIs in insect sodium channels remains undefined. We used site-directed mutagenesis, the Xenopus laevis oocyte expression system, and the two-electrode voltage clamp technique to study the effects on SCBI activity of mutating F1817 and Y1824 (analogous to those residues identified in mammalian sodium channels) to alanine, in the voltage-sensitive sodium channel of the German cockroach, Blattella germanica. The mutant channels showed no effect or a marked increase in channel sensitivity to both DCJW (the active metabolite of indoxacarb) and metaflumizone. Thus, it appeared that although the F1817 residue plays a role in the action of SCBIs and that both residues are involved in LA activity in mammalian sodium channels, neither F1817 nor Y1824 are integral determinants of SCBI binding on insect sodium channels. Our results suggest that the receptor site of SCBIs on insect sodium channels may be significantly different from that on mammalian sodium channels. PMID- 19443037 TI - Alterations in acute-phase proteins among HIV-1 infected persons receiving generic HAART in southern India. PMID- 19443038 TI - Long pentraxin PTX3 is associated with mortality and disease severity in severe Leptospirosis. AB - OBJECTIVE: To evaluate the long pentraxin PTX3 in patients with severe leptospirosis and to compare the results with the widely used short pentraxin C reactive protein and the pro-inflammatory cytokines IL-6 and IL-8. METHODS: This observational cohort study was carried out in Semarang, Indonesia, where leptospirosis is endemic and mortality is high. Consecutive patients with severe leptospirosis were sampled on admission and during follow-up. RESULTS: A total number of 52 patients entered the study, the mortality was 27%. Severe leptospirosis patient yielded elevated plasma PTX3 levels. PTX3 correlated with IL-8 and to a lesser extent with CRP and IL-6 levels. High levels of PTX3, IL-6 and IL-8 were associated with mortality (OR 5.6, 95%CI: 1.2-26; OR 3.2, 95%CI: 1.2-8.1; OR 6.5, 95%CI: 1.5-28). Moreover, PTX3 levels were associated with disease severity (OR 9.5; 95%CI: 2.9-45). This association was unique, since none of the other markers showed this relation. C-reactive protein was not able to differentiate the severe from the severest cases. CONCLUSIONS: The long pentraxin PTX3 is elevated in patients with severe leptospirosis and is associated with fatal disease and disease severity. PTX3 may be used as a marker to monitor disease severity in severe leptospirosis or predict outcome. PMID- 19443040 TI - Psychiatric symptoms in caregivers of patients with bipolar disorder: a review. AB - OBJECTIVES: The burden experienced by caregivers of patients with bipolar disorder has been associated with increased caregiver depression, anxiety and mental health service use. As caregiver burden is also associated with poor patient outcome, these findings may indicate a source of distress not only for caregivers, but also for patients. This review presents what is currently known about psychiatric symptoms in this population and suggests directions for future research. METHODS: Computerized databases Medline, Pubmed, PsychINFO and Google Scholar were searched using the keywords 'bipolar disorder', 'manic-depressive disorder', 'caregiver', 'caregiver burden', 'family', 'couple', 'spouse' and 'partner.' Of these, publications both measuring and reporting psychiatric symptoms or mental health service use in adult caregivers were included. RESULTS: Twenty four (24) papers were analyzed. Thirteen (13) of these papers measured general psychiatric distress, 2 measured anxiety symptoms, 9 reported mood symptoms and 8 reported increased mental health service use. 21 total papers reported clinical significance of least one category of psychiatric distress. Significant findings include up to 46% of caregivers reporting depression and up to 32.4% reporting mental health service use. Data suggest that caregiver psychiatric symptoms depend on the nature of the caregiving relationship. Common methodological problems included: lack of control groups, small sample sizes and non-standardized caregiver and patient criteria. CONCLUSIONS: While not all of the data are consistent, the majority of papers report the presence of psychiatric symptoms in caregivers, such as depression, anxiety and increased mental health service use. Future research is needed to address methodological issues and focus on distinguishing symptoms and identifying effects of mediators such as caregiver-patient relationship, coping styles and stigma. Interventions tailored towards the psychiatric needs of bipolar families may result in improved caregiver and patient outcomes, as well as in decreased health care costs. PMID- 19443039 TI - Culturing thick brain slices: an interstitial 3D microperfusion system for enhanced viability. AB - Brain slice preparations are well-established models for a wide spectrum of in vitro investigations in the neuroscience discipline. However, these investigations are limited to acute preparations or thin organotypic culture preparations due to the lack of a successful method that allows culturing of thick organotypic brain slices. Thick brain slice cultures suffer necrosis due to ischemia deep in the tissue resulting from a destroyed circulatory system and subsequent diffusion-limited supply of nutrients and oxygen. Although thin organotypic brain slice cultures can be successfully cultured using a well established roller-tube method (a monolayer organotypic culture) (Gahwiler B H. Organotypic monolayer cultures of nervous tissue. J Neurosci Methods. 1981; 4: 329-342) or a membrane-insert method (up to 1-4 cell layers, <150 microm) (Stoppini L, Buchs PA, Muller D. A simple method for organotypic cultures of neural tissue. J Neurosci Methods 1991; 37: 173-182), these methods fail to support thick tissue preparations. A few perfusion methods (using submerged or interface/microfluidic chambers) have been reported to enhance the longevity (up to few hours) of acute slice preparations (up to 600 microm thick) (Hass HL, Schaerer B, Vosmansky M. A simple perfusion chamber for study of nervous tissue slices in vitro. J Neurosci Methods 1979; 1: 323-325; Nicoll RA, Alger BE. A simple chamber for recording from submerged brain slices. J Neurosci Methods 1981; 4: 153-156; Passeraub PA, Almeida AC, Thakor NV. Design, microfabrication and characterization of a microfluidic chamber for the perfusion of brain tissue slices. J Biomed Dev 2003; 5: 147-155). Here, we report a unique interstitial microfluidic perfusion technique to culture thick (700 microm) organotypic brain slices. The design of the custom-made microperfusion chamber facilitates laminar, interstitial perfusion of oxygenated nutrient medium throughout the tissue thickness with concomitant removal of depleted medium and catabolites. We examined the utility of this perfusion method to enhance the viability of the thick organotypic brain slice cultures after 2 days and 5 days in vitro (DIV). We investigated the range of amenable flow rates that enhance the viability of 700 microm thick organotypic brain slices compared to the unperfused control cultures. Our perfusion method allows up to 84.6% viability (p<0.01) and up to 700 microm thickness, even after 5 DIV. Our results also confirm that these cultures are functionally active and have their in vivo cyto-architecture preserved. Prolonged viability of thick organotypic brain slice cultures will benefit scientists investigating network properties of intact organotypic neuronal networks in a reliable and repeatable manner. PMID- 19443041 TI - Subtypes of postnatal depression? A comparison of women with recurrent and de novo postnatal depression. AB - BACKGROUND: It has been suggested that there may be two groups of women with postnatal depression (PND) - one who have a history of depression and whose depression is etiologically similar to depression experienced at other times of life, and another who develop depression de novo in the postnatal period and whose depression is uniquely 'postnatal'. The primary aim of this study was to clarify the role of negative attitudes (general and maternal-specific) for these proposed subtypes, whilst also considering the role of a range of other potentially relevant etiological factors. METHODS: 157 postnatal women were classified into four groups: (i) 'recurrent depression', (ii) 'de novo PND', (iii) 'prior (but not current) depression', (iv) 'healthy control'. Groups were compared on known vulnerability and situational risk factors for depression including negative attitudes (general and maternal-specific), personality style vulnerability, relationship insecurity, low social support, stressful life events and difficult infant behaviour. Hierarchical regressions were conducted to examine the role of general and maternal-specific negative attitudes in mediating the relationship between previous depression and PND. RESULTS: Women with recurrent depression had more personality vulnerability and maternal-specific negative attitudes than women with de novo PND, but there were no differences in general negative attitudes or relationship insecurity. Non-depressed women with a history of prior depression were characterized by elevated general depression vulnerability but lower maternal-specific negative attitudes. General negative attitudes mediated the relationship between previous depression and PND. LIMITATIONS: All participants had unsettled infants and the generalizability of results to general postpartum samples is not known. CONCLUSIONS: Although these results do not provide support for the proposed subtypes of PND, they highlight encouraging new avenues for cognitively based preventative interventions. PMID- 19443042 TI - Altered expression of lipid metabolism and immune response genes in the frontal cortex of suicide completers. AB - BACKGROUND: Studies investigating the association between low cholesterol and suicidality have generated a range of ideas about how cholesterol might play a role in influencing suicide risk, extending studies to other aspects of lipid metabolism, as well as immune response, in relation to suicide. METHODS: We performed large-scale microarray gene expression analysis using the Affymetrix HG U133 chipset and focused our investigation on the expression profile of genes related to lipid metabolism and immune response in post-mortem brains from suicide completers and comparison subjects. We used tissue from three regions of the frontal cortex (Brodmann areas (BA) 8/9, 11, and 47) from 22 male suicide completers, 15 of whom were diagnosed with major depressive disorder, and 13 male comparison subjects. RESULTS: Fatty acid desaturase (FADS1), leptin receptor (LEPR), phosphoinositide-3-kinase (class 2 alpha; PIK3C2A) and stearoyl-CoA desaturase (SCD) were consistently down-regulated in all three regions of the frontal cortex of depressed suicides compared to comparison subjects, and were among the genes for which significant correlations were observed between our microarray and real-time PCR data. LIMITATIONS: Given the absence of a non suicidal depressed comparison group in this study, it cannot be ascertained whether the gene expression changes identified are associated with depression or suicide. CONCLUSIONS: Our findings suggest a role for lipid metabolism and immune response genes in depressed suicide completers and lend further support to the relationship between lipid metabolism and suicidality. PMID- 19443043 TI - Psychosocial buffers of traumatic stress, depressive symptoms, and psychosocial difficulties in veterans of Operations Enduring Freedom and Iraqi Freedom: the role of resilience, unit support, and postdeployment social support. AB - BACKGROUND: Little research has examined the role of protective factors such as psychological resilience, unit support, and postdeployment social support in buffering against PTSD and depressive symptoms, and psychosocial difficulties in veterans of Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). MATERIALS AND METHODS: A total of 272 OEF/OIF veterans completed a survey containing PTSD and depression screening measures, and questionnaires assessing resilience, social support, and psychosocial functioning. RESULTS: Lower unit support and postdeployment social support were associated with increased PTSD and depressive symptoms, and decreased resilience and psychosocial functioning. Path analyses suggested that resilience fully mediated the association between unit support and PTSD and depressive symptoms, and that postdeployment social support partially mediated the association between PTSD and depressive symptoms and psychosocial functioning. LIMITATIONS: Generalizability of results is limited by the relatively low response rate and predominantly older and reserve/National Guard sample. CONCLUSIONS: These results suggest that interventions designed to bolster unit support, resilience, and postdeployment support may help protect against traumatic stress and depressive symptoms, and improve psychosocial functioning in veterans. PMID- 19443044 TI - Factorial composition of the Aggression Questionnaire: a multi-sample study in Greek adults. AB - The primary aim of the current article was the evaluation of the factorial composition of the Aggression Questionnaire (AQ(29)) in the Greek population. The translated questionnaire was administered to the following three heterogeneous adult samples: a general population sample from Athens, a sample of young male conscripts and a sample of individuals facing problems related to substance use. Factor analysis highlighted a structure similar to the one proposed by Buss and Perry [Buss, A.F., Perry, M., 1992. The Aggression Questionnaire. Journal of Personality and Social Psychology 63, 452-459]. However, the refined 12-item version of Bryant and Smith [Bryant, F.B., Smith, B.D., 2001. Refining the architecture of aggression: a measurement model for the Buss-Perry Aggression Questionnaire. Journal of Research in Personality 35, 138-167] provided a better fit to our data. Therefore, the refined model was implemented in further analysis. Multiple group confirmatory factor analysis was applied in order to assess the variability of the 12-item AQ across gender and samples. The percentage of factor loading invariance between males and females and across the three samples defined above was high (higher than 75%). The reliability (internal consistency) of the scale was satisfactory in all cases. Content validity of the 12-item AQ was confirmed by comparison with the Symptom Check-List 90 Revised. PMID- 19443045 TI - Analysis of the immunoproteome of Mycoplasma mycoides subsp. mycoides small colony type reveals immunogenic homologues to other known virulence traits in related Mycoplasma species. AB - Contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subsp. mycoides small colony type (MmmSC) has been eradicated in the developed world, but it is still present in many countries of sub-Saharan Africa. After initially successful control measures in the 1960s it has been spreading due to a lack of money, fragmentation of veterinary services, uncontrolled cattle movement, insufficient vaccine efficacy and sensitivity of current diagnostic tests. In this study we used two-dimensional polyacrylamide gel electrophoresis followed by immunoblot with sera from MmmSC-infected animals and MALDI-ToF mass spectrometry to identify novel immunogenic proteins as candidate molecules for improved diagnostics and vaccines. We identified 24 immunogens recognized by pooled sera from experimentally infected cattle. Furthermore, a serum from an animal with acute clinical disease as well as severe pathomorphological lesions recognized 13 additional immunogens indicating variation in the antibody responses to CBPP amongst cattle. Most immunogens showed compelling similarity to protein/gene sequences in the two ruminant pathogens M. capricolum subsp. capricolum and M. mycoides subsp. mycoides large colony type both belonging to the mycoides cluster. Three of these proteins, namely glycerol-3-phosphate oxidase, adenylosuccinate synthase, and glyceraldehyde-3-phosphate dehydrogenase, had no compelling homologue in the other distantly related bovine pathogen M. agalactiae. In addition, translation elongation factor Tu, heat shock protein 70, pyruvate dehydrogenase, and FKBP-type peptidyl-prolyl isomerase, which have been found to mediate adhesion to host tissue in other mycoplasmas were shown to be expressed and recognized by sera. These proteins have potential for the development of improved diagnostic tests and possibly vaccines. PMID- 19443046 TI - Bactrian camel (Camelus bactrianus) integrins alphavbeta3 and alphavbeta6 as FMDV receptors: molecular cloning, sequence analysis and comparison with other species. AB - Integrins are heterodimeric adhesion receptors that participate in a variety of cell-cell and cell-extracellular matrix protein interactions. Many integrins recognize RGD sequences displayed on extracellular matrix proteins and the exposed loops of viral capsid proteins. Four members of the alphav integrin family of cellular receptors, alphavbeta3, alphavbeta6, alphavbeta1 and alphavbeta8, have been identified as receptors for foot-and-mouth disease virus (FMDV) in vitro, and integrins are believed to be the receptors used to target epithelial cells in the infected animals. To analyse the roles of the alphav integrins from a susceptible species as viral receptors, we have cloned Bactrian camel alphav, beta3 and beta6 integrin cDNAs and compared them to those of other species. The coding sequences for Bactrian camel integrin alphav, beta3 and beta6 were found to be 3165, 2289 and 2367 nucleotides in length, encoding 1054, 762 and 788 amino acids, respectively. The Bactrian camel alphav, beta3 and beta6 subunits share many structural features with homologues of other species, including the ligand binding domain and cysteine-rich region. Phylogenetic trees and similarity analyses showed the close relationships of integrin genes from Bactrian camels, pigs and cattle, which are each susceptible to FMDV infection, that were distinct from the orders Rodentia, Primates, Perissodactyla, Carnivora, Galliformes and Xenopus. We postulate that host tropism of FMDV may in part be related to the divergence in integrin subunits among different species. PMID- 19443047 TI - CSF oligoclonal band patterns reveal disease heterogeneity in multiple sclerosis. AB - Oligoclonal IgG bands (OCGB) are characteristic of multiple sclerosis (MS). Most patients show OCGB exclusively in cerebrospinal fluid (CSF). Others have serum bands with additional ones in CSF. Moreover, IgM bands against myelin lipids (LS OCMB) associate with aggressive relapsing-remitting MS (RRMS). We studied oligoclonal bands in 424 MS patients. Most primary progressive (PPMS) patients showed serum OCGB with additional bands in CSF. Conversely, most RRMS and secondary progressive (SPMS) patients showed OCGB exclusively in CSF (p<0.0001). Moreover, no PPMS patient presented LS-OCMB, while 31% of RRMS and 60% of SPMS groups showed these antibodies (p<0.0001). This suggests heterogeneous autoimmune mechanisms in MS. PMID- 19443048 TI - Recombinant interferon-beta therapy and neuromuscular disorders. AB - Interferon-beta (IFNbeta) is an extra-cellular protein mediator of host defense and homeostasis. IFNbeta has well-established direct antiviral, antiproliferative and immunomodulatory properties. Recombinant IFNbeta is approved for the treatment of relapsing-remitting multiple sclerosis. The immunomodulatory effects of IFNbeta administration failed to demonstrate consistent benefit during treatment of various autoimmune neuromuscular diseases. Existing studies were flawed due to the often uncontrolled and unblinded nature of protocols, small patient numbers per study, the undetermined optimum dose and schedule of IFNbeta therapy, and the relatively brief periods of IFNbeta administration and clinical follow-up for mostly chronic inflammatory disorders. Additional, controlled, prospective studies are needed to definitely establish the full potential of this cytokine for this group of diseases. IFNbeta therapy may trigger autoantibody production, but only rarely clinically overt autoimmune disease. Anecdotal reports hint at the exceptional association between IFNbeta treatment and the induction or exacerbation of a variety of immune-mediated neuromuscular diseases, likely in genetically predisposed individuals. Thus, recombinant IFNbeta has the theoretical potential to either treat or cause autoimmune neuromuscular disorders by altering the complicated and delicate balances within the immune system networks. PMID- 19443049 TI - Cleft lip and palate treatment of 530 children over a decade in a single centre. AB - OBJECTIVE: We sought to evaluate the process of care and the outcomes of cleft lip and palate operations carried by a multidisciplinary team at a centre of craniofacial anomalies with a high patients' volume. METHODS: A retrospective review of all cleft lips and/or palates cases treated in the centre from 1995 to 2007 was performed. Direct and long term complication rates, clinical, audiologic, speech intelligibility and dental arch assessments were analyzed. RESULTS: A total of 530 children have been operated this period in the centre (64 isolated cleft lip closures). A detailed presentation of the outcomes is performed in relation to the various types of cleft lip and palates. The majority of parents (70%) reported very good or excellent results 2-5 years after the lip closure with the Millard technique, although those with bilateral clefts were significantly less satisfied (P<0.002). Forty-two percent of children with cleft palate and otitis media with effusion were self-improved 2-8 months after palate reconstruction and 83.3% of children treated with the two flaps palatoplasty technique had a rather high or very high intelligibility score. Muscles' retropositioning had a significant effect on intelligibility (P=0.04). CONCLUSIONS: Children with cleft lips and palates have a variety of conditions and functional limitations even after the surgical correction of their problem that need to be evaluated and treated by several specialists. The treatment protocol utilized by the multidisciplinary team of our centre is efficient with a relative low percentage of complications and unfavorable results. PMID- 19443050 TI - Tracheal pH monitoring: a pilot study in tracheostomy dependent children. AB - OBJECTIVES: 1. Determine the feasibility of measuring tracheal pH with a novel non-aqueous probe designed for oropharyngeal pH monitoring. 2. Correlate clinical and subclinical laryngopharyngeal reflux aspiration events with esophageal pH measurements. METHODS: Five children with chronic indwelling tracheostomies undergoing routine endoscopy and pH probe monitoring at a tertiary care pediatric aerodigestive center between October 2007 and January 2008 were identified for this prospective feasibility pilot study. The non-aqueous Restech Dx-pH probe was subsequently affixed to each child's tracheostomy with the probe tip confirmed to be within the tracheal lumen. Esophageal and tracheal probe pH measurements were subsequently recorded until the child was unable to tolerate the study or 24 h elapsed. Tracheal pH tracings were compared directly to esophageal pH tracings. Esophageal biopsy and bronchoalveolar lavage data were reviewed for each child. RESULTS: 3/5 children tolerated the tracheal probe for greater than 18 h. Adequate tracheal pH tracings were demonstrated for all children while the probe was in position. Mean baseline tracheal pH was 7.8. One child demonstrated direct correlation between acidic esophageal reflux events and decreased tracheal pH. Esophageal biopsy confirmed the presence of active inflammation consistent with reflux in this child. CONCLUSION: Tracheal pH can be accurately recorded with the Restech Dx-pH probe. The technology may allow further investigations to determine the impact of gastroesophageal refluxate aspiration and empiric antireflux therapy in children with aerodigestive symptoms. PMID- 19443051 TI - The mid-face in otitis media. PMID- 19443052 TI - Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. AB - The Hedgehog (Hh) signaling pathway regulates body patterning and organ development during embryogenesis. In adults the Hh pathway is mainly quiescent, with the exception of roles in tissue maintenance and repair, and its inappropriate reactivation has been linked to several disparate human cancers. In addition to cancers with mutations in components of the Hh pathway, Hh ligand dependent cancers have been proposed to respond to Hh in an autocrine manner. More recent findings that Hh might instead signal in a paracrine manner from the tumor to the surrounding stroma or in cancer stem cells alter our understanding of Hh mechanisms in cancer, with important implications for choice of preclinical tumor models, drug screening, patient selection and therapeutic intervention. We review here the roles of the Hh pathway in cancer, Hh pathway inhibitors (HPIs) and early clinical trial results using a novel small molecule HPI, GDC-0449. PMID- 19443053 TI - The longitudinal quantitative assessment by transient elastography of chronic hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin. AB - The aim of this study was to assess the association between liver stiffness measured by transient elastography (FibroScan) and the efficacy of pegylated interferon alpha-2b plus ribavirin combination treatment for patients with chronic hepatitis C virus (HCV) infection. We prospectively studied 145 Japanese patients with chronic HCV infection. FibroScan was done at baseline, at the end of treatment, and at 48 and 96 weeks after the end of treatment. The FibroScan values were significantly decreased for sustained virological response (SVR) patients (the mean rate of change; -16.2%, -32.2% and -43.5%) in comparison with non-SVR patients (-7.2%, -2.1% and +17.3%) at the end of treatment (P=0.0127), and 48 weeks (P<0.0001) and 96 weeks (P<0.0001) after the end of treatment. Among the non-SVR patients, the FibroScan values were significantly decreased for patients with biochemical response (BR) (-17.9%, -30.0% and -27.1%) in comparison with non-BR (-4.1%, +6.4% and +30.6%) at the end of treatment (P=0.0270), and 48 weeks (P<0.0001) and 96 weeks (P<0.0001) after the end of treatment. The FibroScan values may predict a progressively better clinical outcome for patients with successful virological and biochemical responses. PMID- 19443054 TI - Fluoxetine treatment affects nitrogen waste excretion and osmoregulation in a marine teleost fish. AB - Measurable quantities of the selective serotonin reuptake inhibitor (SSRI), fluoxetine, have been found in surface waters and more recently in the tissues of fish. This highly prescribed pharmaceutical inhibits the reuptake of the monoamine, serotonin (5-HT; 5-hydroxytryptamine), causing a local amplification of 5-HT concentrations. Serotonin is involved in the regulation of many physiological processes in teleost fish including branchial nitrogen excretion and intestinal osmoregulation. Since the gill and intestine are directly exposed to the environment, environmental exposure to fluoxetine has the potential of affecting both these mechanisms. In the present study, we test the potential sensitivity of these processes to fluoxetine by implanting gulf toadfish, Opsanus beta, intraperitoneally with different concentrations of fluoxetine (0 (control), 25, 50, 75 and 100 microgg(-1)). Fluoxetine treatments of 25 and 50 microgg(-1) were sub-lethal and were used in subsequent experiments. Fish treated with both 25 and 50 microgg(-1) fluoxetine had significantly higher circulating levels of 5 HT than control fish, suggesting that any 5-HT sensitive physiological process could potentially be affected by these two fluoxetine doses. However, only fish treated with 25 microgg(-1) fluoxetine showed a significant increase in urea excretion. A similar increase was not measured in fish treated with 50 microgg( 1) fluoxetine, likely because of their high circulating levels of cortisol which inhibits urea excretion in toadfish. Intestinal fluid absorption appeared to be stimulated in fish treated with 25 microgg(-1) fluoxetine but inhibited in 50 microgg(-1) treated fish. Despite these differing responses, both doses of fluoxetine resulted in lowered plasma osmolality values, which was expected based on the stimulation of fluid absorption in the 25 microgg(-1) fluoxetine-treated fish but is surprising with the 50 microgg(-1) treated fish. In the case of the latter, the corresponding stress response invoked by this level of fluoxetine may have resulted in an additional osmoregulatory response which accounts for the lowered plasma osmolality. Our findings suggest that branchial urea excretion and intestinal osmoregulation are responsive to the SSRI, fluoxetine, and further investigation is needed to determine the sensitivity of these processes to chronic waterborne fluoxetine contamination. PMID- 19443055 TI - Waterborne exposure to fluorotelomer alcohol 6:2 FTOH alters plasma sex hormone and gene transcription in the hypothalamic-pituitary-gonadal (HPG) axis of zebrafish. AB - Fluorotelomer alcohols (FTOHs) have shown estrogenic activity in vitro and in vivo, but the mechanism of this activity is not known. In this study, 18-week-old zebrafish (Danio rerio) were exposed to 0, 0.03, 0.3 and 3.0mg/l 1H,1H,2H,2H perfluorooctan-1-ol (6:2 FTOH) for 7 days, and the effects on plasma sex hormone levels were measured followed by use of real-time PCR to examine selected gene expression in hypothalamic-pituitary-gonadal (HPG) axis and liver. Exposure to 6:2 FTOH significantly increased plasma estradiol (E2) and testosterone (T) levels in both males and females. Furthermore, the ratio of T/E2 was reduced in females while increased in males. In females, the increase of E2 was accompanied by up-regulated hepatic estrogenic receptor alpha (ERalpha) and vitellogenin (VTG1 and VTG3) expression. In males, the elevation of the T level is consistent with the up-regulation of cytochrome P450 c17alpha-hydroxylase, 17, 20-lase (CYP17) and the down-regulation of cytochrome P450 aromatase A (CYP19A). The present study demonstrated that waterborne exposure to 6:2 FTOH alter plasma sex hormone levels and the ratio of T/E2, as well as the transcriptional profiles of some genes in the HPG axis and liver. The results suggested that FTOHs may disturb fish reproduction through endocrine disrupted activity. PMID- 19443056 TI - Functional characterization of stage-specific aminotransferases from trypanosomatids. AB - As part of a study on aminotransferases, genes coding for putative enzymes from Trypanosoma brucei and Leishmania major (alanine aminotransferases: ALATs, Tb927.1.3950 and LmjF12.0630; kynurenine aminotransferase: KAT, Tb10.389.1810; and tyrosine aminotransferase: TAT, LmjF36.2360) were cloned and functionally expressed in Escherichia coli. The putative T. brucei KAT, in fact coded for a glutamine aminotransferase (GlnAT), which exhibited a notably high affinity (in the micromolar range) towards glutamine and cysteine; in addition, like bacterial GlnATs and mammalian KATs, it was able to utilize different 2-oxoacids as amino acceptors. L. major TAT resembled T. cruzi TAT in substrate specificity, although the leishmanial enzyme did not exhibit ALAT activity. On the other hand, T. brucei ALAT, shortened by the first 65 amino acids assigned in the data bases, was functional and actively transaminated the substrate pair l-alanine and 2 oxoglutarate. Moreover in Western blots, the molecular size of the protein detected in crude extracts of T. brucei procyclics was identical to the value of the recombinant enzyme. Like T. brucei and T. cruzi orthologues, L. major ALAT displayed narrow substrate specificity. The leishmanial ALAT, like the T. cruzi enzyme, exhibited a dual subcellular localization, in the cytosol and in the mitochondrion. In line with the findings of comparative proteomic analyses of insect and mammalian stages of T. brucei and Leishmania parasites, our results also showed that T. cruzi ALAT is constitutively expressed, with remarkably higher levels being detected in amastigotes than in epimastigotes. ALATs are expressed in the clinically important stages of TriTryps, probably fulfilling an essential role, which deserves further studies. PMID- 19443057 TI - Evaluating outcomes of Taiwan's first gerontology certification program. AB - The elderly population will approach 20% within the next 20 years. This enhances the need for skilled and experienced health care providers. There is a critical need to strengthen gerontology curricula to prepare health-related professionals for a graying population. The purpose of this article is to investigate student satisfaction with the first National Project for Excellence in Gerontological Care Education (NPEGCE) in Taiwan. A cross-sectional design was used. A sample of 151 medical, nursing, and physical therapy students, who had enrolled in the NPEGCE and had taken at least one core course, completed a satisfaction questionnaire. To ensure content validity, a multidisciplinary, institutional committee of gerontology and geriatric faculty designed the content. Overall satisfaction scores varied between satisfied (4-points) and very satisfied (5 points). Medical students gave higher ratings than others. Two factors (Curriculum and Teaching) were extracted. A strong correlation was found between the subscales and overall satisfaction scores. Internal scale consistency reliability scores ranged from 0.92 to 0.96. Overall, this study demonstrates a moderate level of satisfaction with the NPEGCE. However, these results are from a single institution; they are not generalizable. This is also the first student satisfaction report from Taiwan. There are no similar programs or evaluation results to compare them with. Since the NPEGCE was well received by students and seemed to encourage a more nurturing attitude towards the elderly; it can be regarded as a catalyst for better elderly care in the future. PMID- 19443058 TI - Impact of mental health and caregiver burden on family caregivers' physical health. AB - Caregivers providing care to chronically ill family members at home are potentially at risk for caregiver burden and declining physical and psychological health. This study aims to understand how family caregivers' mental health and caregiver burden affects physical health simultaneously, controlling for factors such as age, education level, caring hours per day, and emotional, functional, and physical support systems used by caregivers. We recruited 388 caregivers from Kaohsiung and Pingtong region in Taiwan. Caregivers had to be 18 years or older and spend most of their time taking care of an ill family member at home. Mental health was assessed by the 12-item Chinese Health Questionnaire (CHQ-12) and burden was measured using a modified scale for caregiver's burden. Health status was assessed by self-perceived health (SPH), illness symptoms and the number of diagnosed chronic diseases. A high number of hours per day of caregiving was associated with low emotional support and SPH, poor mental health and high burden. Higher emotional support was associated with better mental health and fewer illness symptoms. Higher physical support was associated with poorer mental health, higher burden, a greater number of illness symptoms and chronic diseases, and a lower SPH score. Hours per day of caregiving, and use of emotional, functional, and physical support were associated with mental health, and the hours per day of caregiving and use of physical support were predictors of burden. Mental health and burden were significantly associated with caregivers' health problems simultaneously. Our results show the important influence of mental health on caregivers' physical health. Interventions for caregivers need to target health in a holistic way. PMID- 19443059 TI - Effect of freshly isolated autologous tissue resident stromal cells on cardiac function and perfusion following acute myocardial infarction. AB - BACKGROUND: The aim of this study was to investigate the effect of intracoronary administration of freshly isolated, uncultured autologous tissue-derived stromal cells on cardiac function and perfusion after acute infarction in pigs. METHODS: A transmural myocardial infarction in a porcine model was induced by occlusion of the mid LAD with an angioplasty balloon for 3 h. Upon reperfusion, freshly isolated, uncultured autologous stromal cells (1.5*106 cells/kg) or control solution was injected into the infarct artery. Cardiac function and area at risk were determined by (99m)Tc-SPECT. RESULTS: Eight weeks after infarction, cell treated pigs showed a 20% smaller myocardial perfusion defect compared to control animals (35+/-9% vs. 44+/-5% of LV, treated vs. control, respectively, p<0.05). The reduction of the perfusion defect was associated with a significantly higher myocardial salvage index in the cell group as well as a significant increase in ejection fraction compared to control (EF at 8 weeks 43+/-7% vs. 35+/-3%, treated vs. control, respectively, p<0.05). This functional improvement was reflected by an increased wall thickness of the infarct and border zone in the treated group (11.2+/-2.2 mm) compared to control (8.6+/-1.6 mm, p<0.05) as well as an increased capillary density in the border zone (treated vs. control; 41.6+/-17.9 vs. 32.9+/-12.6 capillaries per 0.1 mm2, p<0.05). CONCLUSIONS: This study demonstrates for the first time that recovery and intracoronary delivery of uncultured autologous tissue derived stromal cells at time of vessel reperfusion is feasible and improves ventricular function. PMID- 19443060 TI - Transient left ventricular dysfunction syndrome: patho-physiological bases through nuclear medicine imaging. AB - BACKGROUND: Takotsubo cardiomyopathy (TTC) is a novel heart disease, mimicking acute myocardial infarction. The term "transient left ventricular dysfunction syndrome" (TLVDS) seems to be more appropriate since variant forms of TTC sparing apical segments (mid-ventricular ballooning syndrome (MVBS) and inverted TTC) have been described. Patho-physiological bases of TLVDS remain poorly understood and its optimal management is until now empirical. Our aim was to characterize patho-physiological mechanisms of TLVDS by means of nuclear medicine procedures and to discuss the clinical usefulness of isotopic imaging for a non-invasive diagnosis of TLVDS. METHODS AND RESULTS: During the sub acute phase, eighteen patients with TLVDS (13 TTC and 5 MVBS) underwent myocardial (99m)Tc-tetrofosmin or (201)Thallium Gated Single Photon Emission Computed Tomography (G-SPECT) (n=11), (123)I-mIBG SPECT (n=8) and (18)F-FDG Gated Positron Emission Tomography (G-PET) (n=15), assessing respectively LV perfusion, sympathetic innervation and glucose metabolism. Hypocontractile LV segments were characterized by normal perfusion but reduced uptake of (18)F-FDG and (123)I-mIBG. Topography and extent of metabolic defects and innervation abnormalities were largely overlapping. Follow-up (123)I-mIBG SPECT and (18)F-FDG G-PET were performed in selected patients showing rapid normalization of LV motion and progressive improvement of both glucose metabolism and sympathetic innervation. DISCUSSION: With the hypothesis of neurogenic stunned myocardium as the central causative mechanism of TLVDS, (123)I-mIBG SPECT seems to be the most specific diagnostic technique. Sympathetic function and glucose metabolism seem to be strictly correlated in the hypocontractile LV segments. Finally, our results underline the role of nuclear imaging in the setting of patho-physiological mechanisms of TLVDS. PMID- 19443061 TI - Prevalence and associated management factors of Cryptosporidium shedding in 50 Swedish dairy herds. AB - Cryptosporidium parvum is a protozoan parasite causing diarrhoea in young calves. This cross-sectional study was performed to estimate the prevalence of Cryptosporidium infected herds in a sample of Swedish dairy herds and to identify potential risk factors associated with shedding of oocysts. Fifty dairy herds, selected by stratified random sampling, were included. The herds were visited once during the indoor seasons of 2005-2006 and 2006-2007. Faecal samples were collected from 10 calves, 10 young stock and 5 cows in each herd. Clinical observations of sampled animals and environmental status were recorded, and farmers were interviewed about management procedures. Faecal samples were cleaned by sodium chloride flotation and detection of oocysts was made by epifluorescence microscopy. Cryptosporidium parvum-like oocysts were found in 96% of the herds. Prevalence was 52% in calves, 29% in young stock and 5.6% in cows. Three two-day old calves shed oocysts. Cryptosporidium andersoni was found in seven animals from four different herds. Factors associated with prevalence of shedders among sampled animals in a herd were age at weaning, cleaning of single calf pens, placing of young stock, system for moving young stock, and year of sampling. Factors associated with shedding in calves were age, placing of young stock, routines for moving young stock and time calf stays with the cow. The only significant factor in young stock was age. In cows, number of calves in the herd and type of farming (organic vs. conventional) affected shedding. PMID- 19443062 TI - Evaluation of strategies to improve village chicken production: controlled field trials to assess effects of Newcastle disease vaccination and altered chick rearing in Myanmar [corrected]. AB - Previous research identified Newcastle disease and poor management of chicks (birds younger than 6 weeks of age) as major constraints to village chicken production in Myanmar. Based on these findings, controlled trials were conducted in 124 randomly selected households in nine villages in Myanmar over a period of 12 months to evaluate strategies to enhance survival of village chickens. Two intervention strategies were assessed: Newcastle disease vaccination using the thermostable I-2 vaccine and changes to the management of chick rearing (confinement and supplementary feeding). These interventions were applied in two trials: (1) a randomised controlled trial to compare I-2 vaccination, altered chick management and no intervention (apart from placebo treatment) at household level and (2) nested within this trial, a double-blinded controlled trial at bird level to compare serological titres between I-2 vaccinated and placebo-treated birds both between and within households. Outcomes measured in the first trial were crude incidence rate of mortality, proportional mortality rate for deaths due to disease stratified by age group of birds and mortality attributed to Newcastle disease, number of sales, income from sale of birds, consumption of birds and hatching of birds. Odds of having protective titres two weeks after vaccination were up to 125 times higher in I-2 vaccinated birds and up to 47 times higher in control birds in contact with I-2 vaccinates compared to birds without I-2 contact. Vaccination against Newcastle disease reduced the proportions of mortalities assumed to be caused by disease in growers and chicks. Crude mortality incidence was lower in households that applied management changes to chick rearing. In household-months when birds were sold, numbers sold were higher and income from sale of birds were about 2.50 US dollars per month higher in households allocated to altered chick management. Altered chick management resulted in more households having hatchings of chicks. After a lag period of 7 months, these households were also more likely to consume home-produced chicken meat. This 7-month period reflects the age when birds are consumed and sold and highlights the lag periods that should be expected before beneficial effects of interventions focussed on chicks occur. This field research has shown that I-2 vaccination markedly increases the prevalence of protective titres and reduces proportions of mortality attributed to disease and that chick management using confinement and supplementary feeding can improve health and production of village chickens. These interventions are simple and sustainable intervention strategies. PMID- 19443063 TI - A mathematical model demonstrating indirect and overall effects of lactation therapy targeting subclinical mastitis in dairy herds. AB - A deterministic state-transition model for mastitis transmission was developed to explore population level effects of antibiotic treatment regimens targeting chronic subclinical mastitis caused by major gram-positive pathogens in lactating dairy cows. Behavior and sensitivity of model outputs to changes in key parameters were explored. Outcomes included the size of the state variables describing proportions of infected quarters and basic and effective reproductive numbers. Treatment effects were estimated by calculating proportional reductions in state variables at equilibrium for populations implementing a treatment program relative to populations with no intervention. In general the relationships between parameters were complex and non-linear, although the model outputs were especially sensitive to changes in the value of the transmission rate parameter. Interaction between the parameters resulted in large variations in treatment effect estimates. Effect estimates calculated from model outputs showed a quadratic curve with a clear optimum at low, but not the lowest, transmission rates. These results indicated that overall positive population level effects of lactation therapy would be realized for herds that have successfully implemented practices that reduce the transmission rate of pathogens. A key finding is that in herds with high transmission rates, treatment of chronically infected quarters was predicted to have little impact on the proportion of infected quarters and no positive population level effect in reducing the force of infection and new infection rates. Results of this study suggest that field trials to evaluate efficacy of antimicrobial treatment should include estimates of indirect treatment effects. PMID- 19443064 TI - Modelling sources of variation and risk factors for spinal deformity in farmed Atlantic salmon using hierarchical- and cross-classified multilevel models. AB - Sources of variation and risk factors for spinal deformity were investigated in a 2002-2004 year-class database of farmed Atlantic salmon using multilevel modelling. The prevalence of spinal deformity, recorded on subsamples of Atlantic salmon at individual days of harvest, was used as the outcome variable in the study. The dataset consisted of a multilevel structure with days of harvest (n=1441) nested within sea water pens (n=544), which were nested within sea water sites (n=39), which again were cross-classified with fresh water plants (n=21). A four level combined hierarchical- and cross-classified linear mixed model was built in MLwiN using Markov chain Monte Carlo (MCMC) estimation of variance components and fixed effects. Results revealed that a large part of the variance could be explained as sampling and classification random errors, accounting for 32% of the variation in the random intercept model and 41% of the variation in the final mixed effect model. Of the remaining "biological variation" in the random intercept model, 33% was explained by fixed effects where both the use half-year and 1.5 year old photo-manipulated autumn smolts (compared to using one year old spring smolt), and the use of six component vaccines (compared to using four and five component vaccines), were significantly associated with spinal deformity. The results suggest that the physiological changes at time of smoltification make Atlantic salmon susceptible to stressors causing vertebral deformation and that this is most evident in photo-manipulated fish smoltifying when temperature and growth is at its peak. The study further shows the potential of using multilevel modelling in epidemiological studies based on data from industrial aquaculture. PMID- 19443065 TI - Motor assessment of preschool aged children: A preliminary investigation of the validity of the Bruininks-Oseretsky test of motor proficiency - short form. AB - The aim of this study was to examine the validity of the Bruininks-Oseretsky test of motor proficiency - short form (BOTMP-SF) [Bruininks, R. (1978). Bruininks Oseretsky test of motor proficiency: Examiners manual. Circle Pines, MN] for the assessment of preschool aged children. Three-hundred and eighteen children 48 71months old (M=58.97months, SD=6.73) participated in the study. For the data analysis both an ANOVA and a MANOVA were applied with the total battery score and the 14 item scores being the dependent variables, respectively. Age was found to have a significant effect on both children's total battery score (F(3, 314)=110.65, p<.001, eta(2)=.68) and 13 item scores (minimum F(3, 314)=8.75, p<.001, minimum eta(2)=.145). Although the aforementioned results represent an evidence for the validity of the BOTMP-SF, a closer study on the score of each item revealed a high percentage of zero scores on four items. Task difficulty has caused a floor effect, constituting a threat to the validity of the preschoolers' motor assessment with the above battery. A modification of the battery items is suggested, so that the BOTMP-SF will give valid results for children 4-6years old. PMID- 19443066 TI - Motion pattern analysis of gait in horseback riding by means of Principal Component Analysis. AB - As a consequence of the three interacting systems of horse, saddle, and rider, horseback riding is a very complex movement that is difficult to characterize by a limited number of biomechanical parameters or characteristic curves. Principal Component Analysis (PCA) is a technique for reducing multidimensional datasets to a minimal (i.e., optimally economic) set of dimensions. To apply PCA to horseback riding data, a "pattern vector" composed of the horizontal velocities of a set of body markers was determined. PCA was used to identify the major dynamic constituents of the three natural gaits of the horse: walk, trot, and canter. It was found that the trot is characterized by only one major component accounting for about 90% of the data's variance. Based on a study involving 13 horses with the same rider, additional phase plane analyses of the order parameter dynamics revealed a potential influence of the saddle type on movement coordination for the majority of horses. PMID- 19443067 TI - Shiga toxin-producing Escherichia coli O157 in beef and chicken burgers, and chicken carcasses in Buenos Aires, Argentina. AB - We describe the isolation and characterization of Shiga toxin (Stx)-producing Escherichia coli (STEC) O157:H7 from cooked and uncooked beef and chicken burgers and from chicken carcasses collected during sampling procedures in 2001 and 2002 in Buenos Aires City, Argentina. Of the 24 STEC O157:H7 strains isolated, 20 were recovered from 19 (6.8%) out of 279 samples of beef and chicken burgers, and 4 strains from 4 (10.3%) out of 39 chicken carcasses. The samples were analyzed following the USDA/FSIS 2002 method. The prevalent stx genotype was stx(2) and stx(2c) (12 strains, 50%). All strains were characterized as eae and ehxA positive. By XbaI-PFGE, the strains yielded 10 different patterns. Eighteen out of 24 strains were grouped in four clusters: #1 (4 strains, AREXHX01.0043), #2 (4 strains, AREXHX01.0022), #3 (8 strains, AREXHX01.0139), and #4 (2 strains, AREXHX01.0200). Identical strains by phage typing, stx genotyping and PFGE were detected in uncooked and cooked beef and chicken burgers in different restaurants, which had been collected on the same or different sampling dates. These findings help to underline the importance of STEC O157 detection in meat products, to improve active surveillance, and to define control strategies in order to prevent new cases of STEC infection. PMID- 19443068 TI - Ethnic and gender differences regarding the insulin-blood pressure relationship. AB - Ageing is associated with increased insulin and C-peptide levels. Due to a lack of data, our first aim was to establish whether this also holds true for Africans from South Africa. Our second aim was to determine whether an association between insulin/C-peptide levels and blood pressure exist within an African and Caucasian population with increasing age, as well as to establish gender differences. African men and women (N=260) and Caucasian men and women (N=369) were recruited and stratified into age groups (18-35 years, 36-45 years and >45 years). ANCOVAs and partial correlations were performed. Results showed opposing changes in insulin/C-peptide levels of African and Caucasian men with increasing age. Insulin/C-peptide tended to decrease in African men, whereas insulin tended to increase and C-peptide increased significantly (p=0.03) in Caucasian men. Despite similar obesity levels, the oldest African women had significantly lower insulin (p<0.01) and C-peptide (p<0.01) levels compared to their Caucasian counterparts. In conclusion, insulin/C-peptide levels tended to decrease in the African population with increasing age. Despite significantly lower levels of insulin, blood pressure levels of African men seems to be affected more detrimentally compared to their Caucasian counterparts, leaving them more vulnerable for the development of cardiovascular diseases. PMID- 19443069 TI - Pregnancy in women with known and treated Budd-Chiari syndrome: maternal and fetal outcomes. AB - BACKGROUND/AIMS: Budd-Chiari syndrome (BCS) mainly affects women of childbearing age. We aimed to clarify whether pregnancy, a thrombotic risk factor, should be contraindicated in patients with known and treated BCS. METHODS: A retrospective study of pregnancy in women with known and treated BCS. RESULTS: Sixteen women had 24 pregnancies. Nine women had undergone surgical or radiological treatment. Anticoagulation was administered during 17 pregnancies. Seven fetuses were lost before gestation week 20. Deliveries occurred between week 20 and 31 in two patients, week 32 and 36 in eleven and after week 37 in four. There was one stillbirth, but 16 infants did well. Factor II gene mutation was a factor for a poor outcome of pregnancies. In two patients, symptomatic thrombosis recurred during pregnancy or postpartum. All patients were alive after a median follow-up of 34 months after the last delivery. Bleeding at delivery, although non-lethal, occurred only on anticoagulation therapy. CONCLUSIONS: When known and treated BCS is well controlled, pregnancy should not be contraindicated as maternal outcome, and fetal outcome beyond gestation week 20, are good. The risk-benefit ratio of anticoagulant therapy needs to be further clarified. Patients should be fully informed of the persistent risks of such pregnancies. PMID- 19443070 TI - Identification of proteomic changes during human liver development by 2D-DIGE and mass spectrometry. AB - BACKGROUND/AIMS: The aim of this study was to identify human liver proteins that are associated with different stages of liver development. METHODS: We collected liver samples from 14 fetuses between 14 and 41 weeks of development, one child and four adults. Proteins which exhibited consistent and significant variations during development by two-dimensional differential in gel electrophoresis (2D DIGE) were subjected to peptide mass fingerprint analysis by MALDI-TOF mass spectrometry. Real-time PCR analysis confirmed, at the transcriptional level, the data obtained by the proteomic approach. RESULTS: Among a total of 80 protein spots showing differential expression, we identified 42 different proteins or polypeptide chains, of which 26 were upregulated and 16 downregulated in developing in comparison to adult liver. These proteins could be classified in specific groups according to their function. By comparing their temporal expression profiles, we identified protein groups that were associated with different developmental stages of human fetal liver and suggest that the changes in protein expression observed during the 20- to 36-week time window play a pivotal role in liver development. CONCLUSIONS: The identification of these proteins may represent good markers of human liver and stem cells differentiation. PMID- 19443071 TI - Treatment with nucleos(t)ide analogues in chronic hepatitis B: where does the road map lead us? PMID- 19443072 TI - Hepatitis C virus single-stranded RNA induces innate immunity via Toll-like receptor 7. AB - BACKGROUND/AIMS: Innate immune responses to HCV infection are triggered through host recognition of pathogen-associated molecular patterns. Interferons are critical for the protection against HCV infection. However, the pathways linking virus recognition to IFN induction remain poorly understood. METHODS: Immune cells and Huh-7 cells were infected with HCV cell culture (HCVcc) or transfected with HCV-derived immunostimulatory RNA oligonucleotides (ORNs), and immune activation was assessed. RESULTS: We found that HCVcc suppressed immune responses because the HCVcc protein impaired the PBMC and pDC responses. However, HCVcc genomic RNA had an immunostimulatory effect. HCV encodes G/U-rich ssRNA TLR7 ligands that significantly activate innate immunity, and induced IFN-alpha production. Moreover, HCV-derived ORNs also activated IRF7 and NF-kappaB in Huh-7 cells. In particular, the HCV 3'-UTR strongly induced cytokine production. Different lengths of polyuridine tract in the 3'-UTR of different HCV strains induced IFN-alpha production. These data demonstrate that the HCV-specific G/U fragment is a motif sequence, and is recognized by TLR7 as a PAMP. The requirement for TLR7 to recognize HCV RNA was confirmed using specific inhibitors, RNAi and by TLR7overexpression. CONCLUSION: These results provide an insight into the development of immune adjuvant for vaccines and for the production of new antiviral drugs. PMID- 19443073 TI - Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice. AB - BACKGROUND/AIMS: Resident macrophages and myofibroblasts derived from hepatic stellate cells play a key role in liver wound healing. We previously reported that these sinusoidal cells secrete the growth arrest-specific protein 6 (Gas6) and express Axl, one of its receptors. Here we address the role of Gas6 in the healing process during acute liver injury. METHODS: Toxic hepatitis was induced by a single carbon tetrachloride injection in Gas6 deficient (Gas6(-/-)) mice and liver recovery was compared with wild-type animals. RESULTS: Gas6 deficiency did not cause any change in CCl(4)-induced liver damage. At 72 h, an efficient tissue repair was observed in wild-type animals whereas in Gas6(-/-) mice, we noticed a defective wound healing accounted by reduced Kupffer cell activation revealed by a decrease in the induction of CD14, TNF-alpha, IL6 and MCP-1. Gas6-deficiency, by limiting cytokine/chemokine release, prevents hepatocyte proliferation, recruitment of circulating monocytes and accumulation of myofibroblasts in healing areas. We also report a direct chemotactic effect of Gas6 on circulating monocytes which might explain defective macrophage infiltration in liver necrotic areas of Gas6(-/-) mice. Interestingly in Gas6(-/-) mice, we observed a high and constitutive expression of Axl and an induction of the suppressor of cytokine signaling SOCS1 after CCl(4) treatment. CONCLUSIONS: The lower level of cytokines/chemokines in Gas6(-/-) mice after CCl(4) injury, is the consequence of an inhibitory signal arising from Axl receptor overexpression, leading to delayed liver repair in deficient mice. PMID- 19443074 TI - Planning for what? Challenging the assumptions of health human resources planning. AB - OBJECTIVES: Health human resource planning has traditionally been based on simple models of demographic changes applied to observed levels of service utilization or provider supply. No consideration has been given to the implications of changing levels of need within populations over time. Recently, needs based resource planning models have been suggested that incorporate changes in needs for care explicitly as a determinant of health care needs. METHODS: In this paper, population indicators of morbidity, mortality and self-assessed health are analyzed to determine if health care needs have changed across birth cohorts in Canada from 1994 to 2005 among older age groups. Multivariate regression analysis was used to estimate the age pattern of health by birth year with interaction terms included to examine whether the association of age with health was conditional on the birth year. RESULTS: Results indicate that while the probability of mortality, mobility problems and pain rises with age, the rate of change is greater for those born earlier. The probability of self-assessed poor health increases with age but the rate of change with age is constant across birth years. CONCLUSIONS: Even in the short time period covered, our analysis shows that health care needs by age are changing over time in Canada. PMID- 19443075 TI - Origin and evolution of Y chromosomes: Drosophila tales. AB - Classically, Y chromosomes are thought to originate from X chromosomes through a process of degeneration and gene loss. Now, the availability of 12 Drosophila genomes provides an opportunity to study the origin and evolution of Y chromosomes in an informative phylogenetic context. Surprisingly, the majority of Drosophila Y-linked genes are recent acquisitions from autosomes and Y chromosome gene gains are more frequent than gene losses. Moreover, the Drosophila pseudoobscura Y chromosome lacks homology with the Y of most Drosophila species. Thus, the Drosophila Y has a different evolutionary history from canonical Y chromosomes (such as the mammalian Y) and it also might have a different origin. PMID- 19443076 TI - Simultaneous multi-modality ROI delineation in clinical practice. AB - The delineation of tumors and their surrounding organs at risk is a critical step of the treatment planning for radiation therapy. Besides computer tomography (CT), other imaging modalities are used to improve the quality of the delineations, such as magnetic resonance imaging (MRI) and positron emission tomography (PET). A practical framework is presented for using multiple datasets from different modalities during the delineation phase. The system is based on two basic principles. First, all image datasets of all available modalities are displayed in their original form (in their own coordinate system, with their own spatial resolution and voxel aspect ratio), and second, delineations can take place on all orthogonal views of each dataset and changes made to a delineation are visualized in all image sets, giving direct feedback to the delineator. The major difference between the described approach and other existing delineation tools is that instead of resampling the image sets, the delineations are transformed from one dataset to another. The transformation used for transferring the delineations is obtained by rigid normalized mutual information registration. The crucial components and the benefits of the application are presented and discussed. PMID- 19443077 TI - SURVSOFT-Software for nonparametric survival analysis. AB - Long-term observed and relative survival are important outcome measures of cancer patient care reported routinely by many cancer registries, but no commercial statistical software exists for estimating relative survival or performing period survival analysis. The programs publicly available focus only on certain methods, require specific input data formats and often are macros or functions which require underlying software packages. Here we introduce SURVSOFT, a comprehensive, user-friendly Windows program with graphical user interface. It can handle different input data formats and incorporates a variety of nonparametric statistical methods for survival data analysis. SURVSOFT produces high-resolution graphs, which can be printed, saved or exported to be used with standard graphics editors. The use of SURVSOFT is illustrated by the analysis of survival data from the Bavarian Cancer Registry. PMID- 19443078 TI - Double-lumen central venous catheters impregnated with chlorhexidine and silver sulfadiazine to prevent catheter colonisation in the intensive care unit setting: a prospective randomised study. AB - Antimicrobial- and antiseptic-impregnated catheters are strategies recommended to prevent central venous catheter (CVC) colonisation. Few data regarding chlorhexidine/silver sulfadiazine-impregnated catheters in intensive care unit (ICU) patients have been reported. We performed a prospective, randomised study comparing the colonisation rates of chlorhexidine/silver sulfadiazine-impregnated CVCs (group 1) against standard CVCs (group 2). In order to assess catheter colonisation rates, a 4cm segment from the tips of aseptically removed catheters was cultured by the roll-plate method. In all, 109 patients were enrolled with successful catheter insertion, 51 of them in group 1 and 58 in group 2. There were no statistically significant differences between the two groups with regards to age, Sequential Organ Failure Assessment (SOFA) score, ICU admission diagnosis, infection risk, catheter insertion sites or catheter length of stay. The colonisation rates were 29.4% (15 catheters) for group 1 and 34.5% (20 catheters) for group 2 (P=0.50). Double-lumen CVCs impregnated with chlorhexidine and silver sulfadiazine were not effective in reducing the incidence of catheter colonisation in ICU patients. PMID- 19443079 TI - In-vitro bactericidal activity of colistin against biofilm-associated Pseudomonas aeruginosa and Acinetobacter baumannii. PMID- 19443080 TI - Hepatitis B virus and hepatitis C virus in medical waste handlers in Tripoli, Libya. AB - Medical waste handlers (MWHs) are at risk of exposure to serious viral infections. No data are available on the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) among MWHs in Libya. During a one-year period (January to December 2004) blood samples from 300 (59 females) MWHs employed by a local contractor in Tripoli and 300 blood samples from non-medical waste handlers (NMWHs) who had no direct or indirect contact with medical waste were examined for HBV, HCV and HIV using enzyme-linked immunosorbent assays. HBV was detected in 7 (2.3%) and 1 (0.3%) and HCV in 8 (2.7%) and 0 (0.0%) of MWHs and NMWHs, respectively. Significant differences were observed in the detection rates of HBV (OR: 7.14; P<0.04) and HCV (OR: undefined; P<0.005) in MWHs when compared with NMWHs. HIV was not detected in both groups. Of the MWHs studied, 21% were immunised against HBV and 7% were trained to handle medical waste. In addition, 99.7% wore overalls, 57.7% thick disposable gloves, 55% boots and 17.7% masks while handling medical waste. In conclusion, prevalence rates of HBV and HCV were significantly higher in MWHs than those in NMWHs examined. Training, immunisation, and post-exposure protection of MWHs, in addition to proper management of medical waste by the health authorities, may significantly reduce the risk of acquiring infectious agents by MWHs in Libya. PMID- 19443081 TI - Occupational transmission of bloodborne diseases to healthcare workers in developing countries: meeting the challenges. AB - Healthcare workers have increased chance of acquiring bloodborne pathogens through occupational exposure in developing countries due to a combination of increased risk and fewer safety precautions. As loss of workers can seriously undermine developing health systems, it is important that risks are minimised. A literature search was conducted to investigate the risks of transmission of three pathogens: human immunodeficiency virus, hepatitis B and hepatitis C viruses; and to identify factors that influenced the risk with reference to developing countries. There are many difficulties faced by developing countries in minimising the risk of occupational exposure. Efforts have been made to address the problems both on international and national levels. It is imperative that all healthcare workers are protected in order to prevent the loss of such a crucial component of developing healthcare systems. PMID- 19443082 TI - [How to write and evaluate a scientific article for Revista Espanola de Geriatria y Gerontologia]. PMID- 19443083 TI - [Urgency attend to the older patient in primary health care]. AB - The world population is making older increasing the sanitary resources consum. It makes the elderly patients are the main occupant of hospitalary beds, who generate more mortality, longer stays and more number of readmissions. Also they are who visit more the primary health care doctor and they are the first and the most numerous drugs consumer. The result rise the medical assistance demand in the different primary health care services. The chronic diseases that older patients suffer multiply in keeping with the age, existing one significative association between many chronic diseases and the urgences admissions in the older patients. To offer the necessary service, we must improve the primary health care centers autosufficiency, the resolutive capacity and the human resources management in agreement with the needs of each moment. PMID- 19443084 TI - [HIV Infection in the elderly]. AB - HIV infection is increasingly common in the elderly. This population is a heterogeneous group with particular epidemiologic characteristics and often with associated comorbidities, which frequently delay diagnosis and lead to poor immunological status at the start of highly active antiretroviral therapy (HAART). There are no differences between elderly and young HIV infected patients in the recommended antiretroviral regimens. Tolerance to treatment is good and the virological and immunological response to HAART is positive, although immunological response is slower and lower than in younger patients. Treatment adherence, which has been shown to be the only protective independent factor related to virological failure, is better in the elderly. PMID- 19443085 TI - [Comparative results of total knee arthroplasty according to age]. AB - OBJECTIVE: Surgical treatment of osteoarthritis with total knee arthroplasty (TKA) has become a routine technique in patients of "almost" any age. The aim of the present study was to compare the results of TKA according to patient age. MATERIAL AND METHODS: A prospective study was performed in 112 patients with osteoarthritis who underwent TKA from March 1st, 2007 through May 31st, 2007. There were two groups; the first comprised 61 patients aged 65- to 75-years-old and the second included 51 patients aged 76- to 85-years-old. Sociodemographic data and health system use were evaluated. The results were evaluated by using the Hospital Special Surgery (HSS) scale, the SF-36 health survey questionnaire, the visual analogue scale (VAS) for pain, and joint measurement with manual goniometrics. The patients were evaluated before surgery and at 6 months after surgery. RESULTS: No significant differences were observed between the two groups. Complications and length of hospital stay were similar in both groups. A greater proportion of older patients were referred to a rehabilitation hospital but this difference was not statistically significant. CONCLUSIONS: The results of the present study were similar to those of other studies that found that greater age does not lead to worse functional results. PMID- 19443086 TI - [Stress in elderly hospitalized patients with chronic respiratory disease: assessment in a public geriatric hospital]. AB - INTRODUCTION: Studies of stress during hospitalization have mainly focused on patients admitted for acute problems. However, stress and its relationship with health-related quality of life (HRQOL) has yet to be described in chronic and elderly patients. The objective of this paper is to study the presence of stress and coping strategies in patients with chronic obstructive pulmonary disease (COPD) in a public geriatric hospital and its relationship with HRQL prior to admission, COPD severity, and dyspnea stage. MATERIAL AND METHODS: Fifty-one patients with a diagnosis of COPD were evaluated in the Joan March Hospital (Balearic Islands, Spain) by means of the Hospital Stress Rating Scale, the Dyspnea Scale, the Nottingham Health Profile, and a list of coping strategies. RESULTS: Low stress levels were found in elderly hospitalized COPD patients. Stress levels were independent of the COPD severity stage. Patients with mild dyspnea had higher stress levels than those with the most severe dyspnea (p<0.05). Patients with poor HRQOL before admission had higher stress levels during hospitalization (p<0.05). The most prevalent coping strategies in these hospitalized patients were related to avoidance. CONCLUSIONS: The stress generated during hospitalization in elderly COPD patients was related to prior psychosocial conditions (HRQOL) and had a greater effect on patients with greater functional independence. PMID- 19443088 TI - [Lung cancer as an index of tobacco exposure: association with non-lung cancer mortality]. AB - OBJECTIVE: To assess the possible role of tobacco smoke in non-lung cancer (excluding stomach cancer) using changes in lung cancer mortality rates as a proxy for tobacco exposure. METHODS: A time series analysis of cancer mortality was performed to evaluate the possible association between changes in mortality rates for lung cancer and for non-lung, non-stomach cancer (NLNS) from 1970 to 2003 in Spanish males. To avoid problems with autocorrelation, Prais-Winsten regression was applied. RESULTS: Changes in NLNS cancer death rates showed a parallel trend with lung cancer death rates in the study period, with an adjusted slope of 1.07, 95% CI of 0.98-1.17, and R2 of 0.97. CONCLUSION: Variation in NLNS cancer death rates can be accurately modelled as a function of changes in lung cancer death rates for the study period, suggesting a possible association between tobacco exposure and NLNS cancers. PMID- 19443087 TI - [Self-medication and the elderly. The reality of the home medicine cabinet]. AB - OBJECTIVE: To estimate the prevalence of self-medication in the elderly, to describe the characteristics of self-medication and home medicine cabinets. DESIGN: Cross-sectional descriptive study. SETTING: An urban primary health care (PHC) centre in Spain. PARTICIPANTS: A total of 240 patients 75 years of age or older. MAIN MEASUREMENTS: A structured questionnaire filled in by home care nurses from April to June 2006. Self-medication was classified into 4 sub-groups: pharmacological or herbal, exclusively pharmacological, exclusively herbal and pharmacological and herbal. The study variables were: age, sex, living alone, number of chronic diseases, number of chronic prescriptions and medicine cabinet characteristics (drugs accumulation, expired drugs, chronic drugs out of prescription, location of medicine chest and periodic review). Other variables were: drug types, source, and acute/chronic reason for self-medication. RESULTS: Self-medication frequency was 31,2% (95% CI, 26-36), with 22.9% (95% CI, 17.5 27.5) being pharmacological and 15.4% (95% CI, 23.1-17.3), herbal. The drugs most used in self-medication were analgesics (30.9%) and cold remedies (27.2%). The pharmacy was the most usual source (49.3%). A total of 41.6% contained drugs that were out of chronic prescription, and 34.4% accumulated more than three boxes of the same medication. CONCLUSIONS: There is a significant prevalence of self medication among the elderly. Accumulating drugs in homes is a very extensive practice. Pharmacists and PHC professionals need to be trained in the responsible use of chronic and self-medication. Although self-care has to be encouraged, PHC professionals must make their patients aware of the harmful effects of self medication. PMID- 19443089 TI - Nursing education and practice in a changing environment: the case of Greece. AB - The importance of education in the development of nursing as a profession and as a science has been emphasized over the last decade. Therefore, this article aims to highlight the current situation of undergraduate and postgraduate nursing education in Greece and to propose directions for its improvement. Undergraduate nursing education in Greece is two dimensional. Prospective students can obtain a degree as a registered nurse through both university-based degree studies and Technological Educational Institute (TEI) studies that differ significantly in both the provision of clinical experience and theoretical background due to their different course curricula and teaching staff. University graduates are provided with a better theoretical background while TEI graduates are usually better in clinically skills, even though both programmes lead to professional registration and are in accordance with European Union directives. Postgraduate studies in nursing science are mainly organized by the University of Athens, but recently joint postgraduate degrees of other university departments and TEIs, are possible. Changes that will lead to one common undergraduate nursing education leading to registration as a registered nurse, and organized in such a way that will reduce the gap between theory and practice is a proposal that is gradually gaining acceptance by the profession. However, the development of a single nursing degree in Greece is complex, and close cooperation between the government and the professional authorities is essential. PMID- 19443090 TI - Intramuscular delivery of a cholera DNA vaccine primes both systemic and mucosal protective antibody responses against cholera. AB - Cholera is a potentially lethal diarrhea disease caused by the gram-negative bacterium Vibrio cholerae. The need for an effective cholera vaccine is clearly indicated but the challenges of eliciting both systemic and mucosal immune responses remains a significant challenge. In the current report, we discovered that a DNA vaccine expressing a protective cholera antigen, cholera toxin B subunit (CTB), delivered parenterally can elicit both systemic and mucosal anti CTB antibody responses in mice. The priming effect by DNA immunization was demonstrated by higher mucosal antibody responses following one boost with the inactivated cholera vaccine (KWC-B) delivered orally when compared to the twice oral administration of KWC-B alone. This finding indicates that DNA vaccines delivered parenterally are effective in eliciting mucosal protective immune responses--a unique advantage for DNA vaccination that has not yet been well realized and should bring value to the development of novel vaccination approaches against mucosally transmitted diseases. PMID- 19443091 TI - Immunogenicity of 23-valent pneumococcal polysaccharide vaccine in HIV-infected pregnant women and kinetics of passively acquired antibodies in young infants. AB - Whether gestational immunization of HIV-infected mothers with the 23-valent pneumococcal polysaccharide vaccine (PPV) confers maternal and infant early life, passive protection is not known. We evaluated safety, immunogenicity and placental transfer of antibodies in 44 HIV-infected women. Pneumococcal IgG antibodies against serotypes 1, 3, 5, 6B, 9V, and 14 were measured in mothers (pre-vaccination and at delivery), and infants (at birth, 1, 2, 3, and 6 months). PPV was safe and immunogenic in mothers. Newborns received 46-72% of maternal antibody titers. Overall, infants had antibody levels lower than protective by 2 months of age. Alternative pneumococcal vaccination of HIV-infected pregnant women should be explored with the aim of prolonging passive protection in their infants. PMID- 19443092 TI - Race, place and AIDS: the role of socioeconomic context on racial disparities in treatment and survival in San Francisco. AB - Prior evidence suggests that the health and longevity benefits of antiretroviral therapy (ART) for persons living with AIDS (PLWAs) have not been equally distributed across racial/ethnic groups in the United States. Notably, black PLWAs tend to fare worse than their counterparts. We examine the role of neighborhood socioeconomic context on racial/ethnic differences in AIDS treatment and survival in San Francisco. The study population encompassed 4211 San Francisco residents diagnosed with AIDS between 1996 and 2001. Vital status was reported through 2006. Census data were used to define neighborhood-level indicators of income, housing, demographics, employment and education. Cox proportional hazards models were employed in multivariate analyses of survival times. Compared to whites, blacks had a significant 1.4 greater mortality hazard ratio (HR), which decreased after accounting for ART initiation. PLWAs in the lowest socioeconomic neighborhoods had a significant HR of 1.4 relative to those in higher socioeconomic neighborhoods, independent of race/ethnicity. The neighborhood association decreased after accounting for ART initiation. Path analysis was used to explore causal pathways to ART initiation. Racial/ethnic differences in neighborhood residence accounted for 19-22% of the 1.6-1.8 black white relative odds ratio (ROR) and 14-15% of the 1.3-1.4 Latino-white ROR for delayed or no treatment. Our findings illuminate the independent and synergistic contributions of race and place on treatment disparities and highlight the need for future studies and interventions to address treatment initiation as well as neighborhood effects on treatment differences. PMID- 19443093 TI - Effects of child health on parents' social capital. AB - This paper adds to the literature on social capital and health by testing whether an exogenous shock in the health of a family member (a new baby) affects the family's investment in social capital. It also contributes to a small but growing literature on the effects of children's health on family resources and provides information about associations between health and social capital in a socioeconomically disadvantaged population. We use data from the Fragile Families and Child Wellbeing study, a longitudinal survey of about 5000 births to mostly unwed parents in 20 U.S. cities during the years 1998-2000. Both parents were interviewed at the time of the birth and then again one and three years later. The infants' medical records from the birth hospitalization were reviewed, and poor infant health was characterized to reflect serious and random health problems that were present at birth. Social interactions, reported at three years, include the parents' participation in church groups, service clubs, political organizations, community groups, and organizations working with children; regular religious attendance; and visiting relatives with the child. Education, employment, wages, and sociodemographic characteristics are included in the analyses. The results suggest that infant health shocks do not affect the parents' social interactions. PMID- 19443094 TI - [Free tissue transfers with lengthening of vascular pedicle using interpositional vein grafts. About 10 cases]. AB - The realization of free flaps with lack of reliable vessels nearby the loss of substance is a difficult problem for plastic surgeons. We report 10 cases of free tissue transfers with a one-stage technique lengthening the vascular pedicle of the free flap with interpositional vein grafts. Taking into consideration the good results and the low rate of morbidity, the authors emphasize the use of this technique rather than a two-stage procedure. PMID- 19443095 TI - [Intravascular papillary endothelial hyperplasia of the ankle: a case report]. AB - Intravascular papillary endothelial hyperplasia (IPEH) is an unusual, benign, non neoplasic, vascular lesion characterized histologically by papillary fronds lined by proliferating endothelium. This lesion has the propensity to occur in the skin and the subcutis. Many histological features are similar to those of low-grade angiosarcoma, a common, but more serious condition. Clinical and histological differentiation is important to avoid overtreatment of this benign lesion. We report a case of cutaneous IPEH in the ankle of a 30-year-old girl, which was successfully treated by excision. The pathologic findings, differential diagnosis and a review of recent literature are discussed. PMID- 19443096 TI - Effects of adhesive composite core systems on adaptation of adhesive post and cores under load. AB - OBJECTIVES: To test marginal and internal adaptation of five different adhesive composite core systems under load. METHODS: 30 human premolars were endodontically prepared and obturated with an epoxy sealer and vertically condensed gutta-percha. Thereafter the entire clinical crown was removed. The teeth were randomly assigned to five different composite core groups, all using the same fiber reinforced radicular post (DT White). Gr. 1: Optibond solo plus/Nexus II/Prodigy; Gr. 2: Scotchbond 1/Rely X Arc/Filtek P60; Gr. 3: EBS multi/Compolute applicap/Pertac II; Gr. 4: ART Bond/Parapost cement/Synergy; Gr. 5: Superbond C&B catalyst S+polymer/Metafil CX. Polyvinyl-siloxane impressions of the external margins of the cores were readied before and after 1,200,000 cycles of mechanical loading with max. 100 N at 45 degrees to the longitudinal axis of the tooth. After loading, 5 of the 6 samples of each group were cut longitudinally and the sixth sample was cut transversally to be able to take replicas for evaluation of internal adaptation after loading. RESULTS: Percentages of external "continuous margins" ranged from 97.9+-4.6 to 66.5+-7.8 before and from 87.4+-25.0 to 5.8+-12.5 after loading. Internal adaptation ranged from 96.4+-8.0 to 17.1+-20.4 after loading for the core adaptation and from 89.8+ 12.2 to 65.9+-14.3 for the dentin-luting composite interface and from 99.4+-1.2 to 88.6+-9.4 for the composite-post interface. CONCLUSIONS: Surprisingly, the best materials' combination for the adhesive composite core was a self-etch light cured adhesive with a chemically cured luting agent. PMID- 19443097 TI - Out-of-hospital cardiac arrest due to drowning: An Utstein Style report of 10 years of experience from St. Mary's Hospital. AB - BACKGROUND: Drowning is a unique form of cardiac arrest and is often preventable. "Utstein Style for Drowning" was published in 2003 by the International Liaison Committee on Resuscitation (ILCOR) to improve the knowledge-base, to provide epidemiological stratification, to recommend appropriate treatments and to ultimately save lives. We report on the largest single-center study of the Utstein Style resuscitation for drowning. METHODS: All patients with out-of hospital cardiac arrest (OHCA) due to drowning admitted to St. Mary's Hospital between 1998 and 2007 were included. Utstein Style variables and other time intervals not included in the Utstein Style guidelines were evaluated for their ability to predict survival. The primary end point of this study was survival to discharge. RESULTS: We enrolled 131 patients with OHCA due to drowning; 21 patients (16.03%) had survival to discharge and 9 patients (6.87%) were discharged with a good neurologic outcome, i.e., cerebral performance categories (CPC) of 1 or 2. For the Utstein Style variables witnessed, the duration of submersion and the time of first emergency medical systems (EMS) resuscitation attempt influenced survival. For other time intervals, the transportation time (i.e., time interval from witnessing of the drowning to EMS arrival at the hospital, or if events were not witnessed, the time interval from calling the EMS to EMS arrival at the hospital), the duration of advanced cardiovascular life support (ACLS) and the duration of total arrest time were associated with survival. CONCLUSIONS: Our report is the largest single-center study of OHCA due to drowning reported according to the guidelines of the Utstein Style. Being witnessed, having a short duration of submersion, having early resuscitation by EMS, and rapid transportation are important for survival after drowning. PMID- 19443098 TI - Liver laceration associated with the use of a chest compression device. PMID- 19443099 TI - EMS systems in China. AB - The prehospital emergency service is the initial part of the Emergency Medical Service System (EMSS) in China, and is the de facto overall emergency medical service for China. As the EMSS in China continues to undergo rapid development, it faces the challenge of providing rapid response times with adequate coverage for this highly populated country. The recent Sichuan earthquake on 12 May 2008 tested the ability of the EMSS response. This article focuses on the prehospital emergency service of the EMSS and discusses the strengths and weaknesses of the current system. PMID- 19443101 TI - Stage pT0 in radical prostatectomy with no residual carcinoma and with a previous positive biopsy conveys a wrong message to clinicians and patients: why is cancer not present in the radical prostatectomy specimen? PMID- 19443102 TI - Expression pattern, cellular localization and promoter activity analysis of ovarian aromatase (Cyp19a1a) in protogynous hermaphrodite red-spotted grouper. AB - Aromatase plays a key role in sex differentiation of gonads. In this study, we cloned the full-length cDNA of ovarian aromatase from protogynous hermaphrodite red-spotted grouper (Epinephelus akaara), and prepared the corresponding anti EaCyp19a1a antiserum. Western blot and immunofluorescence studies revealed ovary specific expression pattern of EaCyp19a1a in adults and its dynamic expression change during artificial sex reversal. EaCyp19a1a was expressed by follicular cells of follicular layer around oocytes because strong EaCyp19a1a immunofluorescence was observed in the cells of ovaries. During artificial sex reversal, EaCyp19a1a expression dropped significantly from female to male, and almost no any positive EaCyp19a1a signal was observed in testicular tissues. Then, we cloned and sequenced a total of 1967 bp 5'-flanking sequence of EaCyp19a1a promoter, and showed a number of potential binding sites for some transcriptional factors, such as SOX5, GATA gene family, CREB, AP1, FOXL1, C/EBP, ARE and SF-1. Moreover, we prepared a series of 5' deletion promoter constructs and performed in vitro luciferase assays of EaCyp19a1a promoter activities. The data indicated that the CREB regulation region from -1010 to -898 might be a major cis-acting element to EaCyp19a1a promoter, whereas the elements GATA and SOX5 in the region from -1216 to -1010 might be suppression elements. Significantly, we found a common conserved sequence region in the fish ovary-type aromatase promoters with identities from 93% to 34%. And, the motifs of TATA box, SF-1, SOX5, and CREB existed in the region and were conserved among the most of fish species. PMID- 19443103 TI - A case of Gerstmann-Straussler-Scheinker syndrome with the P105L prion protein gene mutation presenting with ataxia and extrapyramidal signs without spastic paraparesis. AB - We describe the clinical features of a patient with Gerstmann-Straussler Scheinker syndrome with a mutation in the prion protein gene at codon 105 (GSS105) who presented with ataxia. Neurologic examination showed memory disturbance, dysarthria, extrapyramidal signs (bradykinesia and resting tremor) and ataxic gait without spasticity. Although GSS105 has been referred to as "spastic paraparesis-type GSS", the patient did not show spastic paraparesis or pyramidal signs, even 11 years after the onset of symptoms. Thus, the spectrum of the GSS105 phenotype varies among patients and requires further clinicopathologic elucidation. PMID- 19443104 TI - Phosphate adsorption from sewage sludge filtrate using zinc-aluminum layered double hydroxides. AB - A series of layered double hydroxides (LDHs) with different metal cations were synthesized to remove phosphate in waste sludge filtrate from a municipal wastewater treatment plant for phosphorus recovery and to help control eutrophication. The highest phosphate adsorption capacity was obtained by using Zn-Al-2-300, that is LDHs with Zn/Al molar ratio of 2 and calcined at 300 degrees C for 4h. Circumneutral and mildly alkaline waters appeared suitable for the possible application of Zn-Al LDHs due to the amphoteric nature of aluminum hydroxide. Phosphate adsorption from the sludge filtrate by the LDHs followed pseudo-second-order kinetics, and the adsorption capacity at equilibrium was determined to be approximately 50 mg P/g. Adsorption isotherms showed that phosphate uptake in this study was an endothermic process and had a good fit with a Langmuir-type model. The absorbed phosphate can be effectively desorbed (more than 80%) from LDHs particles by a 5 wt% NaOH solution. The regeneration rate of used LDHs was approximately 60% after six cycles of adsorption-desorption regeneration. PMID- 19443100 TI - Epigenetic gene regulation in stem cells and correlation to cancer. AB - Through the classic study of genetics, much has been learned about the regulation and progression of human disease. Specifically, cancer has been defined as a disease driven by genetic alterations, including mutations in tumor-suppressor genes and oncogenes, as well as chromosomal abnormalities. However, the study of normal human development has identified that in addition to classical genetics, regulation of gene expression is also modified by 'epigenetic' alterations including chromatin remodeling and histone variants, DNA methylation, the regulation of polycomb group proteins, and the epigenetic function of non-coding RNA. These changes are modifications inherited during both meiosis and mitosis, yet they do not result in alterations of the actual DNA sequence. A number of biological questions are directly influenced by epigenetics, such as how does a cell know when to divide, differentiate or remain quiescent, and more importantly, what happens when these pathways become altered? Do these alterations lead to the development and/or progression of cancer? This review will focus on summarizing the limited current literature involving epigenetic alterations in the context of human cancer stems cells (CSCs). The extent to which epigenetic changes define cell fate, identity, and phenotype are still under intense investigation, and many questions remain largely unanswered. Before discussing epigenetic gene silencing in CSCs, the different classifications of stem cells and their properties will be introduced. This will be followed by an introduction to the different epigenetic mechanisms. Finally, there will be a discussion of the current knowledge of epigenetic modifications in stem cells, specifically what is known from rodent systems and established cancer cell lines, and how they are leading us to understand human stem cells. PMID- 19443105 TI - Removal of Cd2+ from aqueous solution by adsorption using Fe-montmorillonite. AB - Fe-montmorillonite (Fe-Mont.) is obtained by exchanging the original interlayer cations of montmorillonite by poly-hydroxyl ferric. In this paper, Fe-Mont. was synthesized by using Ca-montmorillonite (Ca-Mont.) directly under ultrasonic treatment with the aim to enhance the ability of removal of heavy metal ions from wastewater. The modified materials were characterized by X-ray diffraction (XRD) and Fourier transform infrared (FT-IR). Batch equilibrium experiments of Cd(II) ions (Cd(2+)) adsorption on the Fe-Mont. were performed. Effects of the initial pH of the solution and contact time on the adsorption of Cd(2+) were studied. Four types of adsorption isotherms were applied to describe the adsorption isotherms of Cd(2+) by Fe-Mont. The relationship between adsorbing capacity (q(e)) and equilibrium mass concentration (C(e)) is in accordance with the isothermal adsorption equation of Langmuir. Three kinetic models, including pseudo-first-order, pseudo-second-order and the Elovich equation model, were used to analyze the Cd(2+) adsorption process. The pseudo-second-order chemical reaction kinetics provide the best correlation of the experimental data, therefore the adsorption dynamics follows the laws of pseudo-second-order kinetics. PMID- 19443106 TI - Enhanced adsorption of phenol from water by a novel polar post-crosslinked polymeric adsorbent. AB - A novel post-crosslinked polymeric adsorbent PDM-2 was prepared by Friedel-Crafts reaction of pendant vinyl groups without external crosslinking agent. Both the specific surface area and the pore volume of starting copolymer PDM-1 increased significantly after post-crosslinking. Batch adsorption runs of phenol from aqueous solution onto PDM-1 and PDM-2 were investigated. Commercial macroporous resins XAD-4 and AB-8 were chosen as the comparison. Experimental results showed that isotherms of phenol adsorption onto these four polymeric adsorbents could be represented by Freundlich model reasonably. PDM-2 exhibited higher adsorption capacity of phenol than other three adsorbents, which resulted from synergistic effect of larger specific surface area and polar groups on the network. The adsorption process for phenol was proved to be exothermic and spontaneous in nature. Thermodynamic parameters such as Gibb's free energy (DeltaG), change in enthalpy (DeltaH) and change in entropy (DeltaS) were calculated. Kinetics studies indicated that phenol uptake onto PDM-1 and PDM-2 followed the pseudo second order model and the intraparticle diffusion process was a rate-controlling step. Column adsorption runs demonstrated that nearly 100% regeneration efficiency for PDM-2 by 3BV industrial alcohol and the adsorbate phenol can be easily recovered by further distilling. Continuous column adsorption-regeneration cycles indicated negligible capacity loss of PDM-2 during operation. PMID- 19443107 TI - Iron and manganese removal by using manganese ore constructed wetlands in the reclamation of steel wastewater. AB - To reclaim treated steel wastewater as cooling water, manganese ore constructed wetland was proposed in this study for the removal of iron and manganese. In lab scale wetlands, the performance of manganese ore wetland was found to be more stable and excellent than that of conventional gravel constructed wetland. The iron and manganese concentration in the former was below 0.05 mg/L at hydraulic retention time of 2-5 days when their influent concentrations were in the range of 0.16-2.24 mg/L and 0.11-2.23 mg/L, respectively. Moreover, its removals for COD, turbidity, ammonia nitrogen and total phosphorus were 55%, 90%, 67% and 93%, respectively, superior to the corresponding removals in the gravel wetland (31%, 86%, 58% and 78%, respectively). The good performance of manganese ore was ascribed to the enhanced biological manganese removal with the aid of manganese oxide surface and the smaller size of the medium. The presence of biological manganese oxidation was proven by the facts of good manganese removal in wetlands at chemical unfavorable conditions (such as ORP and pH) and the isolation of manganese oxidizing strains from the wetlands. Similar iron and manganese removal was later observed in a pilot-scale gravel-manganese-ore constructed wetland, even though the manganese ore portion in total volume was reduced from 100% (in the lab-scale) to only 4% (in the pilot-scale) for the sake of cost-saving. The quality of the polished wastewater not only satisfied the requirement for cooling water but also suitable as make-up water for other purposes. PMID- 19443108 TI - Removal of cobalt ions from aqueous solutions by polymer assisted ultrafiltration using experimental design approach. part 1: optimization of complexation conditions. AB - The polymer assisted ultrafiltration process combines the selectivity of the chelating agent with the filtration ability of the membrane acting in synergy. Such hybrid process (complexation-ultrafiltration) is influenced by several factors and therefore the application of experimental design for process optimization using a reduced number of experiments is of great importance. The present work deals with the investigation and optimization of cobalt ions removal from aqueous solutions by polymer enhanced ultrafiltration using experimental design and response surface methodological approach. Polyethyleneimine has been used as chelating agent for cobalt complexation and the ultrafiltration experiments were carried out in dead-end operating mode using a flat-sheet membrane made from regenerated cellulose. The aim of this part of experiments was to find optimal conditions for cobalt complexation, i.e. the influence of initial concentration of cobalt in feed solution, polymer/metal ratio and pH of feed solution, on the rejection efficiency and binding capacity of the polymer. In this respect, the central compositional design has been used for planning the experiments and for construction of second-order response surface models applicable for predictions. The analysis of variance has been employed for statistical validation of regression models. The optimum conditions for maximum rejection efficiency of 96.65% has been figured out experimentally by gradient method and was found to be as follows: [Co(2+)](0)=65 mg/L, polymer/metal ratio=5.88 and pH 6.84. PMID- 19443109 TI - Mechanisms of arsenic and lead release from hydrothermally altered rock. AB - This paper describes the effects of pH, dissolved oxygen (DO), redox conditions, and mixing ratio of different rocks on the leaching behaviors of As and Pb from hydrothermally altered rock as well as the functional groups incorporating As and Pb in the rock. Most of As and Pb were incorporated in the residual or crystalline phase although significant amounts were also determined to be exchangeable, with carbonates and with Fe-Mn oxides. Under oxic conditions, As and Pb showed similar leaching behaviors at similar pH values, a higher mobilization in the acidic and alkaline regions and a minimum at circumneutral pH. The absence of DO restricted the oxidation of sulfide minerals that also contained significant quantities of As resulting in a lower As release under these conditions. Strongly reducing conditions favored the release of As by the reductive dissolution of Fe-Mn oxides and prevention of carbonate precipitation while the same conditions immobilized Pb because of its re-precipitation under reducing conditions. In general, depending on the pH, DO, and redox conditions, the major modes of As and Pb release from these sources could be either one or more of the following mechanisms: acid dissolution, reductive dissolution, ion exchange, desorption and sulfide oxidation processes. PMID- 19443110 TI - Photocatalytic decouloration of malachite green dye by application of TiO2 nanotubes. AB - The nanotubes of titania were synthesized in a hydrothermal system and characterized by scanning electronic microscopy (SEM), FT-IR, FT-Raman, and surface charge density by surface area analyzer. These nanomaterials were applied to photocatalyse malachite green dye degradation. Photodegradation capacity of TiO(2) nanotubes was compared to TiO(2) anatase photoactivity. Malachite dye was completely degraded in 75 and 105 min of reaction photocatalysed by TiO(2) nanotubes and TiO(2) anatase, respectively. Catalysts displayed high photodegradation activity at pH 4. TiO(2) nanotubes were easily recycled whereas the reuse of TiO(2) anatase was not effective. Nanotubes maintained 80% of their activity after 10 catalytic cycles and TiO(2) anatase presented only 8% of its activity after 10 cycles. PMID- 19443111 TI - A combination method to study microbial communities and activities in zinc contaminated soil. AB - Zinc (Zn) plays a special role in soil ecology and fertility because it can support the growth of soil organisms or inhibit their growth depending on its concentrations. In this work, the effects of different concentrations of Zn on soil microbial communities and activities were analyzed by loading five different doses of Zn (160-6000 microg g(-1)) into a wheat surface soil. The microbial metabolic process revealed a significant bimodal pattern at high concentrations of Zn (>1920 microg g(-1)). This phenomenon suggested that soil microorganisms were very sensitive to zincous poisoning. A variety of soil quality properties were also measured and assessed. The results showed slower bacterial growth in soil cultures polluted with high levels of Zn. In addition, two kinds of fungi were identified by morphology and glomalin-related soil protein content in the Zn contaminated soil. The growth of the first kind was inhibited with increase in Zn concentration. By contrast, the second kind could survive and continue to grow with increasing doses of Zn at 160-1920 microg g(-1) and its growth began to decline with further increase in Zn concentration. Finally, the fungus could not survive at very high (6000 microg g(-1)) Zn concentration. In this work, we conclude that soil microbial communities and activities can adapt to Zn pollution to a certain extent. PMID- 19443112 TI - Reduction of trihalomethane precursors of dissolved organic matter in the secondary effluent by advanced treatment processes. AB - Wastewater effluent collected from the Wenchang Wastewater Treatment Plant (Harbin, China) was used as source water for advanced treatment and reclamation. Since dissolved organic matter (DOM) in the secondary effluent contains a high concentration of trihalomethanes (THMs) precursors, several processes of advanced treatments including granular activated carbon (GAC) adsorption, sand column biodegradation, horizontal subsurface flow wetland (HSFW) treatment, laboratory scale soil aquifer treatment (SAT) and GAC+SAT were used in this study to compare and differentiate the removal mechanisms of DOM. DOM in the secondary effluent and the treated effluents was fractionated into five classes using XAD resins: hydrophobic acid (HPO-A), hydrophobic neutral (HPO-N), transphilic acid (TPI-A), transphilic neutral (TPI-N), and hydrophilic fraction (HPI). Results showed that HPO-A and HPI were two main fractions of the DOM in the secondary effluent, accounting for 30.0% and 45.5% of the bulk DOM, respectively. HPO-A exhibited higher trihalomethane formation potential (THMFP) and specific THMFP (STHMFP) than HPI during the chlorination process. The order of the dissolved organic carbon (DOC) removal with respect to different advanced treatments was observed to be GAC+SAT>SAT>GAC>sand column>HSFW. As for the DOM removal mechanisms, the advanced treatment processes of GAC adsorption, SAT and GAC+SAT tended to adsorb more HPO-A, HPO-N and TPI-A and could reduce the aromaticity of those DOM fractions efficiently. Correspondingly, the advanced treatment processes of sand column, SAT, HSFW and GAC+SAT removed more HPI and TPI-N through biodegradation and each of the DOM fractions had an increased aromaticity. The removal order of the THMs precursor by the advanced treatment processes was GAC+SAT>GAC>SAT>sand column>HSFW. The adsorption reduced the STHMFP of the DOM fractions effectively, whereas the biodegradation mechanism of the treatments (sand column, SAT, GAC+SAT and HSFW) showed a converse trend. Moreover, the THMFP and STHMFP of the DOM in the HSFW effluent were obviously affected by the DOM derived from the leaves and roots. PMID- 19443113 TI - Ozonation of azo dyes (Orange II and Acid Red 27) in saline media. AB - Ozonation of two azo dyes was investigated in a monitored bench scale bubble column reactor (8.5-L), varying liquid media salt content (0, 1, 40 and 100 g L( 1), NaCl). In experiments with Orange II pH was varied (5, 7.5 and 9) but ozonation of Acid Red 27 was performed at pH 7.5. Ozone self-decomposition rate constant increased with salt concentration. Color removal was very effective and fast achieved under all experimental conditions. For the two azo dyes tested, more than 98% of color intensity was removed in 30-min ozonation assays. However, only partial mineralization of azo dyes (45%-Orange II; 20%-Acid Red 27) was attained in such experiments. The degree of mineralization (TOC removal) was negatively affected by salt concentration. Biodegradation assays conducted by respirometry revealed the inhibitory effect of dye degradation products formed during ozonation. PMID- 19443114 TI - Study on nanomagnets supported TiO2 photocatalysts prepared by a sol-gel process in reverse microemulsion combining with solvent-thermal technique. AB - A sol-gel process in reverse microemulsion combined with solvent-thermal technique was developed for synthesizing a series of nanomagnets supported TiO(2) (TiO(2)/NMs) photocatalysts in this study. The structure of TiO(2)/NMs photocatalysts was characterized by Fourier transform infrared (FTIR), TG-DSC, X ray diffraction (XRD), Raman spectrometry, TEM, BET, and VSM. The influence of CoFe(2)O(4) dosage on the photocatalytic activity and magnetism of TiO(2)/NMs photocatalysts was investigated. The results showed that nanosized anatase TiO(2) were uniformly coated on spinel CoFe(2)O(4) in the prepared TiO(2)/NMs photocatalysts. They possessed typical ferromagnetic hysteresis and performed better photocatalytic activity in degradation of methylene blue than TiO(2) prepared by the same method. The existence of CoFe(2)O(4) nanomagnets played an important role on the crystalline grain size of TiO(2) and the specific surface area of the prepared TiO(2)/NMs photocatalysts, thus had an important influence on its photocatalytic performance and magnetism. The photocatalytic performance of TiO(2)/NMs photocatalysts is related to their specific surface area, crystalline grain sizes of TiO(2) and particle size, as well as the doping effect of Fe(3+). The highest photocatalytic activity in degradation of methylene blue for TiO(2)/NMs photocatalysts at the CoFe(2)O(4) content of 20wt.% was achieved, with k(p) 28.32% higher than that of pure TiO(2) photocatalyst. Moreover, the experiments on recycled use of TiO(2)/NMs photocatalyst demonstrated a good repeatability of the photocatalytic activity. PMID- 19443115 TI - Biosorption equilibria of binary Cd(II) and Ni(II) systems onto Saccharomyces cerevisiae and Ralstonia eutropha cells: application of response surface methodology. AB - Present study investigated the biosorption of Cd(II) and Ni(II) from aqueous solution onto Saccharomyces cerevisiae and Ralstonia eutropha non-living biomass. Biomass inactivated by heat and pretreated by ethanol was used in determination of optimum conditions. The important process parameters, such as initial solution pH (2-8), initial Ni(II) concentration (11-42 mg/l), initial Cd(II) concentration (11-42 mg/l), and biomass dosage (0.2-4.7 g/l) were optimized using design of experiments (DOE). A central composite design (CCD) under response surface methodology (RSM) was applied to evaluate and optimize the efficiency of removing each adsorbent. Moreover, the two responses were simultaneously studied by using a numerical optimization methodology. The optimum removal efficiency of Cd(II) and Ni(II) onto S. cerevisiae was determined as 43.4 and 65.5% at 7.1 initial solution pH, 4.07 g/l biomass dosage, 16 mg/l initial Ni(II) concentration and 37 mg/l initial Cd(II) concentration. The optimum removal efficiency of Cd(II) and Ni(II) onto R. eutropha was ascertained as 52.7 and 50.1% at 5.0 initial solution pH, 2.32 g/l biomass dosage, 28 mg/l initial Ni(II) concentration and 37 mg/l initial Cd(II) concentration. The present analysis suggests that the predicted values are in good agreement with experimental data. The characteristics of the possible interactions between biosorbents and metal ions were also evaluated by scanning electron microscope (SEM) and Fourier transform infrared (FT-IR) spectroscopy analysis. PMID- 19443116 TI - Speciation and removal of chromium from aqueous solution by white, yellow and red UAE sand. AB - Removal of Cr(III) and Cr(VI) from aqueous solutions by different types of sand as a low cost abundant adsorbent was investigated. White, yellow and red sands from the United Arab Emirates (UAE) were employed at various adsorbent/metal ion ratios. The effect of contact time, pH, temperature, metal concentration and sand dosage was studied. The optimal pH for adsorption was ca. 5.0 for Cr(III) and 2.0 for Cr(VI). The optimal adsorption time for both ions was ca. 3h. Even at the optimal pH, adsorption of Cr(VI) on all sand forms was very low (removal 0.21). These results must be confirmed in experiments on pasture, with other ratios and combinations of earthworms. PMID- 19443124 TI - Acaricidal activity of four fractions and octadecanoic acid-tetrahydrofuran-3,4 diyl ester isolated from chloroform extracts of neem (Azadirachta indica) oil against Sarcoptes scabiei var. cuniculi larvae in vitro. AB - Four fractions obtained from chloroform extracts of neem (Azadirachta indica) oil by column chromatography were investigated for acaricidal activity against Sarcoptes scabiei var. cuniculi larvae in vitro. Octadecanoic acid tetrahydrofuran-3,4-diyl ester was isolated from an active fraction of the chloroform extract and its toxicity against S. scabiei larvae was tested in vitro. A complementary log-log model was used to analyse the toxicity data. Activity was found in the third fraction, with 100% corrected mortality after 4.5 h of exposure at a concentration of 200 mg ml(-1). This fraction was repeatedly re-crystallised in acetone to yield a white amorphous powder, identified as octadecanoic acid-tetrahydrofuran-3,4-diyl ester, with a median lethal concentration (LC(50)) of 0.1 mg ml(-1) at 24 h post-treatment. The median lethal time (LT(50)) for this compound was 15.3 h at a concentration of 7.5 mg ml(-1). PMID- 19443125 TI - A prospective double-blinded comparative analysis of framycetin and silver sulphadiazine as topical agents for burns: a pilot study. AB - Burn wound sepsis remains the leading cause of mortality if conservative methods of wound management are employed. Topical agents are still the mainstay of such wound management in the developing world. Non availability of agents like Mafenide or silver ion dressings in the developing world due to corporate strategies or cost concerns necessitates a search for alternatives to silver sulphadiazine, which is the gold standard. We report the use of framycetin 1% cream (Soframycin) in 20 patients of major burns (ranging from 15% to 40% TBSA), and in a double blinded study quantitatively comparing the bacterial load on day 4 and day 7 with a group of similar patients in whom silver sulphadiazine was used. The age group of the 40 patients was 10-50 years and they were without any co-morbid condition. All bacterial isolates from the 40 patients were also tested for framycetin sensitivity. Serial kidney function tests were done on all patients, and patients in the framycetin group underwent an audiometric testing at a mean time of 28 days. All results were statistically analyzed. It was noted that there was no statistically significant difference in the colony counts on days 4 and 7 between the two groups. As a corollary, it was also evident that there was no statistically significant difference in the rise in colony counts from day 4 to day 7 in the two groups. Sixty-four percent of all bacterial isolates were sensitive to framycetin, although, this could not be compared with sensitivity to silver sulphadiazine. It was not possible to do assays for framycetin levels in blood but no patient developed nephrotoxicity or ototoxicity with its use. According to our pilot study results framycetin appears to be an alternative to silver suphadiazine as a topical agent for major burns. Framycetin application is also painless and it leads to no discoloration of the wound. PMID- 19443126 TI - An endocrine perspective on the role of steroid hormones in the antidepressant treatment efficacy of transcranial magnetic stimulation. AB - Evidence from recent meta-analyses indicates that transcranial magnetic stimulation (TMS) is moderately effective in the treatment of major depressive disorder (MDD). Individual differences in the susceptibility to TMS are suggested to underlie a significant portion of the variability in antidepressant efficacy observed in TMS trials. Interestingly, recent findings suggest a moderating role for steroid hormones in the antidepressant efficacy of TMS in women. Steroid hormones are known to have strong activational and organizational influences on the brain and may upregulate the efficacy of TMS by way of modulating cortical excitability in a sex-dependent manner. Here we propose that the measurement and manipulation of steroid hormones could be crucial steps in the development of successful individually based TMS protocols for the treatment of MDD. PMID- 19443128 TI - Is there a link between insulin resistance and inflammatory activation in preeclampsia? AB - Preeclampsia is a severe complication of human pregnancy and an insulin resistant state has been demonstrated in this multisystem disorder, although its bases remain unclear. Inositol phosphoglycans P-type belongs to a family of putative insulin mediators and was described to exert many insulin-like effects on lipid and glucose metabolism. A definite association between this molecule and preeclampsia was reported. The systemic inflammatory activation that occurs in preeclampsia as a consequence of the immunological dysfunction can exacerbate placental insulin resistance leading to an over-expression of P-IPG as a counterregulatory mechanism to insulin resistance. Besides, the lipidic form of P IPG was reported to be similar to endotoxins, and may represent the link between insulin resistance, systemic inflammation and increased angiogenic factors. In this article we propose a new working theory on insulin resistance and preeclampsia. PMID- 19443127 TI - Alcohol use and comorbid anxiety, traumatic stress, and hopelessness among Hispanics. AB - Little is known about the comorbidity of alcohol use, anxiety, hopelessness, and trauma among Mexican Americans, especially those living in impoverished and often isolated communities or neighborhoods (colonias in Spanish) along the U.S.-Mexico border that may be particularly vulnerable due to stressful living conditions. The current study utilized a community participatory model to investigate the relationships of alcohol use, acculturation, anxiety, hopelessness, and trauma in 100 Mexican origin colonia residents. Significant comorbidity was expected and that anxiety, hopelessness, and post-traumatic symptoms were hypothesized to be associated with the severity of the alcohol use disorders of participants. Participants who met DSM-IV criteria for alcohol dependence reported significantly more symptoms of anxiety and post-traumatic stress, and symptoms of anxiety were significantly associated with alcohol use disorders. This study provides evidence of the need for further investigation of stress, trauma, anxiety, hopelessness, and alcohol abuse in Mexican American residents and to inform future prevention and treatment efforts to improve both the physical and mental health of this population. PMID- 19443129 TI - Borderline personality disorder: a review and reformulation from evolutionary theory. AB - A number of authors have provided a useful evolutionary perspective on personality disorders, arguing that personality traits can be conceptualized in terms of evolutionary strategies. If we consider personality traits not as illnesses but as stable evolutionary strategies, the characteristic features of borderline personality disorder may respond to a behavioral pattern which, although deviating from the norm, would be in the service of survival of the species. Early environments involving factors such as childhood physical/sexual abuse may prove useful for explanation of personality traits based on gene environment interaction, potentially providing a model for understanding borderline personality traits. We also review the question of whether personality traits exist in animals to also provide a translational perspective. We propose that certain traits in borderline personality disorder may derive from evolved mechanisms which in the short-term serve to help respond to adversity, but which when activated in an ongoing way prove maladaptive. PMID- 19443130 TI - Route of administration influences substitution patterns in rats trained to discriminate methadone vs. vehicle. AB - Replacement therapy with the synthetic mu-opioid agonist methadone is an efficacious treatment for opioid abuse. While much is known about methadone's pharmacology, its discriminative stimulus properties remain largely unexplored. The present study sought to establish methadone discrimination in rats. Moreover, some research suggests that route of administration alters the discriminative stimulus of methadone. Thus, the present study also compared intraperitoneal (i.p.) and subcutaneous (s.c.) routes of administration. Male Sprague-Dawley rats were trained to discriminate 3.0mg/kg methadone (i.p.) from vehicle in a two lever discrimination procedure. Generalization tests were conducted with a variety of compounds administered i.p. and s.c. Methadone fully substituted for itself, yielding ED(50)s of 1.5mg/kg (i.p.) and 0.2mg/kg (s.c.). Naltrexone (i.p.), an opioid antagonist produced a dose-dependent reduction in methadone appropriate responding. The methadone stereoisomers fully substituted for methadone when given s.c.; however, when administered i.p., (+) and (-) methadone produced partial and no substitution, respectively. Heroin fully generalized to methadone regardless of administration route, while morphine fully substituted when given s.c., but not i.p. The kappa-agonist U50-488 failed to generalize to methadone with either route of administration. These results demonstrated that methadone's discriminative stimulus is mediated through mu-opioid receptor activity and is similar to that of commonly abused opioids (heroin, morphine). Additionally, route of administration produced differential results for many of the drugs tested, suggesting decreased drug bioavailability following i.p. administration due to hepatic first pass metabolism. Taken together, these results suggest that methadone's shared subjective effects with abused opioids, as well as its unique metabolic properties contribute to its efficacy in opioid maintenance therapy. PMID- 19443131 TI - Daily ratings measures of alcohol craving during an inpatient stay define subtypes of alcohol addiction that predict subsequent risk for resumption of drinking. AB - BACKGROUND: Both depressive symptoms and alcohol craving have been postulated as important predictors of relapse in patients with addictive disorders. The purpose of this study was to examine the course of affective symptoms and cravings for alcohol use during the initial 25 days of residential treatment for middle aged and older adults addicted to alcohol and the relationship between these symptoms and recovery outcomes. METHODS: 95 alcohol-dependent subjects were enrolled in this observational study. Participants completed a daily diary of alcohol craving, positive affect, and negative affect during residential treatment. Participants were interviewed 1 and 6 months after discharge to assess clinical symptoms of relapse and functioning. RESULTS: Latent class analysis identified three groups of individuals for each of the three daily measures. For alcohol craving, 17 subjects reported elevated cravings during the entire treatment stay, 37 subjects reported initially elevated but then a slight improvement in craving, and 41 subjects reported relatively low craving from the time of admission to the end of residential treatment. Alcohol craving class was associated with negative affect but not positive affect. Alcohol craving class but not affective class was predictive of time to relapse to any drinking in the 6 months after residential treatment (p<0.05). CONCLUSION: Results suggest that non-cue induced alcohol craving may define a subtype of alcohol dependence that is less responsive to treatment and may explain heterogeneity in treatment outcomes. These results also may suggest a role for differential treatment programming to address high states of craving for alcohol. PMID- 19443132 TI - Comparison of subjective, pharmacokinetic, and physiological effects of marijuana smoked as joints and blunts. AB - Recent increases in marijuana smoking among the young adult population have been accompanied by the popularization of smoking marijuana as blunts instead of as joints. Blunts consist of marijuana wrapped in tobacco leaves, whereas joints consist of marijuana wrapped in cigarette paper. To date, the effects of marijuana smoked as joints and blunts have not been systematically compared. The current within-subject, randomized, double-blind, placebo-controlled study sought to directly compare the subjective, physiological, and pharmacokinetic effects of marijuana smoked by these two methods. Marijuana blunt smokers (12 women and 12 men) were recruited and participated in a 6-session outpatient study. Participants were blindfolded and smoked three puffs from either a blunt or a joint containing marijuana with varying Delta(9)-tetrahydrocannabinol (THC) concentrations (0.0, 1.8, and 3.6%). Subjective, physiological (heart rate, blood pressure, and carbon monoxide levels) and pharmacokinetic effects (plasma THC concentration) were monitored before and at specified time points for 3h after smoking. Joints produced greater increases in plasma THC and subjective ratings of marijuana intoxication, strength, and quality compared to blunts, and these effects were more pronounced in women compared to men. However, blunts produced equivalent increases in heart rate and higher carbon monoxide levels than joints, despite producing lower levels of plasma THC. These findings demonstrate that smoking marijuana in a tobacco leaf may increase the risks of marijuana use by enhancing carbon monoxide exposure and increasing heart rate compared to joints. PMID- 19443133 TI - Interim methadone treatment: impact on arrests. AB - AIMS: This study examines the frequency and severity of arrest charges among heroin addicts randomly assigned to either interim methadone (IM) maintenance or to remain on a waiting list for methadone treatment. It was hypothesized that IM participants would have a: (1) lower number of arrests at 6 and 12 months and (2) lower mean crime severity scores at 6 and 12 months post-baseline. METHODS: Available official arrest data were obtained for all 319 study participants for a period of 2 years before and after study enrollment. Crime severity ratings of charges were made using an established measure of crime severity. FINDINGS: Participants randomly assigned to IM as compared to those on a waiting list had a significant reduction in number of arrests at 6 but not at 12 months from study enrollment. There were no significant differences in whether participants were arrested for a more severe crime but frequency of severe crime was relatively low in both groups. Additional post hoc analyses based on whether participants were in methadone treatment at 4 and 10 months after original random assignment to treatment condition revealed that those participants not in treatment at these follow-up assessment points were significantly more likely to be arrested and to have a higher mean crime severity rating at 12 and 24 months post-baseline assessment. CONCLUSIONS: IM as compared to the waiting list condition, had a significant reduction in number of officially recorded arrests from baseline to 6 months post-baseline. Those who were enrolled in methadone treatment at the 4- and 10-month follow-up assessment, regardless of initial assignment, had fewer arrests at 12 and 24 months post-baseline. PMID- 19443134 TI - An interaction between DAT1 and having an alcoholic father predicts serious alcohol problems in a sample of males. AB - The current study examines whether the dopamine transporter (DAT1) VNTR polymorphism and paternal alcoholism are related to serious alcohol problems. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we found that the DAT1 polymorphism interacted with paternal alcoholism to predict serious alcohol problems among males. Specifically, the 10-repeat allele conferred an increase of alcohol problems only among males who also had an alcoholic father; the 10-repeat allele was unrelated to alcohol problems for males without an alcoholic father. Coefficient tests revealed that this interaction effect was stronger among African-American males. Females who possessed the 9-repeat allele were more likely to report serious alcohol problems, but this effect was not moderated by paternal alcoholism. These analyses suggest that additive and interactive effects of DAT1 and paternal alcoholism may operate differently across genders and races. PMID- 19443135 TI - The association between cannabinoid receptor 1 gene (CNR1) and cannabis dependence symptoms in adolescents and young adults. AB - OBJECTIVE: This study examined the genetic association between variation in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence symptoms. METHOD: Adolescent and young adult subjects were recruited from three settings: a treatment program for youth with substance use disorders, the criminal justice system, and the community. A case-control sample consisted of 224 cases who endorsed at least one dependence symptom and 108 controls who tried cannabis but endorsed no symptoms. A family-based sample of 219 families was also analyzed. RESULTS: Case-control analysis identified a nominal association between SNP rs1049353 and having one or more cannabis dependence symptoms (p=.029), but the association did not hold up in a combined sample. Family-based analysis found a trend for the same SNP (p=.07). We did not replicate a previous report that SNP rs806380 was associated with the development of cannabis dependence. CONCLUSION: These results provide inconclusive evidence of association between rs1049353/rs806380 and the development of cannabis dependence, and underscore the importance of replicating results of genetic association studies. Additional family-based studies are needed to clarify the role of the CNR1 gene, and its various SNPs, in the development of cannabis use disorders. PMID- 19443136 TI - Does delay discounting play an etiological role in smoking or is it a consequence of smoking? AB - Although higher delay discounting rates have been linked to cigarette smoking, little is known about the stability of delay discounting, whether delay discounting promotes smoking acquisition, whether smoking contributes to impulsive choices, or if different relationships exist in distinct subgroups. This study sought to fill these gaps within a prospective longitudinal cohort study (N=947) spanning mid-adolescence to young adulthood (age 15-21 years old). Smoking and delay discounting were measured across time. Covariates included peer and household smoking, academic performance, depression, novelty seeking, inattention and hyperactivity/impulsivity symptoms, and alcohol and marijuana use. The associated processes latent growth curve modeling (LGCM) with paths from the delay discounting level factor (baseline measure) and the trend factor (slope) to the smoking trend factor (slope) fit the data well, chi(2)((19,n=947)) =15.37, p=.70, CFI=1.00, RMSEA=0, WRMR=.36. The results revealed that delay discounting did not change significantly across time. Baseline delay discounting had a significant positive effect on smoking trend (beta=.08, z=2.16, p=.03). A standard deviation (SD=1.41) increase in baseline delay discounting resulted in an 11% increase (OR=1.11, 95% CI=1.03, 1.23) in the odds of smoking uptake. The alternative path LCGM revealed that smoking did not significantly impact delay discounting (p's>.05). Growth mixture modeling identified three smoking trajectories: nonsmokers, early/fast smoking adopters, and slow smoking progressors. Delay discounting was higher in the smoking versus nonsmoking trajectories, but did not discriminate between the smoking trajectories, despite different acquisition patterns. Delay discounting may provide a variable by which to screen for smoking vulnerability and help identify subgroups to target for more intensive smoking prevention efforts that include novel behavioral components directed toward aspects of impulsivity. PMID- 19443138 TI - Comparing overdose mortality associated with methadone and buprenorphine treatment. AB - AIM: To compare overdose mortality associated with methadone and buprenorphine treatment for opioid dependence. METHODS: Data linkage study. Since 1 April 2006, the Division of Analytic Laboratories (DAL) has routinely tested all New South Wales (NSW) coronial post-mortem samples for both methadone and buprenorphine. Names of all methadone or buprenorphine-positive cases between April and December 2006 inclusive were linked to the National Coroners Information System (NCIS) database, which provided information on cause of death, autopsy findings and circumstances of death. Names were linked to the Pharmaceutical Services Branch Drugs of Addiction System (PHDAS) database to identify whether people were in treatment, and in decedents not registered in treatment, the source of methadone or buprenorphine was presumed to be diversion from treatment programs. Mean number in treatment during 2006 for methadone and buprenorphine were derived from the PHDAS database. Rate of opioid overdose per thousand people in treatment were calculated for methadone and buprenorphine. RESULTS: In the 9-month period there were 13,718 in methadone treatment and 2716 people in buprenorphine. There were 60 sudden deaths positive for methadone (32 in-treatment) and 7 buprenorphine positive decedents (none in treatment). Most out-of-treatment deaths occurred in people with known histories of drug misuse. Forty-three methadone positive cases 19/32 in treatment, and 24/28 out-of-treatment - and 2 of the 7 buprenorphine positive deaths were due to overdose. The risk of overdose death per thousand people in treatment was lower for buprenorphine than for methadone (RR 4.25 [1.03, 17.54]). CONCLUSION: In this short-term study, buprenorphine was associated with lower overdose risk than methadone. PMID- 19443137 TI - Principles of laboratory assessment of drug abuse liability and implications for clinical development. AB - Abuse liability testing plays an important role in informing drug development, regulatory processes, and clinical practice. This paper describes the current "gold standard" methodologies that are used for laboratory assessments of abuse liability in non-human and human subjects. Particular emphasis is given to procedures such as non-human drug discrimination, self-administration, and physical dependence testing, and human dose-effect abuse liability studies that are commonly used in regulatory submissions to governmental agencies. The potential benefits and risks associated with the inclusion of measures of abuse liability in industry-sponsored clinical trials is discussed. Lastly, it is noted that many factors contribute to patterns of drug abuse and dependence outside of the laboratory setting and positive or negative signals in abuse liability studies do not always translate to high or low levels of actual abuse or dependence. Well-designed patient and physician education, pharmacovigilance, and postmarketing surveillance can reduce the diversion and misuse of drugs with abuse liability and can effectively foster the protection and promotion of public health. PMID- 19443139 TI - Infectivity of pestivirus following persistence of acute infection. AB - Bovine viral diarrhoea virus (BVDV) is an endemic pathogen worldwide and eradication strategies focus on the identification and removal of persistently infected (PI) animals arising after in utero infection. Despite this, acute infections with BVDV can persist for months or years after the removal of the PI source despite repeated screening for PIs and tight biosecurity measures. Recent evidence for a prolonged duration of viraemia in the testicles of bulls following acute BVDV infection suggests the possibility of a form of chronic persistence that may more closely resemble the persistence strategies of hepatitis C virus (HCV). To investigate the potential for virus transmission from infected and recovered cattle to virus naive hosts we established an acute infection of 5 BVDV naive calves and monitored animals over 129 days. Infectious BVDV was detected in white blood cells between days 3 and 7 post-challenge. The animals seroconverted by day 21 post-infection and subsequently were apparently immune and free from infectious virus and viral antigen. Animals were further monitored and purified white blood cells were stimulated in vitro with phytohaemagglutinin A (PHA) during which time BVDV RNA was detected intermittently. Ninety-eight days following challenge, blood was transferred from these apparently virus-free and actively immune animals to a further group of 5 BVDV-naive calves and transmission of infection was achieved. This indicates that BVDV-infected, recovered and immune animals have the potential to remain infectious for BVDV naive cohorts for longer than previously demonstrated. PMID- 19443140 TI - Phylogentic analysis of Anaplasma ovis strains isolated from sheep and goats using groEL and mps4 genes. AB - Evidence of Anaplasma spp. in goats and sheep in Cyprus has been demonstrated by previous research. Herein, further research was performed for the identification of the exact Anaplasma spp. resulting in the identification of Anaplasma ovis strains in all samples examined. We used a bioinformatics as well as a molecular approach (study of groEl and mps4 genes) in order to verify the validity of the results. All samples depicted the presence of A. ovis regardless of the host (goat or sheep). PMID- 19443141 TI - Ethyl methanesulfonate toxicity in Viracept--a comprehensive human risk assessment based on threshold data for genotoxicity. AB - Based on a production accident Viracept (nelfinavir mesilate) tablets, an HIV protease inhibitor supplied by Roche outside the US, Canada and Japan was contaminated with relatively high levels of ethyl methanesulfonate (EMS) for at most 3 months in spring of 2007. On the basis of a wide variety of toxicological data including critical experiments for mutation induction under chronic exposure conditions and cross-species exposure scaling experiments to extrapolate to humans, we estimate the added risk of adverse effects (cancer, birth abnormalities, heritable defects) in any individual patient accidentally exposed to EMS via contaminated Viracept tablets in the context of this production accident as essentially zero. Of critical important for this risk assessment are pivotal in vivo genotoxicity studies (MNT, MutaMouse) providing evidence for 'hockey-stick', like dose-response relationships for the risk defining induction of gene mutations and chromosomal damage by EMS [Gocke, E., Muller, L., Pfister, T., Buergin, H., 2009a. Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate. Toxicol. Lett.; Gocke, E., Muller, L., Pfister, T., 2009b. EMS in Viracept-initial ('traditional') assessment of risk to patients based on linear dose response relations. Toxicol. Lett.; Gocke, E., Muller, L., Ballantyne, M., Whitwell, J., Muller, L., 2009c. MNT and MutaMouse studies to definde the in vivo dose-response relations of the genotoxicity of EMS and ENU. Toxicol. Lett.]. As outlined in Gocke and Wall [Gocke, E., Wall, M., 2009. In vivo genotoxicity of EMS: Statistical assessment of the dose response curves. Toxicol. Lett.], several statistical approaches are in support of a threshold model to best fit the data. The presence of clear no effect levels in bone marrow, liver and GI-tract tissue with several dose levels tested below the NOEL permits the calculation of safety factors with considerable confidence. In calculating the ratio of the NOEL dose in the animal studies (25mg/kg/day) divided by the calculated maximal daily dose of the patients (1068ppm EMS in 2.92g Viracept tablets=2.75mg EMS or 0.055mg/kg for a 50kg person) we derive a safety factor of 454 based on oral intake. Detailed absorption, distribution and metabolism studies in mice, rats and monkeys and with human surrogates in vitro enable us to estimate the safety factors also for the calculated likely highest exposure (AUC and C(max)) of patients to EMS [Lave, T., Birnbock, H., Gotschi, A., Ramp, T., Pahler, A., 2009a. In vivo and in vitro characterization of ethyl methanesulfonate pharmacokinetics in animals and in human. Toxicol. Lett.; Lave, T., Paehler, A., Grimm, H.P., 2009b. Modelling of patient EMS exposure: translating pharmacokinetics of EMS in vitro and in animals into patients. Toxicol. Lett.]. We calculate the total exposure (AUC) based safety factor to amount to at least 28. This lower value is due to the conservative prediction of a longer half-life of EMS in man versus mouse, rat and monkey. Based on the estimated human C(max) the safety factor for affected Viracept patients is calculated to be 370, as C(max) is mainly dependent on volume of distribution, which is not much different for EMS in different species. We consider that the total exposure based safety factor constitutes a minimal value since the considerations regarding evidence of error-free repair at sub threshold concentrations argues in favor of using the highest EMS concentration (C(max)) rather than the AUC as basis for risk assessment. The 'true value' very likely lies somewhere between these two numbers as aspects such as repair enzyme availability and status of the cell cycle relative to the insult are important parameters that may not fully support safety factors based solely on C(max) estimates. Potential adverse effects of EMS such as cancer, birth abnormalities and heritable effects are considered to be sequelae of its genotoxic activity. Hence, the thresholded dose-response relationships should also apply to these endpoints. We also provide a comprehensive discussion of the specific disease situation of the HIV infected target population and potential influences of co medications on the susceptibilities and repair capacities of EMS induced DNA lesions. PMID- 19443142 TI - Processing and subcellular localization of ADAM2 in the Macaca fascicularis testis and sperm. AB - Fertilin, a heterodimeric protein complex composed of ADAM1 and ADAM2 located on the sperm surface, is involved in sperm-egg interaction. In our study, we examined the physiological processing and subcellular localization of M. fascicularis ADAM2 during spermatogenesis in the testis and epididymal tract. M. fascicularis ADAM2 was initially synthesized as a 100 kDa precursor in testicular germ cells. After passing into 50 kDa intermediate form in the epididymal tracts, the precursor form was finally processed into a 47 kDa protein in sperm. We found that M. fascicularis ADAM2 is localized on the sperm surface and contributes to the formation of a candidate fertilin complex. In particular, Far-Western blot analysis revealed that M. fascicularis ADAM2 cystein-rich domain may be related to protein-protein interaction. Therefore, the cystein-rich domain of ADAM2 could provide a mechanism to form a fertilin complex. PMID- 19443143 TI - Prostaglandin H synthase Type 2 is differentially expressed in endometrium based on pregnancy status in pony mares and responds to oxytocin and conceptus secretions in explant culture. AB - The equine embryo must signal its presence to the uterus for pregnancy to continue to term. Mobility of the conceptus throughout the uterus is crucial for its survival, and this action presumably permits the conceptus to transmit its antiluteolytic signal to the endometrium. Studies were completed to establish whether this unidentified antiluteolytic signal targets prostaglandin G/H synthase 2 (PGHS2), a rate limiting enzyme in converting arachidonic acid to prostaglandins (PGs). In the first study, quantitative RT-PCR was used to determine the relative abundance of PGHS2 mRNA in endometrium derived from estrous cyclic and pregnant mares on day 14 post-ovulation. PGHS2 mRNA abundance was substantially greater in endometrium from estrous cyclic mares. Additional studies were completed to better understand PGHS2 in equine endometrium. An estrogen and progesterone treatment regimen in ovariectomized mares was developed as a test model for detecting endometrial PGHS2 mRNA. Also, exposing endometrial explants to conceptus secretions (conditioned culture medium) decreased PGHS2 mRNA abundance whereas exposing explants to oxytocin increased PGHS2 mRNA abundance. Exposure to conceptus secretions also decreased PGF2alpha concentrations in explant-conditioned medium whereas oxytocin supplementation increased PGF2alpha concentrations in medium. These data support the hypothesis that PGHS2 is a target for the antiluteolytic signal produced by equine conceptuses during early pregnancy. Also, the endometrial explant culture system used for these studies can serve as a model for identifying and characterizing the maternal recognition of pregnancy factor in equids. PMID- 19443145 TI - Menopause: knowledge, attitude and practice among Italian women. AB - OBJECTIVES: Investigating women's knowledge, attitude and practice in relation to menopause and systemic hormone therapy (HT) through a sample survey implemented within the preliminary works for the Consensus Conference "Informing women on hormone replacement therapy" that took place in Turin in May 2008 [Available at www.partecipasalute.it. Last access 7/8/2008]. METHODS: The survey involved representative samples of women 45-60 years from five Italian regions. Twenty trained interviewers distributed the questionnaires reaching participants at their homes. A total of 969 women were selected from electoral rolls. 720 of them completed the interview (74.3% response rate). RESULTS: Participants reported positive attitudes about menopause; more than 90% believed menopause is a normal phase in women's life and more than 40% stated it is a good experience for a woman. Nevertheless, more than half of the sample did not receive any information about menopause and possible therapies, and those who did, often rated it as poor and contrasting. Moreover, clinicians who prescribed HT reported advantages (94%) much more frequently than disadvantages (22%) and risks (39%) in relation to this treatment. Lack of knowledge was associated with women's low educational level and their no or scarce attitude to attend health services. CONCLUSIONS: More and qualified information should be provided to support women in making informed choices in relation to menopause and the use of systemic HT. Therefore, actions' should be carried out in order to strengthen the advisory role of clinicians and other sources of information, when taking care of women who may be using or thinking of using HT. PMID- 19443144 TI - Carotid atherosclerosis and the risk factors in early postmenopausal Chinese women. AB - OBJECTIVES: To describe the distribution of intima-media thickness (IMT) and the prevalence of plaque by carotid segments, walls and sides, and to examine their associated risk factors in asymptomatic, early postmenopausal Chinese women in Hong Kong. METHODS: Between 2002 and 2004, the study recruited 518 postmenopausal women aged 50-64 years. They were examined by B-mode ultrasound to measure the IMT and the prevalence of plaque at the near and far walls of common carotid (CCA), bifurcation (bulb), and internal carotid (ICA) of both the left and right carotid arteries. Blood pressures, obesity indices, lipids and glucose levels, sociodemographic, medical and lifestyle factors were also obtained. RESULTS: The mean IMT was 0.76+/-0.12 mm (range: 0.53-1.33 mm). IMT was significantly thicker on the far wall than on the near wall and differed among segments (being thickest at the bulb and the narrowest at the ICA). 21.8% had at least one plaque in the carotid artery with most of the plaque found at the bulb area. Systolic blood pressure had statistically significant relationship with IMT that were fairly homogeneous among different segments. Lipids were associated with the CCA and bulb IMT, but not the ICA IMT. Diabetes predicted only CCA IMT. Older age, higher waist-hip-ratio and low-density lipoprotein cholesterol were significant predictors of plaques at all sites combined. CONCLUSIONS: We described the distribution of IMT and the prevalence of plaque in asymptomatic, early postmenopausal Chinese women. Associations of risk factors with IMT of different arterial segments were also observed. PMID- 19443146 TI - Characterization of a new inhalable thymopentin formulation. AB - The present work describes a new dry powder containing thymopentin (TP5) suitable for inhalation. A total of 21 dry powders were produced by co-spray drying TP5 with lactose or mannitol as a bulking agent, leucine as a dispersibility enhancer and poloxamer 188 as a drug stabilizer. Analyses by scanning electron microscopy, laser diffractometry, thermogravimetry, Twin Stage Impactor and HPLC were performed to characterize the manufactured powders. The results revealed that formulation compositions greatly influenced the physical characteristics of the powders, such as the angle of repose, tapped density, particle size and aerodynamic diameter which, in turn, affected their aerodynamic behavior. A higher loading of leucine in the formulations (>63% by dry weight) improved the aerosolization properties of the powders by producing aerodynamically lighter particles. The optimum formulation, which had a tapped density of 0.31 g/cm(3), an aerodynamic diameter of 1.9 microm and an in vitro deposition of 45%, was obtained by combining TP5/mannitol/leucine in the ratio of 10/18/72. In addition, it was interesting to find that poloxamer 188 had a significant impact on improving the powder flowability rather than stabilizing TP5. In conclusion, the chosen composition promises an enhanced aerosol performance for the new TP5 inhalation formulation, suitable for deep lung deposition. PMID- 19443147 TI - Anti-inflammatory and analgesic effects of ethanol and aqueous extracts of Pterocephalus hookeri (C.B. Clarke) Hoeck. AB - AIM OF THE STUDY: This study evaluates the anti-inflammatory and analgesic activities of the ethanol and aqueous extracts of a Tibetan herb Pterocephalus hookeri (C.B. Clarke) Hoeck to provide experimental evidence for its traditional use such as cold, flu and rheumatoid arthritis. MATERIALS AND METHODS: Investigations on the analgesic effects of P. hookeri (C.B. Clarke) Hoeck were carried out, including hot-plate test and acetic acid-induced writhing. The anti inflammatory activities were observed by utilizing the following models: carrageenin-induced edema of the hind paw of rats, cotton pellet-induced granuloma formation in rats, acetic acid-induced permeability, and xylene-induced ear edema in mice. The effects of the administration of indomethacin were also studied. RESULTS: It has been shown that the ethanol and aqueous extracts significantly increased the hot-plate pain threshold and reduced acetic acid induced writhing response in mice. The ethanol and aqueous extracts remarkably inhibited the increase in vascular permeability induced by acetic acid and ear edema induced by xylene. The ethanol extract also significantly decreased the carrageenin-induced rat paw edema perimeter and inhibited the increase of granuloma weight. CONCLUSION: The results show that the ethanol and aqueous extracts have both central and peripheral analgesic activities and as anti inflammatory effects, supporting the traditional application of this herb in treating various diseases associated with inflammation and pain. PMID- 19443148 TI - Hypoglycemic and antihyperglycemic effect of Begonia malabarica Lam. in normal and streptozotocin induced diabetic rats. AB - AIM OF THE STUDY: The stem of Begonia malabarica was used traditionally by the Malasar tribe to treat diabetes. To validate the hypoglycemic and antihyperglycemic effects of the hexane, ethylacetate and methanol extracts obtained from an ethnomedicinal plant, Begonia malabarica. MATERIALS AND METHODS: The doses for the study were fixed based on Irwin test. The hypoglycemic effect of hexane, ethylacetate and methanol extracts of Begonia malabarica stems were studied in normal animals. The antihyperglycemic effect of the methanol extract was studied in streptozotocin induced diabetic rats. RESULTS: In normal rats the treatment with the methanol extract of Begonia malabarica had shown a highly significant reduction (16.54 and 34.47%) in plasma glucose levels from the 0 h values at the dose of 100 and 200 mg/kg respectively. In streptozotocin induced diabetic rats the body weight of the Begonia malabarica methanol extract treated animals had shown a significant increase (13.38% at 200 mg/kg) after 4 weeks treatment. The plasma glucose levels were reduced significantly by 46.57 and 50.20% after 4 weeks treatment at 100 and 200mg/kg respectively. Likewise the absolute kidney weight was also reduced in a significant manner. After 25 days treatment the Begonia malabarica methanol extract treated animals had shown low fasting plasma glucose levels (54.29, 61.34% in 100 and 200 mg/kg) and reduced postprandial plasma glucose levels (54.23, 65.96% in 100 and 200 mg/kg) when compared with diabetic control values. Serum insulin levels and liver glycogen levels were increased to 40.04 and 42.18% in 200 mg/kg Begonia malabarica methanol extract treated animals respectively. The treatment with Begonia malabarica methanol extract did not change the triglycerides and total cholesterol levels. The urea and creatinine levels were also reduced significantly by this treatment. The reduction in SGPT levels indicated the absence of toxicity of Begonia malabarica extract at this dose level. CONCLUSION: This study supports the use of Begonia malabarica by the Malasar tribe for the treatment of diabetes. Fractionation of this extract may yield novel prototypes to manage diabetes mellitus. PMID- 19443149 TI - An herbal decoction of Radix astragali and Radix angelicae sinensis promotes hematopoiesis and thrombopoiesis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A decoction containing Radix angelicae sinensis and Radix astragali (Danggui Buxue Tang, DBT) has been used to raise the "Qi" and nourish the "Blood". However, its effects on haematopoiesis and particularly thrombopoiesis have not been studied. AIMS: This study aims to examine the effects of DBT on hematopoiesis and thrombopoiesis. MATERIALS AND METHODS: A myelosuppression mouse model was treated with DBT (10mg/kg/day). Peripheral blood cells from DBT and thrombopoietin-treated samples were counted on days 0, 7, 14 and 21. Then CFU assays were used to determine the effects of DBT on the megakaryocytic progenitor cells and other lineages. Last, analyses of annexin V, caspase-3, and mitochondrial membrane potential were conducted in megakaryocytic cell line M-07e. RESULTS: Morphological examination showed that DBT treatment significantly increased the recovery of the megakaryocytic series. DBT significantly enhanced the platelet recovery and CFU-MK formation in vivo. DBT significantly promoted CFU-MK and CFU-F formation. Last, we observed the antiapoptotic effects of DBT on M-07e cells. CONCLUSION: DBT might promote haematopoiesis and thrombopoiesis in the mouse model through (i) directly promoting the growth of megakaryocytes; (ii) indirectly promoting the growth of bone marrow stromal cells; (iii) inhibiting apoptosis of megakaryocytes. PMID- 19443150 TI - Sex identification and software development using digital femoral head radiographs. AB - The determination of sex is considered one of the first essential steps in positive identification. The current study aspires to accomplish a threefold purpose: to develop an easy and rapid sex determination technique using digital radiographs from the proximal epiphysis of the femur, to develop a simplified tool for pathologists that will provide accurate sex identification using radiographs and to compare this method with standard osteometric techniques applied to the same population. A total of 70 (36 males and 34 females) left femora were measured according to standard osteometric techniques. The proximal epiphyses of the same sample were then radiographed using a digital X-ray machine (TCA 4R PLUS). The skeletal remains were selected from the exhumed skeletons of St. Konstantinos and Pateles Cemeteries, Heraklion, Crete. Nine classical measurements were taken from the entire dry femora. Stepwise discriminant function analysis selected only 2 dimensions (maximum head diameter and anterior posterior midshaft diameter) producing an accuracy rate of 88.6% for both original and cross-validated data. If assuming that only the proximal part of the femur is present, direct procedure results in 87.1% correct group membership. Six landmarks were selected in the radiograph and 15 variables representing all possible combinations of these landmarks were calculated using a specially designed calibrated Java program. Measurements were submitted to discriminant function analysis using SPSS subroutines. Stepwise discriminant function analysis selected only 3 out of 15 dimensions, producing an accuracy rate of 92.9%. The formula generated was then incorporated into the Java application, resulting in the development of a sex identification software (SIS). A sample of 36 (23 left and 13 right) femoral radiographs was used in order to test the software's reliability and sex was correctly identified in 32/36 cases, giving an accuracy rate of 91.7%. The radiographic technique proposed here performed better compared to conventional methods in the same population. From a forensic point of view it is a useful alternative method when semi-decomposed or charred remains are recovered in mass disasters or crime scenes and maceration is not an option. The application of metric methods in radiographs and the development of a highly specific software provides a useful and easy tool for sex identification that can be used in certain forensic cases in which osteometry does not apply. PMID- 19443151 TI - Manufacturing by-products from, and stereochemical outcomes of the biotransformation of benzaldehyde used in the synthesis of methamphetamine. AB - Clandestine synthesis of methamphetamine in Australia has predominantly started from pseudoephedrine extracted from over the counter cold and flu medications. However, recently introduced restrictions on the sale of these products have made pseudoephedrine much more difficult to obtain. As a result clandestine chemists have had to resort to other means of obtaining the necessary chemical precursors. A recent drug raid (Adelaide, January 2008) resulted in the seizure of an unusual reaction mixture that indicated a novel approach involving the fermentation of glucose by yeast in the presence of benzaldehyde to give 1-hydroxy-1 phenylpropanone, also known as l-phenylacetylcarbinol (l-PAC), a known precursor to ephedrine and pseudoephedrine and hence methamphetamine. A study was undertaken into this process with the aim of determining the characteristic reaction by-products associated with methamphetamine made in this way. The study also looked at the stereochemical selectivity of the fermentation reaction and the stereochemistry of the subsequent reaction products, ephedrine and pseudoephedrine, and the final methamphetamine. PMID- 19443152 TI - MRI findings in the young infant with brainstem disconnection and extracerebral features. Report of one case and review of the literature. AB - We present the young infant with the extremely rare brain abnormality-brainstem disconnection. Additionally, several extracerebral abnormalities were diagnosed: bilateral anotia, micrognatia, hypertelorism, scoliosis, ribs and vertebral anomalies. MR brain examination precisely demonstrated absence of the pons, with disruption between midbrain and hypoplastic medulla oblongata. The thin strands connecting the medulla with the midbrain and medulla with both cerebellar hemispheres were revealed. The large hamartoma of the tuber cinereum was found. In this study we review case reports published previously. PMID- 19443153 TI - Perspective of child neurology in Japan. PMID- 19443154 TI - Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet. AB - PURPOSE: New evidence is emerging that the availability of nutrients plays a key role in regulating the mammalian target of rapamycin complex-1 (mTORC1) signaling pathway in human cancers. Tuberous sclerosis complex (TSC) is a genetic disorder which results in the growth of hamartomatous lesions in multiple organs due to insufficient suppression of the mTORC1 pathway. A minority of patients with TSC who develop epilepsy which is intractable to standard anticonvulsant medical and/or surgical treatments are treated with the ketogenic diet. To provide insight into the effects of nutrient manipulation on tumor growth in this condition, we describe our experience in a unique group of patients with known tuberous sclerosis complex who are on the ketogenic diet for seizure control. METHODS: A retrospective chart review was performed of patients with TSC treated with the ketogenic diet between January 2002 and May 2007 at Massachusetts General Hospital. RESULTS: Five patients with definite TSC underwent serial imaging for tumor growth while on the ketogenic diet or had unchanged imaging prior to the onset of the diet and after termination. Three out of five patients, all children, had progression of a known tumor or tumors or the development of a new tumor while on the ketogenic diet. CONCLUSION: In this limited case series of five TSC patients, the ketogenic diet did not induce tumor regression or suppress the growth of TSC-related tumors. PMID- 19443156 TI - Impact of guidelines for endoscopy in patients with Barrett's esophagus: a multifaceted interventional study. AB - OBJECTIVE: To evaluate the impact of a multifaceted interventional program on the compliance of hepatogastroenterologists with guidelines for Barrett's esophagus. DESIGN: In both 2002 and 2005, anonymous postal surveys were sent out, involving eight criteria pertaining to three main areas to assess compliance, to 245 hepatogastroenterologists based in private and public hospitals, and in the community, in a specific region of France. The multifaceted intervention was based on reminders, conferences, postal campaigns and esophageal mapping. Main outcome measures were based on biopsies for diagnosis, surveillance intervals and management of patients with high-grade dysplasia. RESULTS: In 2002 and 2005, survey response rates were 81.6 and 73.9%, respectively. In terms of diagnosis, compliance with the systematic performance of biopsies increased from 26.5 to 59.9% (p<0.01) and, with follow-up, from 41.0 to 52.0%, respectively (p<0.02). Management of high-grade dysplasia increased from 16.0 to 24.3% (p<0.01). Total compliance (with all criteria) was achieved by 5.0% of hepatogastroenterologists in 2002 and by 10.7% in 2005 (p<0.01). CONCLUSION: The present study suggests that a multifaceted interventional program can dramatically improve physician compliance with the guidelines for Barrett's esophagus. For this reason, we recommend that national scientific societies disseminate their guidelines through targeted activity to ensure that they are followed by hepatogastroenterologists. PMID- 19443157 TI - Whole-brain voxel-based morphometry of white matter in mild cognitive impairment. AB - PURPOSE: The purpose of this study was to analyze whole-brain white matter changes in mild cognitive impairment (MCI). MATERIALS AND METHODS: We studied 14 patients with MCI and 14 age- and sex-matched healthy control subjects using voxel-based morphometry (VBM) on T1-weighted 3D datasets. The data were collected on a 3T MR system and analyzed by SPM2 to generate white matter volume maps. RESULTS: Voxel-based morphometry revealed diffusively reduced white matter in MCI prominently including the bilateral temporal gyrus, the right anterior cingulate, the bilateral superior and medial frontal gyrus and right parietal angular gyrus. White matter reduction was more prominent in anterior regions than that in posterior regions. CONCLUSION: Whole-brain white matter reduction in MCI patients detected with VBM has special distribution which is in line with the white matter pathology of MCI. PMID- 19443158 TI - Regional diffusion changes of cerebral grey matter during normal aging--a fluid inversion prepared diffusion imaging study. AB - BACKGROUND AND PURPOSE: Although diffusion characteristics of white matter (WM) and its aging effects have been well described in the literature, diffusion characteristics of grey matter (GM), especially the cortical GM, have not been fully evaluated. In the present study, we used the fluid-inversion prepared diffusion imaging (FLIPD) technique to determine if there are age-related water diffusivity changes in GM. MATERIALS AND METHODS: 120 healthy volunteers were recruited for our study. They were divided into three age groups: group one (20 39 years old), group two (40-59 years old) and group three (60 years or older). All patients were evaluated with MRI using FLIPD at 3.0T. Apparent diffusion coefficient (ADC) values of the frontal GM, cingulate cortex and thalami were determined bilaterally by region-of-interest analysis. RESULTS: Group three had significantly higher ADC values in both thalami and the left frontal GM compared to group two or group one. No ADC value difference was found among the three groups in the right frontal GM and bilateral cingulate cortex. There was a significant positive correlation between individual ADC values and age in both thalami and left frontal GM. For the cingulate cortex and the right frontal GM, ADC values did not correlate significantly with advancing age. CONCLUSION: Statistically significant age-related diffusion changes were observed in both thalami and the left frontal cortex. The data reported here may serve as a reference for future studies. PMID- 19443160 TI - Pelvimetry revisited: analyzing cephalopelvic disproportion. AB - The objective of this study was to assess the clinical value of pelvimetry to predict dystocia due to cephalopelvic disproportion. 63 patients who had received an abdominal CT scan postpartum were included. Pelvimetry was performed retrospectively with these datasets on a 3D workstation; there were no CT examinations performed solely for pelvimetry, and there was no radiation exposure for study purposes. Patients were divided into three groups by the course of birth, i.e. normal vaginal delivery (A), dystocia due to cephalopelvic disproportion (B) and other patients (C). Previously described methods were evaluated for their accuracy in diagnosing cephalopelvic disproportion. The pelvimetric parameters did not show significant differences between groups A (n=20) and B (n=20) except for the sagittal mid-pelvic diameter (q) with 12.7+/ 0.6 cm vs. 11.9+/-0.6 cm (p=0.0001). The ROC analysis of the previously described methods showed areas under the curve between 0.50 and 0.67. The ROC curves for q had an area of 0.88, providing 85% sensitivity with 85% specificity. In conclusion, the sagittal mid-pelvic diameter shows potential to detect cephalopelvic disproportion with acceptable accuracy. With the information gained on the CT data, a prospective trial based on MR imaging can be set up to validate the diagnostic accuracy. PMID- 19443159 TI - DCE-MRI using small-molecular and albumin-binding contrast agents in experimental carcinomas with different stromal content. AB - OBJECTIVES: To compare DCE-MRI experiments performed using a standard small molecular (Gd-DTPA) and an albumin-binding (MS-325) contrast agent in two carcinoma models with different stromal content. MATERIALS AND METHODS: DU-145 or BXPC-3 cancer cells were subcutaneously injected into nude mice. DCE-MRI was performed by a bolus injection of Gd-DTPA or MS-325 about 2 weeks after inoculation. For quantitative analysis a volume of interest was manually drawn over each tumor. To address the heterogeneous enhancement, each tumor volume was then divided into the 20% most-enhancing and the remaining 80% least-enhancing fractions. Mean tumor enhancement was calculated over these selected tumor volumes and compared between tumor groups and contrast agents. Maps of differential enhancement, peak enhancement and time-to-peak were used for visual evaluation. CD31 and VEGF immunohistochemistry were performed in excised tumors. RESULTS: In the 80% least-enhancing volume, at late time points of the dynamic scan, the mean enhancement elicited by MS-325 was higher in BXPC-3 than in DU-145 tumors. In the 20% most-enhancing volume, using either contrast agents, significant difference between the two tumors types were observed only early, while at later time points of the dynamic scan the difference were obscured by the faster washout observed in the BXPC-3 tumors. Enhancement maps confirmed that BXPC-3 tumors were characterized by marked washout rate using either contrast agent, particularly in the higher enhancing peripheral rim. With MS-325 this washout pattern appeared to be specific to the BXPC-3 carcinomas, since it was not observed in the DU-145 tumors. Finally, in both tumor types, MS-325 produced significantly higher enhancement than Gd-DTPA in the late phase of the dynamic scan. Ex vivo analysis confirmed the marked presence of aberrant infiltrative stroma in BXPC-3 tumors, in which tumor vessels were embedded. In all tumors the central portion was less viable and less infiltrated by stromal tissue then the peripheral areas. CONCLUSIONS: Contrast distribution proved to be related to stromal content, which presumably produced the higher enhancement and faster washout observed in the BXPC-3 tumors. In particular, 'early' contrast-enhanced MRI, appeared as the most sensitive technique to detect the tumor portions characterized by a high stromal content, i.e. the peripheral rim of the BXPC-3 tumors. Since the same tumor models were recently investigated using FDG-PET imaging, showing inverse relationship between FDG uptake and stromal content, contrast-enhanced MRI and FDG-PET could provide complementary and comprehensive sensitivity in the assessment of carcinomas. PMID- 19443161 TI - Hybrid cardiac SPECT/64-slice CTA-derived LV function parameters: correlation and reproducibility assessment. AB - The purpose of this study is to define the relationship between SPECT and CTA measured parameters of left ventricular (LV) function and volumes obtained in a single session using SPECT/64-slice CT hybrid imaging device, and in addition, to assess the reproducibility of LV parameters measured using 64-slice CTA. MATERIALS AND METHODS: Seventy-six patients with suspected or known coronary artery disease underwent cardiac CTA and GSPECT in one session using a hybrid SPECT/CT device. LV end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) were measured on each component of the hybrid device. For the CTA component, these parameters were re-measured by the same investigator and by a second investigator with an interval of 3-54 weeks. Corresponding GSPECT and CTA measured parameters were compared. For CTA, intra-observer and inter-observer variability of LV function and volume measurements were calculated. RESULTS: A very good correlation was found between the GSPECT and CTA measured LVEF (r=0.81), ESV (r=0.90) and EDV (r=0.82). There was a small positive difference by CTA measured LVEF (3.9+/-14.2%), and more prominent positive differences by CTA measured ESV and EDV (9.8+/-14.8 and 44.9+/-23.1cm(3), respectively). There was excellent reproducibility in the measurements of all parameters with very low intra- and inter-observer variability (r=0.93 for EF and 0.98 for EDV and ESV). CONCLUSIONS: Although a good correlation was found between the EF measurements obtained from CTA and SPECT, interchangeable use of EF measurements between the two modalities should be done cautiously and interchangeable use of LV EDV and ESV should be avoided. PMID- 19443162 TI - New HPLC assay for urinary salbutamol concentrations in samples collected post inhalation. AB - A new reversed phase high performance liquid chromatography (HPLC) method with fluorescence detection and two solid phase extraction (SPE) methods have been developed, optimised and validated for determining salbutamol in human urine after an inhalation. SPE methodology for unchanged salbutamol (USAL) and salbutamol plus its metabolites (USALMET) concentrations in urine has been developed using terbutaline as the internal standard. Confirm HCX cartridges were used for USAL and Oasis HLB for USALMET. Calibration lines of salbutamol urine standards were linear over the range 25-300 microg/L with mean (RSD) r(2) values of 0.9983 (0.06%) for USAL and 0.9976 (0.202%) for USALMET. The HPLC method was accurate (mean bias -0.40% for USAL and 0.46% for USALMET) and precise (mean RSD 5.0% for USAL and 2.90% for USALMET). The calculated LOD and LOQ for salbutamol using a 1 mL urine sample were 4.0 and 12.12 microg/L for USAL, and 4.80 and 14.56 microg/L for USALMET, respectively. The mean (RSD) SPE recoveries of salbutamol were 90.82% (2.32%) for USAL and 91.54% (2.96%) for USALMET. Both HPLC and SPE methods were applied to quantify unchanged and metabolised salbutamol excreted in urine after the inhalation of 200 microg salbutamol from metered dose inhalers (MDIs) by 14 healthy volunteers. Charcoal slurries were also ingested to prevent gastro-intestinal absorption. Urine samples were collected at 30 min post inhalation and then pooled for the next 24h. All urine concentrations were within the sensitive portion of the assay. The volunteer study revealed that following inhalation from an MDI about 20% of the nominal dose is deposited into the lungs and 46% is delivered to the systemic circulation. The results confirm the application, sensitivity, reliability and robustness of the HPLC and SPE methods for urinary pharmacokinetic studies after salbutamol inhalations using therapeutic doses. PMID- 19443163 TI - A case of pylephlebitis secondary to cecal diverticulitis. AB - BACKGROUND: Pylephlebitis, which has high rates of morbidity and mortality, is thrombosis in the hepatic and portal veins. Hypercoagulability and intra abdominal sepsis can lead to pylephlebitis, which can progress to liver abscess, mesenteric ischemia, and infarction. CASE REPORT: A 47-year-old man presented to the Emergency Department complaining of fever, epigastric pain, and jaundice. He was diagnosed with pylephlebitis secondary to diverticulitis, as well as having a diverticular abscess, and was treated with antibiotic therapy without surgery or anticoagulation. CONCLUSION: Early diagnosis is essential for the treatment of pylephlebitis. Antibiotics and anticoagulants are the mainstay of treatment for pylephlebitis; although the use of anticoagulants remains controversial. In the present case, pylephlebitis was treated successfully without anticoagulants. PMID- 19443164 TI - Severe accidental overdose of 4-aminopyridine due to a compounding pharmacy error. AB - BACKGROUND: 4-Aminopyridine (4-AP) is a potassium channel-blocking drug used to ameliorate symptoms of multiple sclerosis and spinal cord injury by facilitating neural impulse conduction. It is not Food and Drug Administration (FDA) approved, but information about it is disseminated via the Internet, and it is currently available from compounding pharmacies with a physician's prescription. Dose related toxicity is frequent and includes dizziness, insomnia, paresthesia, asthenia, headache, tremor, delirium, choreoathetosis, and seizures. OBJECTIVES: To report a case of life-threatening accidental overdose of 4-AP resulting from a pharmacy error. CASE REPORT: A 42-year-old man with a history of C3 spinal cord injury with residual left-sided weakness and anesthesia, taking 4-AP, presented to the Emergency Department with the sudden onset of abdominal pain, vertigo, anxiety, profuse diaphoresis, hypersalivation, hypertension, bradycardia, agitation, and choreoathetosis, followed by status epilepticus. Toxicity due to 4 AP was suspected and the patient was treated symptomatically. He recovered with permanent short-term memory loss after a prolonged and complicated hospital course. Analysis of the pills, which had been prescribed for him by a physician and specially compounded by a pharmacist, showed that they contained approximately 10 times the dose indicated on the label, a dose that reliably produces severe toxicity. CONCLUSION: Emergency physicians should be familiar with the signs of 4-AP toxicity. Additionally, they should be aware that 4-AP and other non-FDA-approved medications may be available to patients from compounding pharmacies, and that quality control of made-to-order drug compounding may not be up to the standard that is expected with mass-produced pharmaceuticals. PMID- 19443165 TI - Absence of electrocardiographic change after prolonged application of a conducted electrical weapon in physically exhausted adults. AB - BACKGROUND: Conducted electrical weapons (CEWs) are used by law enforcement for control of subjects by causing neuromuscular incapacitation. There has been scrutiny of CEWs and their potential role in the occasional sudden death of subjects in custody. There is a hypothesized causal relationship due to induced cardiac dysrhythmia. Previous work has not shown dysrhythmia induction in resting humans. However, these devices are not often used on resting individuals in the field. OBJECTIVE: We sought to determine if exposure to a CEW in a physically exhausted human sample population caused detectable change in the 12-lead electrocardiogram (ECG). METHODS: Human volunteers were enrolled. All subjects had a baseline ECG obtained and then underwent an exercise regimen until exhaustion. The volunteers then received a continuous 15-s application from a TASER(r) X26 CEW (TASER International, Scottsdale, AZ). CEW electrodes were placed on random positions of their anterior thoraces. Electrode positions involved at least a 12-inch spread and always encompassed the normal anatomic position of the heart. An ECG was obtained immediately after CEW exposure. ECGs were interpreted by a blinded cardiologist. RESULTS: At baseline, 24/25 ECGs were normal. One baseline ECG was abnormal due to several monomorphic premature ventricular complexes. After CEW exposure, all 25 ECGs were interpreted as normal. CONCLUSIONS: Prolonged CEW application in an exhausted human sample did not cause a detectable change in their 12-lead ECGs. Theories of CEW-induced dysrhythmia in non-rested humans are not supported by our findings. PMID- 19443166 TI - Airway compromise after dental extraction. PMID- 19443167 TI - Covert cryptococcal meningitis in a patient with systemic lupus erythematous. AB - BACKGROUND: Cryptococcal meningitis is a rare but well-recognized illness with a high mortality rate in immunosuppressed patients with systemic lupus erythematosus (SLE). The diagnosis of cryptococcal meningitis in these patients can be challenging, especially in the emergency department (ED), as the clinical presentation may be non-specific, which can lead to delayed treatment. OBJECTIVE: To recognize risk factors associated with the development of cryptococcal meningitis infection in patients with SLE and to provide an update on the clinical presentation, prognosis, and therapeutic options. CASE REPORT: A 21-year old man with SLE presented with a 4-day history of headache, fever, nausea, and vomiting after being discharged from the ED 1 day before this visit, after lumbar puncture showed normal values. One week before, he had completed 7-day pulse therapy with intravenous cyclophosphamide and intravenous methylprednisone for lupus nephritis. The patient was febrile, but the remainder of the examination was normal. Laboratory data showed lymphopenia. Given his immunocompromised state, a cryptococcal antigen was added to cerebrospinal fluid (CSF) sent from the prior ED visit and was positive at a titer of 1:8. The patient was treated with amphotericin B and 5-flucytosine for 6 weeks. Ten months later the patient remained free of infection. CONCLUSION: Normal neurological and CSF examination do not exclude cryptococcal meningitis in immunocompromised patients with SLE. India ink or, preferably, latex agglutination test and CSF fungal culture are recommended. A high level of suspicion is the key in the diagnosis of cryptococcal meningitis and will help avoid delays in treatment. PMID- 19443168 TI - Chronic aortic dissection in a young adult. AB - BACKGROUND: Acute aortic dissection is a life-threatening disease that is often a diagnostic challenge in the Emergency Department (ED). Patients with acute aortic dissection often have underlying hypertension and atherosclerotic disease, and commonly present with acute-onset severe chest or back pain in their sixth or seventh decades of life. Aortic dissection, however, can also be seen in patients < 40 years old and may present chronically, with symptom duration longer than 2 weeks. OBJECTIVE: We present an unusual case of chronic aortic dissection in a young patient, followed by a review of the literature on chronic aortic dissections and aortic dissections in young patients. CASE REPORT: We report a case of chronic aortic dissection in a 32-year-old man with a history of untreated hypertension who presented to the ED with palpitations and mild shortness of breath. CONCLUSION: Acute and chronic thoracic aortic dissections can occur in patients of all ages, as well as in patients with atypical signs and symptoms. PMID- 19443169 TI - The evaluation of an intervention based on the application of patient self completion concordance forms in Dutch community pharmacies and the effect on adherence to chronic medication. AB - OBJECTIVE: To evaluate the use of patient self-completion concordance forms and to determine the effect of patient counselling by using concordance forms on adherence to chronic medication. METHODS: Patients with a prescription for new chronic treatment were randomised in an intervention or control group. The intervention group received a concordance form to fill in at home and to discuss during a consultation 2 weeks later in the pharmacy. The control group received the usual information and instruction on how to use the medicine. Afterwards, all patients were asked to fill in a questionnaire about their use of medicines and contact with the pharmacy employees. Adherence to the medicine was determined using rates of prescription refills after 6 months of use. RESULTS: The questionnaires showed that patients were satisfied about the concordance model. After 6 months of use, 79% of the patients from both intervention and control group were defined as adherent. CONCLUSIONS: There was no significant difference found in adherence between intervention and control group. PRACTICE IMPLICATIONS: Use five selected questions from the concordance form which provided most answers. Focus on one drug group and have more consultation moments. PMID- 19443170 TI - Evaluating existing measures of health numeracy using item response theory. AB - OBJECTIVE: To evaluate existing measures of health numeracy using item response theory (IRT). METHODS: A cross-sectional study was conducted. Participants completed assessments of health numeracy measures including the Lipkus expanded health numeracy scale (Lipkus), and the Medical Data Interpretation Test (MDIT). The Lipkus and MDIT were scaled with IRT utilizing the two-parameter logistic model. RESULTS: Three-hundred and fifty-nine (359) participants were surveyed. Classical test theory parameters and IRT scaling parameters of the numeracy measures found most items to be at least moderately discriminating. Modified versions of the Lipkus and MDIT were scaled after eliminating items with low discrimination, high difficulty parameters, and poor model fit. The modified versions demonstrated a good range of discrimination and difficulty as indicated by the test information functions. CONCLUSION: An IRT analysis of the Lipkus and MDIT indicate that both health numeracy scales discriminate well across a range of ability. PRACTICE IMPLICATIONS: Health numeracy skills are needed in order for patients to successfully participate in their medical care. The accurate assessment of health numeracy may help health care providers to tailor patient education interventions to the patient's level of understanding and ability. Item response theory scaling methods can be used to evaluate the discrimination and difficulty of individual items as well as the overall assessment. PMID- 19443171 TI - The influence of primary health care professionals in encouraging exercise and physical activity uptake among White and South Asian older adults: experiences of young older adults. AB - OBJECTIVE: To explore the influence of primary health care professionals in increasing exercise and physical activity among 60-70-year-old White and South Asian community dwellers. METHOD: Fifteen focus groups and 40 in-depth interviews with community dwelling White and South Asian 60-70-year olds. The sample was selected to include people with very different experiences of participation and non-participation in exercise and physical activity. Data were analysed using framework analysis. RESULTS: Primary health care professionals' advice and support was found to be a motivator to the initiation of exercise and physical activity. However, this was usually in relation to advice on weight reduction, cardiac conditions and mobility issues, but not generally to improve or increase activity levels. An underlying attitude of genuine interest and empathy was valued and shaped decisions about initiating and/or increasing activity levels. CONCLUSION: Primary health care professionals should be encouraged to show interest and empathy with older people about the positive benefits of exercise and physical activity to them individually. This advice needs to be tailored to the older adult's symptoms. PRACTICE IMPLICATIONS: Primary health care professionals need to be able to provide specific advice as to the quantity (frequency, duration, intensity and type) of exercise or physical activity to undertake. Practitioners need to listen to their patients' needs, show empathy and avoid ageism during consultations. PMID- 19443172 TI - Microarray analysis of microRNA expression in renal clear cell carcinoma. AB - AIM: To explore the microRNA (miRNA) expression in renal clear cell carcinoma (RCCC). METHODS: We compared the miRNA expression profiles in 11 pairs of RCCC and adjacent nontumorous tissue (NT) from 11 RCCC patients, using a mammalian miRNA microarray containing whole human mature and precursor miRNA sequences. To verify microarray results, Northern blotting was carried out on 5 randomly selected miRNAs. RESULTS: Totally 81 miRNAs were identified valid expression in RCCC samples, 48 of which specifically detected in RCCC samples, 17 of which detected downregulated in RCCC compared to NT sample, 2 upregulated and 14 without significant difference. MiRNAs in RCCC tissues exhibit an overall higher expression level than NT tissue. The chip results were confirmed by northern blot analysis. CONCLUSION: Our study may help to clarify the molecular mechanisms involved in the pathogenesis of RCCC, and miRNAs potentially serve as a novel diagnostic biomarker of RCCC. PMID- 19443173 TI - Predictors and prognostic significance of operative complications in patients with hepatocellular carcinoma who underwent hepatic resection. AB - AIMS: The morbidity rate of hepatic resection for hepatocellular carcinoma (HCC) remains high. To clarify predictors and the prognostic significance of operative complications in patients with HCC, we conducted a comparative retrospective analysis of 291 patients with HCC who underwent hepatic resection. METHODS: Operative complications included hyperbilirubinemia, ascites, hemorrhage, respiratory and cardiovascular diseases, bile leakage and abscess formation, renal failure, wound infection, and pleural effusion. Predictors of operative complications and their prognostic value for long-term survival were studied by univariate and multivariate analyses. RESULTS: Mortality and morbidity rates were 7.2% and 42.6%. The main operative complications were ascites (n = 30), intraabdominal abscess (n = 25), hyperbilirubinemia (n = 19), wound infection (n = 16), pleural effusion (n = 10) and intraabdominal hemorrhage (n=9). By a multivariate logistic regression model, Child-Pugh class B and increased operative blood loss (> or = 1200ml) were independent predictors of postoperative complications. Among 243 patients without operative death, the 5-year overall survival rate was significantly lower in patients with operative complications (34.3%) than in those without these complications (48.7%). By the multivariate Cox proportional hazards model, the presence of operative complications was an independent predictor of poor overall survival as well as presence of portal invasion. CONCLUSIONS: Child-Pugh class B and operative blood loss > or = 1200ml were independent predictors of complications after hepatic resection for HCC. Long-term survival is poorer in patients with postoperative complications. Decreasing operative blood loss may result in fewer postoperative complications and better long-term survival of HCC patients. PMID- 19443174 TI - Staging chest radiography is not useful in patients with colorectal cancer. AB - INTRODUCTION: International guidelines recommend a staging chest X-ray (SCXR) in patients with colorectal cancer to exclude pulmonary metastases. The SCXR is controversial, because evidence to support its use is insufficient. The aim of this study was to determine the value of the SCXR in patients with colorectal cancer. PATIENTS AND METHODS: Between January 1992 and August 2006, data from all patients with colorectal cancer, who presented to the surgical clinic of the Maasland Hospital, were prospectively collected and analysed. The main outcome was the rate of pulmonary metastases on SCXR. The secondary outcome was the influence of SCXR on patient management. RESULTS: Out of 1410 patients, 1057 had a chest X-ray before their operation. Median follow-up time was 4 years and 6 months (25th percentile 1 year and 7 months, 75th percentile 6 years and 11 months). Eight patients were excluded because follow-up data were incomplete. In 24 patients the chest X-ray was suggestive of malignancy; 9 of these patients actually had pulmonary metastases. Patient management was changed in 5 of them. Four patients were identified to have primary lung cancer. These data indicate a 0.86% detection rate of pulmonary metastases (confidence interval, 0.3-1.4%). DISCUSSION: Our results show that SCXR has a low detection rate of pulmonary metastases and a small influence on patient management. In accordance with previous studies our data do not support the routine use of the SCXR in patients with colorectal cancer. PMID- 19443175 TI - The role of secondary cytoreductive surgery for recurrent mucinous epithelial ovarian cancer (mEOC). AB - BACKGROUND: Mucinous epithelial ovarian cancer (mEOC) may exhibit a distinct biological behavior in epithelial ovarian cancer (EOC). The role of secondary cytoreductive surgery was evaluated in patients with recurrent mEOC, and the prognosis was assessed. METHODS: Twenty-one patients with stages IIc to IV mEOC who experienced disease recurrence and received secondary cytoreductive surgery at Fudan University Cancer Hospital between Jan. 1997 and Dec. 2005 were retrospectively reviewed. Survival curves were generated using the Kaplan-Meier method and the significant comparison of survival rate was estimated by the log rank test. RESULTS: The median progression-free interval (PFI) was 14 months (range, 5-46 months) after the first cytoreduction. Seven patients (33%) who received secondary cytoreductive surgery were optimally cytoreduced with residual disease less than or equal 1cm, and the other 14 patients (67%) underwent suboptimal surgical cytoreduction. The overall median survival time was 27 months (range, 8-64 months). The median survival time after recurrence was 10 months (range, 3-32 months). There was no significant statistical difference in median survival between patients with optimal and suboptimal secondary surgical cytoreduction, with an estimated survival of 10 months and 9.8 months, respectively (P>0.05). CONCLUSION: Optimal primary cytoreductive surgery for advanced mEOC was very important. Once it recurs, the prognosis is very poor. Patients with recurrent mEOC should be carefully assessed before performing secondary cytoreductive surgery, as this may have limited impact on the overall survival rates. PMID- 19443176 TI - Measuring obsessive-compulsive symptoms: Padua Inventory-Revised vs. Yale-Brown Obsessive Compulsive Scale. AB - Although the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Padua Inventory-Revised (PI-R) are the most widely used instruments for assessing presence and severity of symptoms in obsessive-compulsive disorder (OCD), the correlation between the two instruments is surprisingly low. The aim of the present investigation was to test two possible explanations for the discrepancy between these instruments by comparing both scales in 120 OCD patients. The tested hypotheses included: (1) differences in the way the measures are administered, i.e. observer-rated vs. self-rated; and (2) differences in the way severity is calculated, i.e. the PI-R measures severity by aggregating symptoms, while the Y-BOCS measures severity unrelated to the number of symptoms. Results indicated that neither hypothesis satisfactorily explains the differences between the measures. The investigation concludes that the Y-BOCS and PI-R measure relatively unrelated features of OCD, and the combined use of multiple measures is recommended to assess the complexity of OCD phenomena. PMID- 19443177 TI - Global asymptotic stability of neural networks with discontinuous activations. AB - Without assuming the boundedness and monotonicity of the neuron activations, we discuss the dynamics of a class of neural networks with discontinuous activation functions. The Leray-Schauder theorem of set-valued maps is successfully employed to derive the existence of an equilibrium point. A Lyapunov-like approach is applied to differential equations with discontinuous right-hand sides modeling the neural network dynamics, which yields conditions for global convergence or convergence in finite time. The obtained results extend previous works on global stability of neural networks with continuous neuron activations or discontinuous neuron activations. PMID- 19443178 TI - Optimal exponential synchronization of general chaotic delayed neural networks: an LMI approach. AB - This paper investigates the optimal exponential synchronization problem of general chaotic neural networks with or without time delays by virtue of Lyapunov Krasovskii stability theory and the linear matrix inequality (LMI) technique. This general model, which is the interconnection of a linear delayed dynamic system and a bounded static nonlinear operator, covers several well-known neural networks, such as Hopfield neural networks, cellular neural networks (CNNs), bidirectional associative memory (BAM) networks, and recurrent multilayer perceptrons (RMLPs) with or without delays. Using the drive-response concept, time-delay feedback controllers are designed to synchronize two identical chaotic neural networks as quickly as possible. The control design equations are shown to be a generalized eigenvalue problem (GEVP) which can be easily solved by various convex optimization algorithms to determine the optimal control law and the optimal exponential synchronization rate. Detailed comparisons with existing results are made and numerical simulations are carried out to demonstrate the effectiveness of the established synchronization laws. PMID- 19443179 TI - Another look at statistical learning theory and regularization. AB - The paper reviews and highlights distinctions between function-approximation (FA) and VC theory and methodology, mainly within the setting of regression problems and a squared-error loss function, and illustrates empirically the differences between the two when data is sparse and/or input distribution is non-uniform. In FA theory, the goal is to estimate an unknown true dependency (or 'target' function) in regression problems, or posterior probability P(y/x) in classification problems. In VC theory, the goal is to 'imitate' unknown target function, in the sense of minimization of prediction risk or good 'generalization'. That is, the result of VC learning depends on (unknown) input distribution, while that of FA does not. This distinction is important because regularization theory originally introduced under clearly stated FA setting [Tikhonov, N. (1963). On solving ill-posed problem and method of regularization. Doklady Akademii Nauk USSR, 153, 501-504; Tikhonov, N., & V. Y. Arsenin (1977). Solution of ill-posed problems. Washington, DC: W. H. Winston], has been later used under risk-minimization or VC setting. More recently, several authors [Evgeniou, T., Pontil, M., & Poggio, T. (2000). Regularization networks and support vector machines. Advances in Computational Mathematics, 13, 1-50; Hastie, T., Tibshirani, R., & Friedman, J. (2001). The elements of statistical learning: Data mining, inference and prediction. Springer; Poggio, T. and Smale, S., (2003). The mathematics of learning: Dealing with data. Notices of the AMS, 50 (5), 537-544] applied constructive methodology based on regularization framework to learning dependencies from data (under VC-theoretical setting). However, such regularization-based learning is usually presented as a purely constructive methodology (with no clearly stated problem setting). This paper compares FA/regularization and VC/risk minimization methodologies in terms of underlying theoretical assumptions. The control of model complexity, using regularization and using the concept of margin in SVMs, is contrasted in the FA and VC formulations. PMID- 19443180 TI - Bone regenerative properties of rat, goat and human platelet-rich plasma. AB - To explore the reported contradictory osteogenic capacity of platelet-rich plasma (PRP), the aim of the study was to examine and compare the bone regenerative effect of: PRPs of different species (rat, goat, human); human bone graft (HB) vs. HB combined with human PRP (HB+hPRP); and HB+hPRP vs. synthetic hydroxyapatite-tricalcium phosphate bone substitute combined with hPRP (HA/TCP+hPRP). For this purpose, 72 implants, divided into 6 groups (n=6) were inserted in critical-sized defects of immunodeficient rats. After 2 and 4 weeks, descriptive and quantitative histological, and micro-CT analyses were performed on the specimens. Rat and goat PRP combined with HA/TCP did not enhance bone regeneration compared with HA/TCP. In contrast, human PRP combined with HA/TCP resulted in significantly increased bone fill compared to HA/TCP. The addition of human PRP to human bone graft increased significantly the amount of newly formed bone after 2 weeks. HB+hPRP demonstrated enhanced bone healing compared to HA/TCP+hPRP. In conclusion, rat and goat PRP had no effect on bone formation. Human PRP improved the initial osteogenic response of human bone graft. Human PRP combined with human bone graft had better osteogenic capacity than human PRP combined with synthetic bone substitute. PMID- 19443181 TI - Plasmablastic lymphoma of the oral cavity in an HIV-positive patient: a case report and review of literature. AB - Plasmablastic lymphoma (PBL) of the oral cavity is an uncommon, recently described B-cell derived lymphoma that is most commonly seen in patients with human immunodeficiency virus (HIV) infections. The authors report a rare case of PBL in the oral cavity of a 40-year-old man with HIV. The lymphoma cells were positive for leukocyte common antigen, CD79a, CD138, Epstein-Barr virus (EBV) and kappa light chain restriction and negative for CD20, CD3, S100, HMB45 and cytokeratins. The lesion regressed after treatment with local radiotherapy and systemic chemotherapy. The features of this rare disease are summarized based on a comprehensive review of the epidemiological, clinical and immunohistochemical findings of previously reported cases. PMID- 19443182 TI - Association of adolescent catatonia with increased mortality and morbidity: evidence from a prospective follow-up study. AB - This paper examined outcomes among youth with catatonic syndrome and determined whether the characteristics suggesting the relevance of chronic catatonic schizophrenia (CCS) at index episode remained stable at follow-up. From 1993 to 2004, 35 individuals aged 12 to 18 years were prospectively admitted for management of catatonic syndrome and followed up after discharge. Mean duration from discharge to follow-up was 3.9 years (range 1-10). Four patients were lost to follow-up. Among the remaining 31 subjects (mean age=19.5 years, range 15-26), life-time diagnosis using the Diagnostic Interview for Genetic Studies was unchanged in 28 patients, and included schizophrenia (all subtypes; N=20), major depressive episode (N=5), bipolar disorder type I (N=4) and brief psychotic episode (N=2). Mortality (all-cause Standardized Mortality Ratio=6266; 95% CI=1181-18,547) and morbidity were severe, with 3 deaths (including 2 suicides), 6 patients presenting with a causal organic condition and 14 subjects needing continuous psychiatric care. All males in the study (N=8) who had chronic catatonic schizophrenia at the index episode still had chronic catatonic signs at follow-up. Catatonia is one of the most severe psychiatric syndromes in adolescents. It is associated with a 60-fold increased risk of premature death, including suicide, when compared to the general population of same sex and age. This increased risk of premature death remains higher than the one measured in former adolescent psychiatric patients (all-cause SMR=221; 95% CI=156-303; Engqvist and Rydelius, 2006), or in schizophrenia irrespective to age and subtype (all-cause SMR=157; 95% CI=153-160; Harris and Barraclough, 1998). PMID- 19443183 TI - DNA microarray analyses and interactomic predictions for atopic dermatitis. PMID- 19443184 TI - A possible mechanism underlying the ceramide deficiency in atopic dermatitis: expression of a deacylase enzyme that cleaves the N-acyl linkage of sphingomyelin and glucosylceramide. AB - A deficiency of ordinary ceramides in the stratum corneum is an essential etiologic factor for the dry and barrier-disrupted skin of patients with atopic dermatitis (AD). We have proposed that the mechanism underlying that deficiency involves a novel sphingolipid metabolizing enzyme, termed sphingomyelin (SM) glucosylceramide (GCer) deacylase, which hydrolyzes SM or GCer at the acyl site to yield their lysoforms sphingosylphosphorylcholine (SPC) or glucosylsphingosine (GSP) instead of ceramide, leading to the ceramide deficiency in the AD skin. The enzymic characteristics observed showed a pH dependency of catalytic activity with a peak at pH 5.0 and a molecular weight of 40,000. Analytical isoelectric focusing (IEF) chromatography demonstrated that the pI values of SM deacylase, GlcCDase, SMase and ceramidase were 4.2, 7.4, 7.0 and 5.7, respectively. Those enzymic characteristics of SM-GCer deacylase are completely distinct from ceramidase as well as the other known deacylases. Our enzymic measurements demonstrated that SM-GCer deacylase activity is enhanced more than 5-fold in involved stratum corneum, more than 3-fold in uninvolved stratum corneum and approximately 3-fold in the involved epidermis from patients with AD compared with healthy controls. Our findings suggest that the novel enzyme, SM-GCer deacylase, is expressed in situ at significant levels in the epidermis of AD patients. This results in the production of SPC and GSP, instead of ceramides, which leads in turn to the ceramide deficiency seen in the stratum corneum of those patients. It is likely that the biogenesis of SM-GCer deacylase may be critical to the pathogenesis of AD. PMID- 19443185 TI - Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis. AB - BACKGROUND: Epidermal nerve densities are increased in patients with atopic dermatitis (AD), suggesting that it is partly responsible for the intense itching in the skin. Epidermal hyperinnervation in AD patients is decreased by ultraviolet (UV) phototherapy, although the underlying mechanisms are poorly understood. Interestingly, abnormal expression of axonal guidance molecules, such as nerve growth factor (NGF) and semaphorin 3A (Sema3A), is found in the epidermis of AD patients. Therefore, UV phototherapy may alter levels of axonal guidance molecule expression in atopic skin. OBJECTIVE: This study was performed to investigate whether epidermal Sema3A and NGF levels in AD are influenced by psoralen-UVA (PUVA) therapy. METHODS: Skin biopsies obtained from chronic AD patients before and after PUVA therapy were used. Both Sema3A and NGF in the skin were examined at mRNA and protein levels by quantitative RT-PCR and immunohistochemistry, respectively. Nerve fibers in the skin were stained with anti-PGP9.5 antibody, and the number of epidermal nerve fibers was counted. RESULTS: PUVA therapy decreased epidermal nerve densities in AD patients, concomitant with decreases in both visual analog scale (VAS) scores for pruritus and clinical severity scores. Increased fluorescence intensity of Sema3A and decreased fluorescence intensity of NGF were observed in the epidermis of PUVA treated group. Moreover, Sema3A mRNA levels were upregulated in the PUVA-treated skins compared with untreated controls, while NGF mRNA levels in the skin were downregulated by the treatment. CONCLUSION: PUVA therapy may reduce epidermal hyperinnervation of AD by normalization of abnormal Sema3A and NGF expression in the epidermis. PMID- 19443186 TI - Principal component analysis in mild and moderate Alzheimer's disease--a novel approach to clinical diagnosis. AB - Principal component analysis (PCA) provides a method to explore functional brain connectivity. The aim of this study was to identify regional cerebral blood flow (rCBF) distribution differences between Alzheimer's disease (AD) patients and controls (CTR) by means of volume of interest (VOI) analysis and PCA. Thirty seven CTR, 30 mild AD (mildAD) and 27 moderate AD (modAD) subjects were investigated using single photon emission computed tomography with (99m)Tc hexamethylpropylene amine oxime. Analysis of covariance (ANCOVA), PCA, and discriminant analysis (DA) were performed on 54 VOIs. VOI analysis identified in both mildAD and modAD subjects a decreased rCBF in six regions. PCA in mildAD subjects identified four principal components (PCs) in which the correlated VOIs showed a decreased level of rCBF, including regions that are typically affected early in the disease. In five PCs, including parietal-temporal-limbic cortex, and hippocampus, a significantly lower rCBF in correlated VOIs was found in modAD subjects. DA significantly discriminated the groups. The percentage of subjects correctly classified was 95, 70, and 81 for CTR, mildAD and modAD groups, respectively. PCA highlighted, in mildAD and modAD, relationships not evident when brain regions are considered as independent of each other, and it was effective in discriminating groups. These findings may allow neurophysiological inferences to be drawn regarding brain functional connectivity in AD that might not be possible with univariate analysis. PMID- 19443187 TI - Role of cetyltrimethylammonium bromide (cationic surfactant) on the tryptophan MnO4(-) reaction. AB - Upon addition of permanganate to a solution of tryptophan (Trp), yellow-brown color species appears within the time of mixing of tryptophan in absence and presence of cetyltrimethylammonium bromide (CTAB), which was stable for some days. Spectroscopic and kinetic evidences suggest the formation of water-soluble colloidal MnO(2) as the most stable reduction product of MnO(4)(-). Carbon dioxide and ammonia are not formed as the oxidation products. Carbon-carbon double bond of indole moiety of Trp is responsible for the fast reduction of permanganate. Cetyltrimethylammonium bromide catalyses the permanganate oxidation of Trp with a rate enhancement of ca. 200-fold. Sub- and postmicellar catalytic effect of CTAB ascribed to the association/incorporation/solubilization of both reactants (MnO(4)(-) and Trp) with the CTAB aggregates and into the Stern layer of cationic micelles. Quantitative kinetic analysis of the rate constant-[CTAB] data has been performed on the basis of modified pseudo-phase model of the micelles. A comparison was made of the oxidation rates of different amino acids by permanganate. The order of the effectiveness was as follows: tryptophan>>tyrosine>>phenylalanine. PMID- 19443188 TI - Mortality in alpha-1-antitrypsin deficiency in the United Kingdom. AB - BACKGROUND: Four hundred and eighty-eight PiZ alpha-1-antitrypsin deficient patients, who had joined the UK registry over a 9-year period, were followed in an observational study to determine mortality. None had received A1AT augmentation therapy. METHODS: Cause of death was confirmed from death certification and medical records. Patients were censored according to length of time on the program or until they withdrew from the program. RESULTS: There were 56 deaths of which 30 were attributed to respiratory causes. Of the remaining 26 deaths, 4 were due to complications from lung transplant, 6 due to liver disease (including 2 post-liver transplant) and the other 16 due to a variety of causes. Kaplan-Meier plots indicated a cumulative hazard for mortality of 18.1% in 9 years, correcting for time of follow up. When categorised for FEV1 percent predicted, the group with severe impairment had increased mortality (p = <0.001) compared with the mild group and there was a direct relationship between severity and mortality. The severe group had increased mortality compared with the mild group when categorised for KCO percent-predicted (p<0.001), RV/TLC ratio (p<0.001) or emphysema score on CT scan (p<0.001 upper zone). Cox regression analyses indicated that these relationships remained when corrected for age. There were no differences in mortality after categorisation for educational level or occupational group. CONCLUSION: Mortality in a cohort of A1AT deficient patients (PiZ phenotype) in the UK was 2% per year and was associated with lung function impairment and emphysema severity on CT scan, but not social status. PMID- 19443189 TI - Clinical effects of purified air administered to the breathing zone in allergic asthma: A double-blind randomized cross-over trial. AB - BACKGROUND: Exposure to inhaled allergens is a pathogenetic factor in allergic asthma. However, most studies that previously looked at air cleaning devices have shown little or no effect on patients with perennial allergic asthma. AIMS AND OBJECTIVES: We examined a novel treatment using temperature regulated laminar airflow with a very low particle concentration directed to the breathing zone of teenagers and young adults with mild to moderate allergic asthma during night sleep. We hypothesised that the decreased allergen exposure during the night would have an effect on bronchial inflammation and quality of life. METHOD: Twenty-two patients (mean 18.8 years) were randomized to start with active or placebo treatment for 10 weeks. All patients received both active and placebo treatment with unfiltered air, with a 2-week wash-out period in between treatments. Maintenance treatment with inhaled corticosteroids was unaltered during the trial period. Health related quality of life (miniAQLQ) was the primary effectiveness measure. Exhaled nitric oxide (FeNO) and spirometry were also investigated. RESULTS: Active treatment resulted in an improved miniAQLQ compared to placebo (mean score 0.54, p<0.05, n=20). An effect on bronchial inflammation was also detected with significantly lower FeNO values during the active treatment period (mean -6.95 ppb, p<0.05, n=22). Both effects were evident after 5 weeks. The change in lung function was not statistically significant. CONCLUSION: Clean air, administered directly to the breathing zone during sleep, can have a positive effect on bronchial inflammation and quality of life in patients with perennial allergic asthma. PMID- 19443190 TI - Viruses and endosome membrane dynamics. AB - Cell surface molecules, ligands, and solutes can be endocytosed into animal cells via several pathways in addition to clathrin-mediated endocytosis, which all seem to lead to canonical endosomes. It seems that viruses can enter and infect cells through most of, if not all, endocytic routes, having evolved different, sometimes elaborate, strategies to (mis)use cellular machineries to their own benefit during infection. In this short review, I will discuss recent progress in understanding the pathways followed by animal viruses into cells, and how these studies are also providing novel insights into our understanding of some molecular mechanisms that control endocytic membrane transport. PMID- 19443191 TI - Peptide trafficking and translocation across membranes in cellular signaling and self-defense strategies. AB - Cells are metastable per se and a fine-tuned balance of de novo protein synthesis and degradation shapes their proteome. The primary function of peptides is to supply amino acids for de novo protein synthesis or as an energy source during starvation. Peptides are intrinsically short-lived and steadily trimmed by an armada of intra and extracellular peptidases. However, peptides acquired additional, more sophisticated tasks already early in evolution. Here, we summarize current knowledge on intracellular peptide trafficking and translocation mediated by ATP-binding cassette (ABC) transport machineries with a focus on the functions of protein degradation products as important signaling molecules in self-defense mechanisms. PMID- 19443192 TI - Substrate-specific mediators of ER associated degradation (ERAD). AB - Approximately one-third of newly synthesized eukaryotic proteins are targeted to the secretory pathway, which is composed of an organellar network that houses the enzymes and maintains the chemical environment required for the maturation of secreted and membrane proteins. Nevertheless, this diverse group of proteins may fail to achieve their native states and are consequently selected for ER associated degradation (ERAD). Over the past few years, significant effort has been made to dissect the components of the core ERAD machinery that is responsible for the destruction of most ERAD substrates. Interestingly, however, some ERAD substrates associate with dedicated chaperone-like proteins that target them for proteolysis or protect them from destruction. Other substrates fold and function normally but can be selected for ERAD by protein adaptors that identify and transmit regulatory cues. PMID- 19443193 TI - Antioxidant and cognitive promotion effects of anthocyanin-rich mulberry (Morus atropurpurea L.) on senescence-accelerated mice and prevention of Alzheimer's disease. AB - In the present study, we evaluated the beneficial effect of mulberry extracts (ME), which are rich in phenolics and anthocyanins, on the induction of antioxidant enzymes and on the promotion of cognition in senescence-accelerated mice (SAMP). Six-month old SAMP8 and SAMR1 mice were fed a basal diet supplemented with 0.18% and 0.9% ME for consecutive 12 weeks. The results showed that the mice fed the ME supplement demonstrated significantly less amyloid beta protein and showed improved learning and memory ability in avoidance response tests. ME-treated mice showed a higher antioxidant enzyme activity and less lipid oxidation in both the brain and liver, as compared to the control mice. Furthermore, treatment with ME decreased the levels of serum aspartate aminotransferase, alanine aminotransferase, triglyceride and total cholesterol that increase with ageing. The hepatoprotective effect of ME appeared to occur through a mechanism related to regulation of the mitogen-activated protein kinases and activation of the nuclear factor-erythroid 2 related factor 2, where the latter regulates the induction of phase 2 antioxidant enzymes and reduction of oxidative damage. Overall, supplementation of ME might be advantageous to the induction of an antioxidant defense system and for the improvement of memory deterioration in ageing animals. PMID- 19443194 TI - Polyunsaturated fatty acids down-regulate in vitro expression of the key intestinal cholesterol absorption protein NPC1L1: no effect of monounsaturated nor saturated fatty acids. AB - Several transporter proteins regulate intestinal cholesterol absorption. Of these proteins, NPC1L1 is a major contributor to this process. Fatty acids (FAs) modulate cholesterol absorption by a mechanism that remains unknown. We evaluate the effect of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) on the expression of NPC1L1 and others proteins associated with cholesterol absorption (SR-BI, ABCG5, ABCG8, ABCA1, CAV 1, ANX-2) in human enterocytes in vitro. The role of SREBPs, PPARs, LXR and RXR in this process was also investigated. Caco-2/TC-7 enterocytes were incubated for 24 h with a wide range of concentrations of FA-bovine serum albumin (50-300 microM). Gene expression was analyzed by quantitative real-time PCR. The NPC1L1 protein present in enterocyte membranes was analyzed using Western blot. NPC1L1 mRNA levels were reduced 35-58% by the n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (P<.05). Linoleic acid (n-6), palmitic acid and oleic acid did not affect NPC1L1 mRNA expression. ABCA1 mRNA levels were reduced 44-70% by n-6 arachidonic acid and 43-55% by n-3 EPA (P<.05). LXR and LXR+RXR agonists decreased NPC1L1 mRNA expression by 28% and 57%, respectively (P<.05). A concentration of 200 microM of EPA and DHA decreased NPC1L1 protein expression in enterocyte membranes by 58% and 59%, respectively. We have demonstrated that the PUFAs n-3 EPA and DHA down-regulate NPC1L1 mRNA expression. In addition, PUFAs also down-regulate NPC1L1 protein expression in enterocyte membranes. LXR and RXR activation induced a similar repression effect. The lipid-lowering effect of n-3 PUFAs could be mediated in part by their action at the NPC1L1 gene level. PMID- 19443195 TI - Inhibition of macrophage adhesion activity by 9trans,11trans-conjugated linoleic acid. AB - Conjugated linoleic acids (CLAs) have anti-atherogenic effects in both in vitro and animal models. Most studies on CLAs were performed with either a CLA mixture or purified 9cis (Z),11trans (E)-CLA or 10E,12Z-CLA isomers. However, the 9E,11E isomer has superior anti-carcinogenic and anti-inflammatory effects compared with the more abundant CLAs. The 9E,11E-CLA isomer specifically increases interleukin 1 receptor antagonist (IL-1Ra), an important anti-inflammatory mediator that is associated with decreased risk of coronary heart disease. The purpose of this present study was to determine if 9E,11E-CLA affects markers of atherogenesis via regulation of IL-1Ra. In human umbilical vein endothelial cells (HUVECs), 9E,11E CLA decreased such atherogenesis-related genes as intercellular adhesion molecule 1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, E selectin, P-selectin and C-C motif chemokine receptor-2. Treatment of RAW 264.7 cells with 9E,11E-CLA decreased their adhesion to HUVECs. This effect was reversed by inhibiting the phosphoinositide 3-kinase or mouse target of rapamycin pathways. IL-1Ra-deficient RAW 264.7 cells (siIL-1Ra RAW) bind more efficiently to HUVECs compared with the control stable cells (si-control RAW). In addition, HUVECs treated with siIL-1Ra RAW-conditioned media induce significantly higher levels of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 and E-selectin than HUVECs treated with si control RAW-conditioned media. Taken together, the data show that 9E,11E-CLA decreases the atherogenesis-related genes in HUVECs and alters adhesion of macrophages. In addition, the induction of IL-1Ra by 9E,11E-CLA is partially responsible for the anti-atherogenic properties of this particular CLA isomer. PMID- 19443196 TI - Ferulic acid augments angiogenesis via VEGF, PDGF and HIF-1 alpha. AB - Therapeutic angiogenesis is critical to wound healing and ischemic diseases such as myocardial infarction and stroke. For development of therapeutic agents, a search for new angiogenic agents is the key. Ferulic acid, a phytochemical found in many fruits and vegetables, exhibits a broad range of therapeutic effects on human diseases, including diabetes and cancer. This study investigated the augmenting effect of ferulic acid on angiogenesis through functional modulation of endothelial cells. Through endothelial cell migration and tube formation assays, ferulic acid (10(-6)-10(-4) M) was found to induce significant angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro without cytotoxicity. With chorioallantoic membrane assay, ferulic acid (10(-6)-10(-5) M) was also found to promote neovascularization in vivo. Using Western blot analysis and quantitative real-time polymerase chain reaction, we found that ferulic acid increased vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) expression in HUVECs. Furthermore, the amounts of hypoxic-induced factor (HIF) 1 alpha mRNA and protein, the major regulator of VEGF and PDGF, also showed up-regulation by ferulic acid. Electrophoretic migration shift assay showed that the binding activity of HIF-1 alpha was also enhanced with ferulic acid treatment of HUVECs. Moreover, inhibitors of extracellular-signal-regulated kinase 1/2 and phosphoinositide-3 kinase (PI3K) abolished the binding activity of HIF-1 alpha and the subsequent activation of VEGF and PDGF production by ferulic acid. Thus, both mitogen-activated protein kinase and PI3K pathways were involved in the angiogenic effects of ferulic acid. Taken together, ferulic acid serves as an angiogenic agent to augment angiogenesis both in vitro and in vivo. This effect might be observed through the modulation of VEGF, PDGF and HIF-1 alpha. PMID- 19443197 TI - Diet and the role of 11beta-hydroxysteroid dehydrogenase-1 on obesity. AB - 11beta-Hydroxysteroid dehydrogenase-1 (11beta-HSD-1) is a key regulatory enzyme in glucocorticoid metabolism, specifically in regulating intracellular concentrations of cortisol, the primary glucocorticoid. While the excessive level of circulating cortisol in Cushing's disease is of adrenal origin, it is the intracellular and not the systemic level of cortisol that is elevated in obesity. This tissue-specific dysregulation of glucocorticoids observed in obesity results from alterations in 11beta-HSD-1 in both liver and mesenteric adipose. While cortisol has been identified as playing a permissive role in obesity, little is known about how diet may regulate message, expression and activity of 11beta-HSD 1. In this review, we have integrated three lines of evidence that, taken together, suggest that dietary composition can play a primary role in promoting increased intracellular cortisol and in that way form the basis of a mechanism that results in excessive adiposity. We review evidence from studies of adrenalectomized rats, as well as studies linking 11beta-HSD-1 to the pentose phosphate pathway and other metabolic pathways via the enzyme hexose-6-phosphate dehydrogenase. Emerging evidence from dietary manipulation experiments suggesting that macronutrient composition may elicit changes in 11beta-HSD-1 and promote obesity is discussed. PMID- 19443198 TI - Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin. AB - Procyanidins are bioactive flavonoid compounds from fruits and vegetables that possess insulinomimetic properties, decreasing hyperglycaemia in streptozotocin diabetic rats and stimulating glucose uptake in insulin-sensitive cell lines. Here we show that the oligomeric structures of a grape-seed procyanidin extract (GSPE) interact and induce the autophosphorylation of the insulin receptor in order to stimulate the uptake of glucose. However, their activation differs from insulin activation and results in differences in the downstream signaling. Oligomers of GSPE phosphorylate protein kinase B at Thr308 lower than insulin does, according to the lower insulin receptor activation by procyanidins. On the other hand, they phosphorylate Akt at Ser473 to the same extent as insulin. Moreover, we found that procyanidins phosphorylate p44/p42 and p38 MAPKs much more than insulin does. These results provide further insight into the molecular signaling mechanisms used by procyanidins, pointing to Akt and MAPK proteins as key points for GSPE-activated signaling pathways. Moreover, the differences between GSPE and insulin might help us to understand the wide range of biological effects that procyanidins have. PMID- 19443200 TI - Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells. AB - Resveratrol (3,4',5-trans-trihydroxystilbene) is a phytoalexin with emerging lines of evidence supporting its beneficial effects on cardiovascular systems and inhibition of carcinogenesis. It has also been reported that certain methylated resveratrol derivatives are more effective than resveratrol in the prevention/treatment of cancer. However, little is known about the impact of resveratrol and its derivatives on the development of Parkinson's disease. In this study, we compared the neuroprotective effects of resveratrol with four methylated (fully or partially) resveratrol derivatives against parkinsonian mimetic 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. Release of lactate dehydrogenase and activity of caspase-3 triggered by 6-OHDA were significantly reduced by resveratrol and one of the methylated derivatives, pinostilbene (3,4'-dihydroxy-5-methoxystilbene), in a dose-dependent manner. In addition, pinostilbene exerted a potent neuroprotective effect with a wider effective concentration range than resveratrol. By using high-performance liquid chromatography, we found that uptake of pinostilbene into SH-SY5Y cells was significantly higher than that of resveratrol. Enhanced bioavailability may thus be a major factor contributing to the neuroprotective activity of pinostilbene. Moreover, Western blot analysis demonstrated that pinostilbene markedly attenuated the phosphorylation of JNK and c-Jun triggered by 6-OHDA. Besides, mammalian target of rapamycin kinase may be an intracellular target accounting for the neuroprotective effects of pinostilbene. Our findings demonstrate the potential of methylated stilbenes in neuroprotection and provide important information for further research in this field. PMID- 19443199 TI - Alpha-, gamma- and delta-tocopherols reduce inflammatory angiogenesis in human microvascular endothelial cells. AB - Vitamin E, a micronutrient (comprising alpha-, beta-, gamma- and delta tocopherols, alpha-, beta-, gamma- and delta-tocotrienols), has documented antioxidant and non-antioxidant effects, some of which inhibit inflammation and angiogenesis. We compared the abilities of alpha-, gamma- and delta-tocopherols to regulate human blood cytotoxicity (BEC) and lymphatic endothelial cytotoxicity (LEC), proliferation, invasiveness, permeability, capillary formation and suppression of TNF-alpha-induced VCAM-1 as in vitro models of inflammatory angiogenesis. alpha-, gamma- and delta-tocopherols were not toxic to either cell type up to 40 microM. In BEC, confluent cell density was decreased by all concentrations of delta- and gamma-tocopherol (10-40 microM) but not by alpha tocopherol. LEC showed no change in cell density in response to tocopherols. delta-Tocopherol (40 microM), but not other isomers, decreased BEC invasiveness. In LEC, all doses of gamma-tocopherol, as well as the highest dose of alpha tocopherol (40 microM), decreased cell invasiveness. delta-Tocopherol had no effect on LEC invasiveness at any molarity. delta-Tocopherol dose dependently increased cell permeability at 48 h in BEC and LEC; alpha- and gamma-tocopherols showed slight effects. Capillary tube formation was decreased by high dose (40 microM) concentrations of alpha-, gamma- and delta-tocopherol, but showed no effects with smaller doses (10-20 microM) in BEC. gamma-Tocopherol (10-20 microM) and alpha-tocopherol (10 microM), but not delta-tocopherol, increased LEC capillary tube formation. Lastly, in BEC, alpha-, gamma- and delta-tocopherol each dose-dependently reduced TNF-alpha-induced expression of VCAM-1. In LEC, there was no significant change to TNF-alpha-induced VCAM-1 expression with any concentration of alpha-, gamma- or delta-tocopherol. These data demonstrate that physiological levels (0-40 microM) of alpha-, gamma- and delta-tocopherols are nontoxic and dietary tocopherols, especially delta-tocopherol, can limit several BEC and LEC endothelial behaviors associated with angiogenesis. Tocopherols may therefore represent important nutrient-signals that limit cell behaviors related to inflammation/angiogenesis, which when deficient, may predispose individuals to risks associated with elevated angiogenesis such as inflammation and cancer; further differences seen from the tocopherols may be due to their blood or lymphatic cell origin. PMID- 19443201 TI - An integrated appraisal of energy recovery options in the United Kingdom using solid recovered fuel derived from municipal solid waste. AB - This paper reports an integrated appraisal of options for utilising solid recovered fuels (SRF) (derived from municipal solid waste, MSW) in energy intensive industries within the United Kingdom (UK). Four potential co-combustion scenarios have been identified following discussions with industry stakeholders. These scenarios have been evaluated using (a) an existing energy and mass flow framework model, (b) a semi-quantitative risk analysis, (c) an environmental assessment and (d) a financial assessment. A summary of results from these evaluations for the four different scenarios is presented. For the given ranges of assumptions; SRF co-combustion with coal in cement kilns was found to be the optimal scenario followed by co-combustion of SRF in coal-fired power plants. The biogenic fraction in SRF (ca. 70%) reduces greenhouse gas (GHG) emissions significantly ( approximately 2500 g CO(2) eqvt./kg DS SRF in co-fired cement kilns and approximately 1500 g CO(2) eqvt./kg DS SRF in co-fired power plants). Potential reductions in electricity or heat production occurred through using a lower calorific value (CV) fuel. This could be compensated for by savings in fuel costs (from SRF having a gate fee) and grants aimed at reducing GHG emission to encourage the use of fuels with high biomass fractions. Total revenues generated from coal-fired power plants appear to be the highest ( 95 pounds/t SRF) from the four scenarios. However overall, cement kilns appear to be the best option due to the low technological risks, environmental emissions and fuel cost. Additionally, cement kiln operators have good experience of handling waste derived fuels. The scenarios involving co-combustion of SRF with MSW and biomass were less favourable due to higher environmental risks and technical issues. PMID- 19443202 TI - Oligopeptide-modified silicon nanowire arrays as multichannel metal ion sensors. AB - Semiconducting nanowires have the potential to function as highly sensitive and selective sensors for label-free detection of biological and chemical species. In this paper, we describe the preparation and applications of oligopeptide-modified single crystal silicon nanowire (SiNW) arrays as multichannel metal ion sensors. Because these SiNW arrays were fabricated by using a "top-down" process, a very high density of individually addressable SiNW (180 SiNWs grouped into 36 clusters) can be manufactured on a single chip. Furthermore, after two different SiNW clusters are modified with Pb(2+)-selective and Cu(2+)-selective oligopeptide, respectively, concentrations of Pb(2+) and Cu(2+) in aqueous solutions can be detected simultaneously and selectively in two different channels. By using the SiNW arrays, we successfully achieved a detection limit of 1 nM for Pb(2+) and 10 nM for Cu(2+), respectively. These results demonstrate the potential utility of oligopeptide-modified SiNW arrays for highly sensitive and selective chemical and biological sensing applications. PMID- 19443203 TI - Fabrication of a cell-adhesive protein imprinting surface with an artificial cell membrane structure for cell capturing. AB - We proposed a new molecular imprinting procedure based on molecular integration for the purpose of cell capture. We selected the cell-adhesive protein fibronectin (FN) as the imprinting protein for preparing templates and evaluated selective cell adhesion on the FN imprinting substrate. Silica beads with a diameter of 15 microm were used as the stamp matrix and FN molecules were adsorbed as a monolayer. The FN recognition sites were constructed by integrating a surfactant as the ligand and immobilizing it with new biocompatible photoreactive phospholipid polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) units. As control substrates, imprinting procedures were carried out using albumin (BSA imprinting substrate) and without imprinting protein (non-imprinting substrate). The binding of FN from the cell culture medium with the fetal calf serum was achieved on the FN imprinting substrate, and induced the cell adhesion. On the other hand, on the non-imprinted and BSA imprinting substrates, the FN scarcely bound from the cell culture medium, and subsequent cell adhesion could not be observed on the substrate. These results indicate that the FN binding sites were well constructed by arranging the ligand surfactant to a suitable position and immobilized by the photoreactive MPC polymer. The MPC polymer prevented the nonspecific adsorption of proteins from the cell culture medium. We concluded that this procedure is convenient and can be potentially used for the preparation of surfaces for cell engineering devices. PMID- 19443204 TI - Theoretical and computational strategies for rational molecularly imprinted polymer design. AB - The further evolution of molecularly imprinted polymer science and technology necessitates the development of robust predictive tools capable of handling the complexity of molecular imprinting systems. A combination of the rapid growth in computer power over the past decade and significant software developments have opened new possibilities for simulating aspects of the complex molecular imprinting process. We present here a survey of the current status of the use of in silico-based approaches to aspects of molecular imprinting. Finally, we highlight areas where ongoing and future efforts should yield information critical to our understanding of the underlying mechanisms sufficient to permit the rational design of molecularly imprinted polymers. PMID- 19443205 TI - Multi-walled carbon nanotubes with immobilised cobalt nanoparticle for modification of glassy carbon electrode: application to sensitive voltammetric determination of thioridazine. AB - Multi-walled carbon nanotubes (MWCNTs) were immobilised with cobalt nanoparticles and analyzed by transmission electron microscopy. This modification procedure substantially improved colloidal dispersion of the immobilised MWCNTs in water and organic solvents, yielding uniform and stable thin films for modification of the glassy carbon electrode surface. The modified electrode showed an efficient catalytic role for the electrochemical oxidation of thioridazine (TR), leading to remarkable decrease in its oxidation overpotential of approximately 100 mV and enhancement of the kinetics of the electrode reaction, which can be confirmed by increasing in the peak current and sharpness of the peak. A remarkable enhancement in microscopic area of the electrode together with the catalytic role of the composite modifier resulted in a considerable increase of the peak current (approximately 55 times), and negative shift in the oxidation potential of TR. The effect of the thickness of the modifier on the GCE surface was optimized by monitoring its cyclic voltammetric responses toward TR. The mechanism of the electrocatalytic process on the surface of the modified electrode was analyzed by obtaining the cyclic voltammograms at various potential sweep rates and pHs of the buffer solutions. Differential pulse voltammetry was applied as a very sensitive analytical method for the determination of sub-micromolar amounts of TR. A linear dynamic range of 5.0 x 10(-7) to 1.0 x 10(-4)M with a detection limit of 5.0 x 10(-8)M TR was obtained. The prepared modified electrode shows several advantages such as simple preparation method, high stability and uniformity in the composite film, high sensitivity, and excellent catalytic activity in physiological conditions, long-term stability and remarkable voltammetric reproducibility. These excellent properties make the prepared sensor suitable for analysis in pharmaceutical and clinical preparations. The modified electrode was successfully applied for the accurate determination of minor amounts of TR in pharmaceutical and clinical preparations. PMID- 19443206 TI - Detection of bacterial 16S rRNA using multivalent dendrimer-reporter enzyme conjugates. AB - Novel enzyme-oligodeoxynucleotide conjugate was synthesized to improve sensitivity of Escherichia coli 16S rRNA detection on gold electrodes. Thermostable esterase 2 from Alicyclobacillus acidocaldarius was multiply conjugated to a polyamidoamine dendrimer functionalized by one universal detector oligodeoxynucleotide. Three components rRNA/DNA hybridization between capture oligodeoxynucleotide covalently immobilized on a gold electrode, 16S rRNA and the multivalent esterase-dendrimer cluster was used for detection of E. coli. The linear dependence of the electrochemical signals to analyte concentration revealed a detection limit of 50 colony forming units E. coli, which represents a tenfold signal enhancement if compared to the detection limit achieved with monovalent esterase-oligodeoxynucleotide conjugate. PMID- 19443208 TI - Construction of Au nanoparticles on choline chloride modified glassy carbon electrode for sensitive detection of nitrite. AB - A promising electrochemical sensor for sensitive determination of nitrite was fabricated by construction of Au nanoparticles on the surface of choline chloride (Ch) modified glassy carbon electrode (GCE). Field emission scanning electron microscope, powder X-ray diffraction, X-ray photoelectron spectroscopy and electrochemical techniques were used for the surface characterization of the modified electrode. It was demonstrated that Ch was covalently immobilized onto the GCE surface forming a planted Ch monolayer, which could provide a suitable supporting material for the construction of Au nanoparticles. As a result, the Au nanoparticles with average size of about 110 nm were assembled to form a flowerlike structure on the surface of Ch monolayer. Moreover, the uniform nano Au/Ch film exhibited remarkable electrocatalytic activity towards the oxidation of nitrite with obvious reduction of overpotential. Under the optimum conditions, the linear range for the detection of nitrite was 4.0 x 10(-7) to 7.5 x 10(-4)M with a high sensitivity of 0.354 microA microM(-1), and a low detection limit of 1.0 x 10(-7)M. The proposed method was successfully applied in the detection of nitrite in water samples and sausage samples, and the results were consistent with those obtained by ion chromatography and UV-visible spectrophotometric methods. PMID- 19443207 TI - Ultrasensitive Qbeta phage analysis using fluorescence correlation spectroscopy on an optofluidic chip. AB - We demonstrate detection and analysis of the Qbeta bacteriophage on the single virus level using an integrated optofluidic biosensor. Individual Qbeta phages with masses on the order of attograms were sensed and analyzed on a silicon chip in their natural liquid environment without the need for virus immobilization. The diffusion coefficient of the viruses was extracted from the fluorescence signal by means of fluorescence correlation spectroscopy (FCS) and found to be 15.90+/-1.50 microm(2)/s in excellent agreement with previously published values. The aggregation and disintegration of the phage were also observed. Virus flow velocities determined by FCS were in the 60-300 microm/s range. This study suggests considerable potential for an inexpensive and portable sensor capable of discrimination between viruses of different sizes. PMID- 19443209 TI - An aptamer-based electrochemiluminescent biosensor for ATP detection. AB - An aptamer-based electrochemiluminescent (ECL-AB) biosensor for ATP detection with high sensitivity and specificity was developed. The biosensor was assembled based on several steps. First, a complementary DNA (cDNA) of the ATP-binding aptamer, which has six complementary bases at both its ends, was hybridized with the aptamer molecule to form a rigid, linear double-stranded DNA (ds-DNA). The ds DNA was then labeled with a ruthenium complex at the 3' terminus of cDNA, followed by the immobilization of this ds-DNA onto Au electrode surface through the 5'-HS on the cDNA. In the presence of ATP, due to the ATP binding to the aptamer, the aptamer molecules dissociated from the ds-DNA complex, which resulted in the formation of stem-loop structure of the single-stranded cDNA and led to the increase of the ECL signal. The increased ECL intensity was found linearly to the logarithm of the concentration of ATP ranging from 0.05 nM to 10 nM with a detection limit of 0.02 nM. Different from other ECL-AB biosensors with aptamers as the probes, this sensing system proposed here is based on the utilization of the cDNA of aptamers as the probes for ECL sensing. Therefore, such sensing system could provide a promising label-free and more readily regenerated model for aptamer-based small-molecules detection. PMID- 19443210 TI - Structural insights into RNA splicing. AB - Intron splicing is a fundamental biological process whereby noncoding sequences are removed from precursor RNAs. Recent work has provided new insights into the structural features and reaction mechanisms of two introns that catalyze their own splicing from precursor RNA: the group I and II introns. In addition, there is an increasing amount of structural information on the spliceosome, which is a ribonucleoprotein machine that catalyzes nuclear pre-mRNA splicing in eukaryotes. Here, we compare structures and catalytic mechanisms of self-splicing RNAs and we discuss the possible implications for spliceosomal reaction mechanisms. PMID- 19443211 TI - Pregnancy after breast cancer: a need for global patient care, starting before adjuvant therapy. AB - Breast cancer (BC) is the most frequently occurring cancer in women; early diagnosis and efficient treatments create higher event-free and overall survival rates. However, the mean age at first pregnancy continues to increase worldwide; the question of pregnancy after BC is thus raised more frequently. Chemotherapy may induce premature ovarian failure, depending largely on the woman's age and the drugs used, as well as the dosage and duration of treatment. It is important that fertility preservation strategies are addressed before chemotherapy. Pregnancy after BC may implicate a potentially higher risk of cancer recurrence, but the available literature provides reassuring data. The delay between cancer treatment and pregnancy should be discussed, depending on the initial stage of the disease. The risk of discontinuing tamoxifen prematurely should be carefully evaluated using standardised tools. The pregnancy outcome may as well be impaired by the history of cancer, leading to an increased likelihood of preterm birth and low birth weight rates. Proper follow-up and prevention should be provided based on the knowledge of these complications. Pregnancy after BC should be possible for most young BC patients in the future. This implies a global care program including multi-disciplinary teams is initiated prior to starting adjuvant treatment and particularly chemotherapy. The patient and her partner should be involved in the various steps of the process, after being properly informed. PMID- 19443212 TI - Stability and maturity of a green waste and biowaste compost assessed on the basis of a molecular study using spectroscopy, thermal analysis, thermodesorption and thermochemolysis. AB - The organic matter (OM) of a green waste and bio waste compost was characterised over 8months and the observed evolution was correlated with physico-chemical parameters (temperature, pH, carbon content, C/N ratio). Thermochemolysis and thermodesorption were used to monitor bacterial activity (stability) whereas diffuse reflectance infrared fourier transform spectroscopy (DRIFTS) and thermodifferential analysis (TDA) permitted to determine the degree of OM humification (maturity). DRIFT spectroscopy and TDA provide two indicators of maturity since, with these two techniques, the signals associated with the biodegradable organic matter decrease relatively to the signals associated with refractory organic matter. This increase in R(TG) and R(IR) ratios between aromatic to aliphatic signals constitutes a proof for OM complexification. It correlates with humic acids/fulvic acids ratio known to be a maturity index. Pyrolysates are mainly constituted of lignin moieties, terpenoids, nitrogen containing compounds, carbohydrates (furanosic moiety), mono- and diacids (as methyl esters), and methoxyesters. The R(branched/linear) ratio between branched to linear acids traduces the evolution of the bacterial activity during composting. Moreover the R(di/mono) ratio between aliphatic mono to diacids correlates with the latter showing that diacids can occur from the biological oxidation of monoacids. These two ratios determined by thermochemolysis are useful to monitor the stability of compost. VOC, observed by thermodesorption are mainly constituted of terpenes, light acids, aldehydes and ketone. An unexpected result was obtained since the amount of phytol increases relatively to the isoprenoid ketone considered to originate from the latter. PMID- 19443213 TI - Pentachlorophenol (PCP) dechlorination in horizontal-flow anaerobic immobilized biomass (HAIB) reactors. AB - This study verifies the potential applicability of horizontal-flow anaerobic immobilized biomass (HAIB) reactors to pentachlorophenol (PCP) dechlorination. Two bench-scale HAIB reactors (R1 and R2) were filled with cubic polyurethane foam matrices containing immobilized anaerobic sludge. The reactors were then continuously fed with synthetic wastewater consisting of PCP, glucose, acetic acid, and formic acid as co-substrates for PCP anaerobic degradation. Before being immobilized in polyurethane foam matrices, the biomass was exposed to wastewater containing PCP in reactors fed at a semi-continuous rate of 2.0 microg PCP g(-1) VS. The applied PCP loading rate was increased from 0.05 to 2.59 mg PCP l(-1)day(-1) for R1, and from 0.06 to 4.15 mg PCP l(-1)day(-1) for R2. The organic loading rates (OLR) were 1.1 and 1.7 kg COD m(-3)day(-1) at hydraulic retention times (HRT) of 24h for R1 and 18 h for R2. Under such conditions, chemical oxygen demand (COD) removal efficiencies of up to 98% were achieved in the HAIB reactors. Both reactors exhibited the ability to remove 97% of the loaded PCP. Dichlorophenol (DCP) was the primary chlorophenol detected in the effluent. The adsorption of PCP and metabolites formed during PCP degradation in the packed bed was negligible for PCP removal efficiency. PMID- 19443214 TI - Critical evaluation of municipal solid waste composting and potential compost markets. AB - Mechanical biological treatment (MBT) of mixed waste streams is becoming increasingly popular as a method for treating municipal solid waste (MSW). Whilst this process can separate many recyclates from mixed waste, the resultant organic residue can contain high levels of heavy metals and physical and biological contaminants. This review assesses the potential end uses and sustainable markets for this organic residue. Critical evaluation reveals that the best option for using this organic resource is in land remediation and restoration schemes. For example, application of MSW-derived composts at acidic heavy metal contaminated sites has ameliorated soil pollution with minimal risk. We conclude that although MSW-derived composts are of low value, they still represent a valuable resource particularly for use in post-industrial environments. A holistic view should be taken when regulating the use of such composts, taking into account the specific situation of application and the environmental pitfalls of alternative disposal routes. PMID- 19443215 TI - A novel class of H3 antagonists derived from the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin. AB - This Letter describes the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin, and the resulting SAR of H(3) antagonism. Multiple rounds of iterative parallel synthesis improved human H(3) IC(50) approximately 33-fold, and afforded a new class of H(3) antagonists based on the novel bromotyramine core of dispyrin. PMID- 19443216 TI - Discovery of a potent and brain penetrant mGluR5 positive allosteric modulator. AB - This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration. PMID- 19443217 TI - Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists. AB - Synthesis, biological evaluation and structure-activity relationships for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, gamma-carbolines 3{8} and 3{14} have been identified as potent small molecule antagonists of histamine H(1) (IC(50)=0.1 microM) and serotonin 5 HT(6) (IC(50)=0.37 microM) receptors, respectively. PMID- 19443218 TI - Facile synthesis of cyclopeptide-centered multivalent glycoclusters with 'click chemistry' and molecular recognition study by surface plasmon resonance. AB - A facile synthesis of cyclopeptide-centered multivalent glycoclusters using Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition of azides and terminal alkynes, so called 'click chemistry', has been developed. The affinities of mannose-specific protein Concanavalin A (Con A) toward two synthetic glycoclusters respectively bearing divalent or tetravalent mannoses were investigated by surface plasmon resonance (SPR). It is founded that the tetravalent glycocluster has 3.0-fold increase in binding affinity relative to the divalent glycoluster (valency corrected values), which indicates the potential of this system in investigating carbohydrate-protein interactions. PMID- 19443220 TI - Non-surgical management of hormone-secreting pituitary tumors. AB - Hormone-secreting pituitary tumors account for about 30% of all pituitary tumors. Successful long-term management of patients with these tumors frequently requires a multimodality team approach. Given that the role and efficacy of neurosurgical resection of hormone-secreting pituitary tumors is well described, we focus this review on the other important treatment modalities that are becoming increasingly crucial in the management of acromegaly, Cushing's disease and prolactinomas. Medical management with standard and novel drugs as well as the role and effectiveness of radiation therapy and radiosurgery are discussed in detail. PMID- 19443221 TI - Ten-year review of extradural spinal abscesses in a New Zealand tertiary referral centre. AB - Despite being a well-understood pathology, patients with an extradural spinal abscess (ESA) still experience delays in diagnosis, with associated morbidity and mortality. This 10-year retrospective audit aimed to define the presentation, findings and prognosis of ESA in a New Zealand tertiary referral centre. Forty two patients were diagnosed and treated between 1 May 1997 and 30 June 2007. The mean age was 55 years, with a male predominance of 1.6:1. Staphylococcus aureus was identified in 67% of patients. On presentation, 27/38 patients with back pain were afebrile and 2/37 patients had a normal C-reactive protein (CRP) level in the first 24 hours. Ten patients were discharged with neurological dysfunction and one died. One reason for the delays in diagnosis and appropriate referral could be the lack of "red flag" symptoms at the time of presentation. Attention needs to be paid to the history and nature of a patient's back pain. We recommend routine CRP and full blood count to help raise clinical suspicion. PMID- 19443219 TI - Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype. AB - This Letter describes the discovery and SAR of three novel series of mGluR5 non competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold. PMID- 19443222 TI - Sweet, bitter and umami receptors: a complex relationship. AB - Sweet and bitter are taste qualities linked to food acceptance and rejection in humans. It was long thought that these taste sensations were closely related, but the discovery and characterization of taste receptors revealed that mammals express a single sweet receptor and many unrelated bitter receptors. Bitter tasting chiral isomers of sweet compounds can bind to the umami receptor, rather than bitter receptors, and elicit the bitter sensation through crosstalk between labelled cells. In support of crosstalk between labelled cells, recent findings suggest that, although most receptor taste cells respond to only one taste, most presynaptic taste cells accept signals from labelled cells that respond to two or more different taste qualities. PMID- 19443223 TI - Total knee arthroplasty in patients with poliomyelitis. AB - We performed a retrospective chart and radiograph review of 10 patients with a history of poliomyelitis involving a limb that subsequently underwent primary total knee arthroplasty between 2000 and 2008. One posterior stabilized (PS), two condylar constrained (CCK), and seven rotating hinge (RHK) prostheses belonging to the same system were implanted. Eight patients were followed for a minimum of 2 years (mean 4.3 years, range 2 to 8.5 years); one patient required revision for prosthesis infection. The last patient was followed for just six months reporting excellent pain relief, and without complications. American Knee Society Score (AKSS) improved postoperatively in all eight patients with at least 2 years follow-up. The improvement was more marked for the knee score, which increased from a mean of 37 points preoperatively (range 20 to 51) to 75.7 points postoperatively (range 50 to 92); for the functional score the mean increase was only 15.8 points, from a mean of 38.5 points (range 20 to 70) to 54.3 points (range 20 to 80) after the intervention. One patient had a recurrence of the recurvatum deformity after implanting a CCK prosthesis. We found that a rotating hinge prosthesis that allowed hyperextension was suitable treatment for patients with knee osteoarthritis and polio as this compensated for loss of quadriceps power. PMID- 19443224 TI - 2-Oxoamide inhibitors of phospholipase A2 activity and cellular arachidonate release based on dipeptides and pseudodipeptides. AB - A series of 2-oxoamides based on dipeptides and pseudodipeptides were synthesized and their activities towards two human intracellular phospholipases A(2) (GIVA cPLA(2) and GVIA iPLA(2)) and one human secretory phospholipase A(2) (GV sPLA(2)) were evaluated. Derivatives containing a free carboxyl group are selective GIVA cPLA(2) inhibitors. A derivative based on the ethyl ester of an ether pseudodipeptide is the first 2-oxoamide, which preferentially inhibits GVIA iPLA(2). The effect of 2-oxoamides on the generation of arachidonic acid from RAW 264.7 macrophages was also studied and it was found that selective GIVA cPLA(2) inhibitors preferentially inhibited cellular arachidonic acid release; one pseudodipeptide gave an IC(50) value of 2muM. PMID- 19443226 TI - Glycogen phosphorylase inhibitory effects of 2-oxo-1,2-dihydropyridin-3-yl amide derivatives. AB - Glycogen phosphorylase (GP) plays a crucial role in the conversion of glycogen to glucose-1-phosphate (and in turn glucose) and is a promising target for therapeutic intervention in diabetes. In this study we synthesized new derivatives of 2-oxo-1,2-dihydropyridin-3-yl amides using a facile aminolysis reaction, in which different alkyl and aryl esters and amides are substituted at N-1 and C-3 of the heterocyclic ring. The in vitro inhibitory activity of compounds against glycogen phosphorylase was evaluated. From this series the most potent compound exhibits good GPa inhibition (IC(50)=6.3 microM). A preliminary study of these compounds showed that anti-GP activity was decreased by the incorporation of a C3-N carbonyl group and favored by increased lipophilicity. PMID- 19443225 TI - Discovery of tetrahydrotetramethylnaphthalene analogs as adult T-cell leukemia cell-selective proliferation inhibitors in a small chemical library constructed based on multi-template hypothesis. AB - Adult T cell leukemia (ATL), caused by infection of human T-lymphotropic virus type 1 (HTLV-1), has a poor prognosis and curative therapy is unavailable, so it is important to find or design superior lead compounds for the drug treatment of ATL. We used our micro-reversed fragment-based drug design hypothesis and multi template hypothesis to extract the tetrahydrotetramethylnaphthalene (TMN) skeleton from tamibarotene, a useful medicament for the treatment of acute promyelocytic leukemia (APL). Structural development of TMN yielded highly ATL cell-selective growth inhibitors, including 2-acetyl-3-hydroxy-5,6,7,8-tetrahydro 5,5,8,8-tetramethylnaphthalene (6). Structure-activity relationship analysis suggests the existence of a specific target molecule for ATL cell-selective inhibition of proliferation through G2 arrest. PMID- 19443227 TI - Inhibitory effects of phloroglucinol derivatives isolated from Ecklonia stolonifera on Fc(epsilon)RI expression. AB - Two bioactive phloroglucinol derivatives, dioxinodehydroeckol (DHE) and phlorofucofuroeckol A (PFF-A) were isolated from edible marine brown alga, Ecklonia stolonifera, and evaluated for effects on cell surface Fc(epsilon)RI expression in KU812F cells. DHE and PFF-A were found to reduce the cell surface expression, and total cellular protein and mRNA levels for the Fc(epsilon)RI alpha chain. Moreover, both compounds exerted inhibitory effects against the elevation of intracellular calcium concentration [Ca(2+)](i) and histamine release from anti-Fc(epsilon)RI alpha chain antibody (CRA-1)-stimulated cells. These inhibitory effects were stronger for PFF-A than for DHE. These results show that two phloroglucinol derivatives, DHE and PFF-A, may exert anti-allergic effects via the inhibition of Fc(epsilon)RI expression, calcium influx, and degranulation in basophils, and contributes to the pharmacological activities of marine brown alga, including E. stolonifera. PMID- 19443229 TI - Lathyrane diterpenes from Euphorbia lathyris as modulators of multidrug resistance and their crystal structures. AB - Two lathyrane diterpenes (1-2) together with previous ones (3-6) were isolated from Euphorbia lathyris. The structures of 1 and 2 were established on the basis of extensive spectroscopic methods, including two-dimensional NMR techniques. Stereo configuration and conformation of 1 and 2 were analyzed by X-ray diffraction for the first time. The configuration of the unique isolathyrol diterpene 2 from the seeds of E. Lathyris, was rectified from S * to R * at C-5. All compounds were examined as modulators of multidrug resistance on MCF-7/ADM cell lines in vitro. Their structure-activity relationship was discussed from aspect of different skeletons. A class of potential P-gp inhibitors with five different types (jokinol, isolathyrol, epoxylathyrol, 7-hydroxylathyrol, lathyrol) was discovered. PMID- 19443228 TI - Synthesis and structure-activity relationship of a novel series of heterocyclic sulfonamide gamma-secretase inhibitors. AB - gamma-Secretase inhibitors have been shown to reduce the production of beta amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma secretase substrate. PMID- 19443230 TI - Evidence for biogenic processes during formation of ferromanganese crusts from the Pacific Ocean: implications of biologically induced mineralization. AB - Ferromanganese [Fe/Mn] crusts formed on basaltic seamounts, gain considerable economic importance due to their high content of Co, Ni, Cu, Zn and Pt. The deposits are predominantly found in the Pacific Ocean in depths of over 1000m. They are formed in the mixing layer between the upper oxygen-minimum zone and the lower oxygen-rich bottom zone. At present an almost exclusive abiogenic origin of crust formation is considered. We present evidence that the upper layers of the crusts from the Magellan Seamount cluster are very rich in coccoliths/coccolithophores (calcareous phytoplankton) belonging to different taxa. Rarely intact skeletons of these unicellular algae are found, while most of them are disintegrated into their composing prisms or crystals. Studies on the chemical composition of crust samples by high resolution SEM combined with an electron probe microanalyzer (EPMA) revealed that they are built of distinct stacked piles of individual compartments. In the center of such piles Mn is the dominant element, while the rims of the piles are rich in Fe (mineralization aspect). The compartments contain coccospheres usually at the basal part. Energy dispersive X-ray spectroscopy (EDX) analyses showed that those coccospheres contain, as expected, CaCO3 but also Mn-oxide. Detailed analysis displayed on the surface of the coccolithophores a high level of CaCO3 while the concentration of Mn-oxide is relatively small. With increasing distance from the coccolithophores the concentration of Mn-oxide increases on the expense of residual CaCO3. We conclude that coccoliths/coccolithophores are crucial for the seed/nucleation phase of crust formation (biomineralization aspect). Subsequently, after the biologically induced mineralization phase Mn-oxide deposition proceeds "auto"catalytically. PMID- 19443231 TI - Fully automated synthesis procedure of 4-[18F]fluorobenzaldehyde by commercial synthesizer: amino-oxi peptide labelling prosthetic group. AB - Automatic synthesis of 4-[18F]fluorobenzaldehyde has been developed by a commercially available TRACERlab FX(F-N) synthesis module to be used as prosthetic group for amino-oxy functionalized peptide labelling in clinical routine application. In addition a handmade purification device (HPD) has been setup to perform automatic cartridge purification as well as to back-up the reactor where one-pot synthesis is not applicable. Cartridges for solid phase extraction such as C18, C8, phenyl has been tested to best perform purification as well as activity recovery. Radiochemical yield (RCY) at end of synthesis (EOS) was in average 67% after about 45 min (90% decay corrected at EOB). The RCY of the entire procedure was 54% with a radiochemical purity above 99%. PMID- 19443232 TI - Nuclear techniques for the on-line bulk analysis of carbon in coal-fired power stations. AB - Carbon trading schemes usually require large emitters of CO(2), such as coal fired power stations, to monitor, report and be audited on their CO(2) emissions. The emission price provides a significant additional incentive for power stations to improve efficiency. In the present paper, previous work on the bulk determination of carbon in coal is reviewed and assessed. The most favourable method is that based on neutron inelastic scattering. The potential role of on line carbon analysers in improving boiler efficiency and in carbon accounting is discussed. PMID- 19443233 TI - Synthesis and biodistribution of a novel [99mTcN(PNP5)(DMCHDTC)]+ complex as a potential myocardial perfusion imaging agent. AB - The [(99m)TcN(PNP5)(DMCHDTC)](+)(DMCHDTC: 2,3-dimethyl cyclohexyl dithiocarbamate, PNP5:bis(dimethoxypropylphosphinoethyl)ethoxyethylamine) complex was synthesized through a ligand-exchange reaction. The two-step procedure involved the initial reaction of (99m)TcO(4)(-) with succinic dihydrazide (SDH) as a donor of nitride nitrogen atom (N(3-)) in the presence of stannous chloride dihydrate as reducing agent and propylenediamine tetraacetic acid (PDTA) as complexant, followed by the addition of the PNP5 ligand and the DMCHDTC ligand. The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 h. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was cationic. The biodistribution results in mice indicated that [(99m)TcN(PNP5)(DMCHDTC)](+) was significantly retained into the heart. The heart uptake (ID%/g) was 14.47, 12.23 and 8.76 at 5, 30 and 60 min post-injection, respectively. The heart/liver, heart/lung and heart/blood ratios of the complex were 1.24, 3.62 and 23.05 at 60 min post-injection, suggesting it will be a potential myocardial imaging agent. PMID- 19443235 TI - Can light absorption and photostability data be used to assess the photosafety risks in patients for a new drug molecule? AB - Photosafety assessments are recommended for all new drug candidates intended for clinical use. In 2002, Testing guidances were issued by the regulatory authorities in the USA (2003) and Europe (2002). A key requirement is to measure the absorption of UV-visible light by a compound in the 290-700 nm range and to assess photostability. Further photosafety evaluation is recommended for molecules which absorb light energy in this region and may be unstable in light. Consequently, the current guidances do not specify what constitutes a significant level of light absorbance or photoinstability. The current study was undertaken to determine the level of light absorption by measuring the molar extinction coefficients (MEC) of a wide range of compounds reported in the literature to have known photosafety issues in humans. The results have shown that all compounds tested have absorbance intensities significantly above an MEC threshold of 1000 L mol(-1)cm(-1) and also display a wide range of photoinstability. The measurement of light absorption is a contributing part of an overall pre-clinical photosafety risk assessment process, whereas photostability assessments have proven to have limited value. Molecules with an MEC less than 1000 L mol(-1)cm( 1)are deemed less of a photosafety risk since this low level of light absorption is unlikely to prove harmful. PMID- 19443236 TI - Screening and structural characterization of alpha-glucosidase inhibitors from hawthorn leaf flavonoids extract by ultrafiltration LC-DAD-MS(n) and SORI-CID FTICR MS. AB - In vitro alpha-glucosidase inhibition assays and ultrafiltration liquid chromatography with photodiode array detection coupled to electrospray ionization tandem mass spectrometry (ultrafiltration LC-DAD-ESI-MS(n)) were combined to screen alpha-glucosidase inhibitors from hawthorn leaf flavonoids extract (HLFE). As a result, four compounds were identified as alpha-glucosidase inhibitors in the HLFE, and their structures were confirmed to be quercetin-3-O-rha- (1-4)-glc rha and C-glycosylflavones (vitexin-2"-O-glucoside, vitexin-2"-O-rhamnoside and vitexin) by high-resolution sustained off resonance irradiation collision-induced dissociation (SORI-CID) data obtained by Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS). Several other C-glycosylflavones (vitexin, isovitexin, orientin, isooriention) and their aglycones apigenin and luteolin were evaluated by in vitro assays, and were found to possess strong alpha-glucosidase inhibitory activities as well. Moreover, the substituent groups on the flavones had a great impact on the enzyme inhibition activity. C-3'-OH of the B-ring of flavones in particular increased the alpha-glucosidase inhibition activity, whereas C-glycosylations at C-6 or C-8 of the A ring weakened the inhibition activity. PMID- 19443237 TI - Genetics and pathogenesis of coeliac disease. AB - Coeliac disease is a common complex disease caused by a dietary intolerance to wheat gluten. Susceptibility is determined by both environmental and genetic factors. Coeliac disease results from complex interactions between the innate immune system, an adaptive T and B cell response and the mucosal barrier where inflammation is ultimately manifested. Genetic variants within the HLA region are well established, while variants outside of the HLA region have recently been identified. These variants are beginning to enhance our understanding of the immunology of the condition. This review focuses on the immunological pathogenesis of coeliac disease with special reference to the influence of genetic susceptibility on disease development. PMID- 19443238 TI - Adjuvant effect of bovine heat shock protein 70 on piroplasm surface protein, p33, of Theileria sergenti. AB - In this study, we investigated the immunological effects of bovine heat shock protein 70 (HSP70) on the major Theileria sergenti surface protein (p33). The gene encoding p33 was expressed as a fusion protein with bovine HSP70 from a plasmid vector. The adjuvant function of HSP70 on p33 was evaluated with regard to antibody response, cytokine production, and a challenge experiment in mice or cattle. HSP-p33 fusion protein provoked higher humoral and cellular immunity than either Escherichia coli-expressed p33 or piroplasm soluble protein. The HSP adjuvant activity toward p33 was also possible to detect in the inoculated cattle. The overall growth of parasites in cattle was significantly restrained in the HSP-p33-inoculated group, up to 50-52 days longer than in the controls. The present results indicate that HSP-p33 fusion protein is a promising candidate vaccine for clinical theileriosis in the field. PMID- 19443239 TI - HCV-related mortality among male prison inmates in Texas, 1994-2003. AB - PURPOSE: The prevalence of hepatitis C virus (HCV) infection is high among adult incarcerated populations, but HCV-related mortality data are lacking. The study purpose was to assess HCV-related mortality over time and across racial/ethnic categories from 1994 through 2003 among male prisoners in the Texas Department of Criminal Justice (TDCJ). METHODS: TDCJ decedent data were linked with Texas Vital Statistics multiple-cause-of-death data. Crude annual HCV death rates, age- and race-adjusted summary rates, and average annual percent changes were estimated. The proportion of deaths due to chronic liver disease/cirrhosis, liver cancer, hepatitis B, and HIV for which HCV was identified as an intervening or contributing cause of death was calculated. RESULTS: Among Texas male prisoners, HCV death rates were high and increased over the 10-year study period by an average 21% annually, with the largest increase occurring among Hispanic prisoners. HCV was identified as an intervening or contributing cause of death in 15% of chronic liver disease/cirrhosis deaths, 33% of liver cancer deaths, 81% of hepatitis B deaths, and 7% of HIV deaths. CONCLUSIONS: Because HCV-related deaths among Texas male prisoners are high and increasing, particularly among Hispanics, targeted prevention, screening, and treatment of HCV infections should be among the priorities of U.S. correctional healthcare systems. PMID- 19443240 TI - Prenatal social support, postnatal social support, and postpartum depression. AB - PURPOSE: To assess the association of antenatal and postnatal social support with postpartum depression (PPD). METHODS: We carried out a prospective cohort study of 534 pregnant women between February and September 2007 in Hunan, China. The association between prenatal and postnatal social support with PPD was examined. RESULTS: A total of 103 (19.29%) women had PPD. Women with low prenatal and postnatal social support had higher rates of PPD. For prenatal support, PPD was 28.20% in the lowest quartile versus 9.90% in the highest quartile (adjusted odds ratio [OR]: 3.38, 95% confidence interval [CI]=1.64,6.98). For postnatal support, PPD was 44.10% in the lowest quartile versus 5.40% in the highest quartile (adjusted OR: 9.64, 95% CI=4.09, 22.69). CONCLUSIONS: Lower or lack of social support is a risk factor of PPD. The association between postnatal social support and PPD is much stronger than that of prenatal social support. PMID- 19443242 TI - Interaction between elastic energy utilization and active state development within the work enhancing mechanism during countermovement. AB - The purpose of this study was to investigate the interaction between elastic energy utilization and the time available for active state development during countermovement, and to determine the contributions of these factors in enhancing work output from a quantitative standpoint. Especially, we focused on the effect of length variation of the series elastic element (SEE) and the speed of active state development. A Hill-type model of the muscle tendon complex (MTC) was constructed. A range of SEE lengths (between 0.625 and 10 times the optimal length of the contractile element) and a range of active state development rates were investigated. Forward dynamics simulations were performed to evaluate the causal factors for the gain in height during concentric (CO) and countermovement (CM) conditions. Simulated outputs suggested that the contribution of the time available for active state development was larger than the contribution of elastic energy utilization for a shorter SEE muscle. On the other hand, the contribution of the elastic energy utilization was larger for a longer SEE muscle. Additionally, the work output of the SEE in CM was considerably augmented due to increasing the speed of active state development. As results, two main findings were obtained. First, a quantitative discussion was developed regarding how the elastic energy utilization and the time available for active state development are contributing within the work enhancing mechanism. Second, it was found that elastic energy utilization and the time available for active state development have a synergistic effect during countermovement. PMID- 19443241 TI - Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. AB - PURPOSE: Lycopene is thought to decrease the risk of cancers, although previous epidemiologic studies have produced inconsistent results. The aim of the present study was to evaluate the protective effect of lycopene against the risk of cancer. METHODS: The study population consisted of 997 middle-aged Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) cohort. During the mean follow-up time of 12.6 years, a total of 141 cancer cases appeared, of which 55 were prostate cancers. The association between the serum concentrations of lycopene and the risk of cancer was studied using the Cox proportional hazard models. RESULTS: An inverse association was observed between serum lycopene and overall cancer incidence. The adjusted risk ratio (RR) in the highest tertile of serum lycopene was 0.55 (95% confidence interval [CI], 0.34-0.89; p=0.015) compared with the lowest serum lycopene group. No association was observed between the lycopene concentrations and a prostate cancer risk. RR for other cancers was 0.43 (95% CI, 0.23-0.79; p=0.007). CONCLUSIONS: These findings suggest that in middle-aged men, the higher circulating concentrations of lycopene may contribute to the lower risk of cancer, with the exception of prostate cancer. PMID- 19443243 TI - Verbal predicates foster conscious recollection but not familiarity of a task irrelevant perceptual feature--an ERP study. AB - Research on the effects of perceptual manipulations on recognition memory has suggested that (a) recollection is selectively influenced by task-relevant information and (b) familiarity can be considered perceptually specific. The present experiment tested divergent assumptions that (a) perceptual features can influence conscious object recollection via verbal code despite being task irrelevant and that (b) perceptual features do not influence object familiarity if study is verbal-conceptual. At study, subjects named objects and their presentation colour; this was followed by an old/new object recognition test. Event-related potentials (ERP) showed that a study-test manipulation of colour impacted selectively on the ERP effect associated with recollection, while a size manipulation showed no effect. It is concluded that (a) verbal predicates generated at study are potent episodic memory agents that modulate recollection even if the recovered feature information is task-irrelevant and (b) commonly found perceptual match effects on familiarity critically depend on perceptual processing at study. PMID- 19443244 TI - The directionality and functional organization of frontoparietal connectivity during consciousness and anesthesia in humans. AB - Frontoparietal connectivity has been suggested to be important in conscious processing and its interruption is thought to be one mechanism of general anesthesia. Data in animals demonstrate that feedforward processing of information may persist during the anesthetized state, while feedback processing is inhibited. We investigated the directionality and functional organization of frontoparietal connectivity in 10 human subjects anesthetized with propofol on two separate occasions. Multichannel electroencephalography and a computational method of assessing directed functional connectivity were employed. We demonstrate that directed feedback connectivity is diminished with loss of consciousness and returns with responsiveness to verbal command. We also applied the Dendrogram classification method to assess the global organization of directed functional connectivity during consciousness and anesthesia. We demonstrate a state-specific hierarchy and subject-specific subhierarchy in functional organization. These data support the hypothesis that specific states of human consciousness are defined by specific states of frontoparietal connectivity. PMID- 19443245 TI - Indian hedgehog supports definitive erythropoiesis. AB - Indian hedgehog (Ihh) has been reported to stimulate haematopoiesis ex vivo. In this study we studied the consequences of loss of function of Ihh for murine haematopoietic development. Ihh has no essential role in primitive erythropoiesis, but it is required in a non cell autonomous fashion for definitive erythropoieisis. Many components of the hedgehog signaling pathway are present in the fetal liver, with Ihh and Gli1 being most highly expressed in the stroma and Ptc1 being most highly expressed in haematopoietic stem and progenitor cells. Ihh knockout HSC and progenitor cell populations are produced in normal numbers in vivo and respond normally to haematopoietic cytokines in vitro, but terminal erythroid differentiation is defective leading to fatal anemia in mid gestation in many Ihh knockout embryos. These loss-of-function studies are consistent with previous gain-of-function studies which show Ihh can induce blood from ectoderm or expand HSCs in stroma-dependent culture. PMID- 19443246 TI - What factors influence the measurement properties of the Roland-Morris disability questionnaire? AB - Although the Roland disability questionnaire (RDQ) is a commonly used questionnaire for patients with low back pain (LBP), several important issues remain understudied. The purposes of this study were to investigate the impact that several parameters (length of test-retest interval, interpretation of the global perceived effect (GPE) scores, methods to estimate standard error of measurement (SEM), intervention and baseline scores) have on various measurement properties, such as agreement (Limits of Agreement (LOA), SEM(agreement)), responsiveness (area under the ROC curve, sensitivity, specificity) and interpretability (optimal cut-off point, Minimal Detectable Change), of the RDQ. RDQ was administered four times to 212 patients with chronic non-specific LBP (first consultation (T-1), eligibility check (T0), randomization/start of treatment (T1) and end of treatment (T2)). They also completed a GPE scale at T2. To study the influence of length of test interval between T-1, T0 and T1, six time intervals were assessed. Analyses of the impact of parameters on responsiveness and interpretability were based on the GPE score and on RDQ score changes (T1 versus T2). Results revealed that agreement parameters decreased with increasing time interval between test-retest. They confirmed the influence of the interpretation of the GPE as well as of the method to calculate the SEM on the magnitude of the Minimal Detectable Change and ROC parameters. Baseline RDQ scores and the way to cluster patients with regard to baseline scores influenced mainly the optimal cut-off point and responsiveness parameters; intervention did not affect the magnitude of the Minimal Detectable Change. PMID- 19443247 TI - Role of RVM neurons in capsaicin-evoked visceral nociception and referred hyperalgesia. AB - Most forms of visceral pain generate intense referred hyperalgesia but the mechanisms of this enhanced visceral hypersensitivity are not known. The on-cells of the rostral ventromedial medulla (RVM) play an important role in descending nociceptive facilitation and can be sensitized to somatic mechanical stimulation following peripheral nerve injury or hindpaw inflammation. Here we have tested the hypothesis that visceral noxious stimulation sensitizes RVM ON-like cells, thus promoting an enhanced descending facilitation that can lead to referred visceral hyperalgesia. Intracolonic capsaicin instillation (ICI) was applied to rats in order to create a hyperalgesic state dependent on noxious visceral stimulation. This instillation produced acute pain-related behaviors and prolonged referred hyperalgesia that were prevented by the RVM microinjection of AP5, an NMDA selective antagonist. In electrophysiological experiments, ON-like RVM neurons showed ongoing spontaneous activity following ICI that lasted for approximately 20 min and an enhanced responsiveness to von Frey and heat stimulation of the hindpaw and to colorectal distention (CRD) that lasted for at least 50 min post capsaicin administration. Moreover, ON-like cells acquired a novel response to CRD and responded to heat stimulation in the innocuous range. OFF-like neurons responded to capsaicin administration with a brief (<5 min) inhibition of activity followed by an enhanced inhibition to noxious stimulation and a novel inhibition to innocuous stimulation (CRD and heat) at early time points (10 min post capsaicin). These results support the hypothesis that noxious visceral stimulation may cause referred hypersensitivity by promoting long lasting sensitization of RVM ON-like cells. PMID- 19443249 TI - [Banking and indications for cord blood grafts]. AB - A cord blood graft is now frequently used in the context of allogeneic hematopoietic transplantation. In 2007, 27% of unrelated allotransplantations performed in France used a cord blood graft. In comparison to other sources of hematopoietic grafts, cord blood has a number of advantages (immediate availability of the graft, possibility of a lesser HLA compatibility between donor and recipient...) and inconveniences (a limited number of stem cells, increased risk of infectious complications...). Recently, the possibility of combining two cord blood grafts has been demonstrated. In 2007, 55% of unrelated cord blood grafts transplantation were performed as such. Results of multicentric studies published as of now, as well as considerable potential associated with cord blood transplantation requires important efforts to increase both the quantity and quality of cord blood grafts made available for transplantation. PMID- 19443250 TI - [The contraindications in blood donation. Impact of the decree of January 12, 2009]. AB - The ministerial decree of 12 January 2009 fixing the criteria for the selection of blood donors establishes the list of contraindications for blood donation according to the appendix to the European directive 2004/33/EC. This text regroups the preexisting guidelines and reinforces their regulatory status, which illustrates the importance attributed to the selection of donors within the dispositions ensuring transfusion safety. It introduces more flexibility with respect to the preexisting criteria taking into account the improvement in life expectancy and the continual increase in transfusion requirements. Thus, the rules for donation authorize up to 24 donations annually and one may give whole blood up to six times per year for men and four times for women, up to the age of 70, the risk of anaemia now being well controlled. The medical rules are more flexible in the areas of haemochromatosis, allergies and autoimmune diseases and for the collection of plasma for fractionation. Some expected changes were not approved in certain cases due to the preeminence of the corresponding criteria in the European directive, like for cured cancers, in other cases in view of an analysis of the available epidemiological data or potential risks like for sexual relations between men and the risks linked to prions or emerging agents (transfusion antecedents). These selection criteria will be revised every year, which should permit their adaptation to the current state of knowledge, although the extent of the revisions will be limited by the updating of the European text on which they are based. PMID- 19443248 TI - A complex between 6-iodolactone and the peroxisome proliferator-activated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer. AB - Recently we and other groups have shown that molecular iodine (I(2)) exhibits potent antiproliferative and apoptotic effects in mammary cancer models. In the human breast cancer cell line MCF-7, I(2) treatment generates iodine-containing lipids similar to 6-iodo-5-hydroxy-eicosatrienoic acid and the 6-iodolactone (6 IL) derivative of arachidonic acid (AA), and it significantly decreases cellular proliferation and induces caspase-dependent apoptosis. Several studies have shown that AA is a natural ligand of the peroxisome proliferator-activated receptors (PPARs), which are nuclear transcription factors thought to participate in regulating cancer cell proliferation. Our results show that in MCF-7 cells: (1) 6 IL binds specifically and with high affinity to PPAR proteins (EMSA assays), (2) 6-IL activates both transfected (by transactivation assays) and endogenous (by lipid accumulation) peroxisome proliferator response elements, and (3) 6-IL supplementation increases PPAR gamma and decreases PPAR alpha expression. These results implicate PPARs in a molecular mechanism by which I(2), through formation of 6-IL, inhibits the growth of human breast cancer cells. PMID- 19443251 TI - [Transfusion of platelet concentrates]. AB - Although a number of research have been realized in the aim to rationalize the use of platelet concentrates, these blood products remain absolutely necessary for patients with therapeutic aplasia and for some surgical patients. We will discuss in this work: the main rules of platelet transfusion procedures, threshold values for platelet transfusion, platelet doses, place of curative and prophylactic strategies, refractoriness to platelet transfusion, HLA immunization. PMID- 19443252 TI - [Evolution of techniques for preparation of labile blood products (LBP): pathogen inactivation in LBP]. AB - The techniques for inactivation of pathogens in labile blood products (LBP) would appear to be the new strategy which will permit us to increase transfusion safety in the face of the risks of transmission of pathogenic agents by LBP. Various methods are in the course of development or already validated and used in France. The latter only apply however to plasma or platelet concentrates. The mechanisms of action and the efficacy of inactivation and attenuation of pathogenic agents vary with the different techniques. Each of these constitutes a preparative procedure composed of unit steps which have to be fully mastered in order to ensure the quality and transfusion efficacy of the treated product. PMID- 19443253 TI - [Platelet immunology and the immune response]. AB - Platelets exert not only hemostatic activities, but also pro-inflammatory effects. Platelet-linked inflammation seems essentially related to their capacity of secreting cytokines, chemokines and related molecules. This activity is important in terms of concentration of secreted products. This secretory function confers to platelets a regulatory role in immunity. Besides, platelets do exhibit non-self infectious danger detection molecules on their surfaces, belonging in particular to the "Toll-like receptor family"; through this property, platelets can bind infectious agents but also deliver differential signals for the secretion of cytokines and chemokines. Platelets, which are non-nucleated cells deprived of nuclear DNA, possess however some cellular machinery which permits intracellular signalling and even the production of RNA transcripts for certain cytokines. Last, platelets express variant surface determinants of hemostatic molecules (referred to as HPA antigens) along with HLA class I variant molecules, the function of which on platelets is still unknown. An intriguing question is to reconcile those diverse properties and to understand whether the pro-inflammatory secretory process can affect the immunogenicity of transfused, allogeneic, platelet components. PMID- 19443254 TI - [Intravenous immunoglobulins in autoimmune and inflammatory disorders: beyond a simple substitution]. AB - Despite their widespread use since many years in autoimmune and inflammatory disorders, the mechanisms of action of IVIg have not been completely understood. These mechanisms depend on Fc and/or F(ab')2. IVIg interacts with the different components of the immune system: Fc receptors, complement, cytokines, T and B lymphocytes, dendritic cells, granulocytes and NK cells. Here, we discuss the recent advances in the understanding of the mechanisms of action of IVIg, in particular the importance of the sialylated Fc fragment. These advances maybe help us conceive better therapeutic strategies against autoimmune and inflammatory disorders. PMID- 19443255 TI - [Cell therapy for acute myocardial infarction]. AB - Despite important progress in cardiology, acute myocardial infarction (AMI) is the major cause of congestive heart failure and subsequent mortality. The rationale for cell therapy to be administered after AMI is derived from the assumption that given the insufficient regeneration in the injured heart tissue, stem cells from the bone marrow may be able to replace or repair damaged vascular and cardiac tissue. Results of the first phase I clinical trials using bone marrow stem/progenitor cell therapy for AMI were published in 2002 to 2004. Although not designed to test the efficacy of the intervention, the initial trials indicated a promising improvement in a number of clinical outcomes and cardiac function and suggested the intervention was safe. Recently, randomized controlled trials of cardiac cell therapy for AMI were published, with mixed results. A meta-analysis including 13 trials with a total of 811 participants showed an improved left ventricular ejection fraction by 2.99%. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy on clinical outcomes. PMID- 19443256 TI - [Understanding the role of the European public institutions in blood transfusion]. AB - In the context of increased demand of blood components, it is highly desirable to ensure development and implementation of established standards for ethical, organisational and regulatory fields in order to guarantee the sufficiency, quality and safety of blood components and their derivatives as well as the protection of donors and recipients. In Europe, the contributions of the European public institutions is fundamental for the achievement of these goals and for the harmonisation of practices inherent to transfusional medicine activities. The Council of Europe with its 47 member states constitutes the ideal platform to tackle these themes: for half a century, its public health and bioethics experts have contributed to the elaboration of conventions and recommendations which serve as a model to elaboration of national or European regulations relevant to this field. PMID- 19443257 TI - [Platelet transfusion: products, indications, dose, threshold and efficacy]. AB - The quality of platelet concentrates had been greatly improved since the implementation of processing techniques based on the use of the buffy-coat in the years 1980. More recently, in the last 10 years, it is in the domain of safety that the greatest advances have been done, by the introduction of platelet additive solutions, on one hand, and by the progressive availability of pathogen reduction techniques, on the other hand. These developments in quality and safety of platelet components are important, as they lead to the conclusion that nowadays, apheresis platelet concentrates and pooled random donor platelet concentrates can be considered as equivalent, the only specific indication of the former being the care of HLA or HPA allo-immunized patients. This review covers the physiological basis of prophylactic and curative platelet transfusions, and the means to evaluate their efficacy. The main investigations that are necessary to perform in the event of an inefficient prophylactic transfusion are also mentioned. Platelet transfusion is an essential part of the transfusion support in case of central thrombocytopenia, and more indications in other medical and surgical situations are well defined. The vast majority of clinical situations in which platelet transfusions are indicated have been defined in the national guidelines published in 2003 by the AFSSAPS French authority, and are still fully valid today. Therefore, only some specific domains for which recent published data are questioning our present practices are discussed, such as the use of platelet concentrates in massive transfusion. Finally, three critical factors for establishing a coherent platelet transfusion strategy are developed: the transfusion trigger for prophylactic platelet transfusion, the platelet dose, and the impact of ABO compatibility between the product and the recipient. PMID- 19443258 TI - [Entrapment of the median nerve after neglected dislocation of the elbow: a case report]. AB - Entrapment of the median nerve is a rare complication following dislocation of the elbow. The authors report a case of incarceration of the median nerve in a neglected dislocation of the elbow in an 18-year-old right-handed boy. The patient sustained a closed injury of the right elbow during a game. The initial treatment was performed by a traditional bonesetter and consisted of attempts at reduction followed by immobilization in extension. There was persistent pain and limitation of movement in the elbow and paraesthesiae in the long finger. This led the patient to consult us at 45 days postinjury. Radiographs showed a posterolateral dislocation of the elbow. Surgical reduction was carried out 6 months posttrauma. After opening of the capsule, we discovered the median nerve blocking the olecranon fossa, passing at the level of the groove of the trochlea where it was wedged between the latter anteriorly and the olecranon posteriorly before resuming its normal course. Reduction was obtained and the nerve replaced in its normal position. The postoperative course was uneventful with disappearance of the paresthesiae and restoration of a good range of movement of the elbow. The authors discuss the mechanism, the clinical forms and propose a new type according to the classification of Fourrier. PMID- 19443259 TI - Irreducible volar dislocation of the proximal interphalangeal finger joint. AB - Volar dislocation of the proximal interphalangeal finger joint is rare. The trauma that causes this injury consists in a rotation mechanism in almost all cases. It may be initially missed and diagnosed at a late sequel stage. Closed reduction should always be attempted first but this procedure may result in failure, necessitating a surgical intervention. In irreducible cases, the surgical investigation shows a longitudinal split which separates one of the lateral bands (ulnar or radial) from the central slip of the terminal extensor tendon. In addition, the lateral band is displaced to the volar aspect of the head of the first phalanx, and partially entrapped into the proximal interphalangeal joint, the head of the first phalanx being trapped between the central slip and the displaced lateral band. Surgical relocation of the displaced lateral band gives an immediate reduction of the dislocated joint. We present a case of irreducible dislocation of the proximal interphalangeal joint of the right index finger in a 42-year-old female patient who required a surgical treatment. We present the diagnostic, anatomic and therapeutic aspects of this rare injury, together with a review of the literature. PMID- 19443260 TI - The association between postural alignment and psychosocial factors to upper quadrant pain in high school students: a prospective study. AB - Prolonged sitting and psychosocial factors have been associated with musculoskeletal symptoms among adolescents. However, the impact of prolonged static sitting on musculoskeletal pain among South African high school students is uncertain. A prospective observational study was performed to determine whether sitting postural alignment and psychosocial factors contribute to the development of upper quadrant musculoskeletal pain (UQMP) in grade ten high school students working on desktop computers. The sitting postural alignment, depression, anxiety and computer use of 104 asymptomatic students were measured at baseline. At three and six months post baseline, the prevalence of UQMP was determined. Twenty-seven students developed UQMP due to seated or computer related activities. An extreme cervical angle (<34.75 degrees or >43.95 degrees; OR 2.8; 95% CI: 1.1-7.3) and a combination of extreme cervical and thoracic angles (<63.1 degrees or >71.1 degrees; OR 2.2; 95% CI: 1.1-5.6) were significant postural risk factors for the development of UQMP. Boys with any extreme angle were more likely to suffer pain compared with boys with all middle range angles (OR 4.9; 95% CI: 1.0-24.5). No similar effect was found for girls. There was no strong relationship between depression, anxiety, computer exposure and UQMP among South African high school students. PMID- 19443261 TI - Effects of posture on the thickness of transversus abdominis in pain-free subjects. AB - The role of transversus abdominis (TrA) on spinal stability may be important in low back pain (LBP). To date, there have not been any investigations into the influence of lumbo-pelvic neutral posture on TrA activity. The present study therefore examines whether posture influences TrA thickness. A normative within subjects single-group study was carried out. Twenty healthy adults were recruited and taught five postures: (1) supine lying; (2) erect sitting (lumbo-pelvic neutral); (3) slouched sitting; (4) erect standing (lumbo-pelvic neutral); (5) sway-back standing. In each position, TrA thickness was measured (as an indirect measure of muscle activity) using ultrasound. In erect standing, TrA (mean TrA thickness: 4.63+/-1.35 mm) was significantly thicker than in sway-back standing (mean TrA thickness: 3.32+/-0.95 mm) (p=00001). Similarly, in erect sitting TrA (mean thickness=4.30 mm+/-1.58 mm) was found to be significantly thicker than in slouched sitting (mean thickness=3.46 mm+/-1.13 mm) (p=0002). In conclusion, lumbo-pelvic neutral postures may have a positive influence on spinal stability compared to equivalent poor postures (slouched sitting and sway-back standing) through the recruitment of TrA. Therefore, posture may be important for rehabilitation in patients with LBP. PMID- 19443262 TI - Defining adverse events in manual therapies: a modified Delphi consensus study. AB - A pragmatic agreed definition of adverse events in manual therapy is required to explore incidence and prevalence. We aimed to identify and describe such adverse events and seek a consensus definition. A focus group identified issues surrounding the definition of adverse events and generated the content for a questionnaire. This questionnaire was used to conduct a modified Delphi consensus survey with an expert panel (n=50). Consensus was defined as >74% agreement. Three consensus rounds were executed. There was a 50% response rate for round one, 62% for round two and 55% for round three. A layered pragmatic definition was agreed: 'Major' adverse events are medium to long term, moderate to severe and unacceptable, they normally require further treatment and are serious and distressing; 'Moderate' adverse events are as 'major' adverse events but only moderate in severity; and 'Mild' and 'not adverse' adverse events are short term and mild, non-serious, the patient's function remains intact, and they are transient/reversible; no treatment alterations are required because the consequences are short term and contained. We concluded that classifying adverse events was difficult without context or detail. Classification may be improved by using the taxonomy and descriptions suggested in this study. PMID- 19443263 TI - Annual conference letter. PMID- 19443264 TI - Proton pump inhibitors: actions and reactions. AB - Proton pump inhibitors are the second most commonly prescribed drug class in the United States. The increased utilization of PPIs parallels the rising incidence of reflux disease. Owing to their clinical efficacy and relative lack of tachyphylaxis, PPIs have largely displaced H-2 receptor antagonists in the treatment of acid peptic disorders. The elevation of intragastric pH and subsequent alterations of gastric physiology induced by PPIs may yield undesired effects within the upper GI tract. The ubiquity of the various types of H(+), K(+)-ATPase could also contribute to non-gastric effects. PPIs may influence physiology in other ways, such as inducing transepithelial leak. PMID- 19443265 TI - Transforming fragments into candidates: small becomes big in medicinal chemistry. AB - Fragment-based drug discovery (FBDD) represents a logical and efficient approach to lead discovery and optimisation. It can draw on structural, biophysical and biochemical data, incorporating a wide range of inputs, from precise mode-of binding information on specific fragments to wider ranging pharmacophoric screening surveys using traditional HTS approaches. It is truly an enabling technology for the imaginative medicinal chemist. In this review, we analyse a representative set of 23 published FBDD studies that describe how low molecular weight fragments are being identified and efficiently transformed into higher molecular weight drug candidates. FBDD is now becoming warmly endorsed by industry as well as academia and the focus on small interacting molecules is making a big scientific impact. PMID- 19443266 TI - The multifaceted role of ABA in disease resistance. AB - Long known only for its role in abiotic stress tolerance, recent evidence shows that abscisic acid (ABA) also has a prominent role in biotic stress. Although it acts as a negative regulator of disease resistance, ABA can also promote plant defense and is involved in a complicated network of synergistic and antagonistic interactions. Its role in disease resistance depends on the type of pathogen, its specific way of entering the host and, hence, the timing of the defense response and the type of affected plant tissue. Here, we discuss the controversial evidence pointing to either a repression or a promotion of resistance by ABA. Furthermore, we propose a model in which both possibilities are integrated. PMID- 19443267 TI - Ocular vestibular-evoked myogenic potentials in children using air conducted sound stimulation. AB - OBJECTIVE: This study compared ocular vestibular-evoked myogenic potentials (oVEMPs) in children and adults using air conducted sound stimulation to determine when oVEMP characteristic parameters in children reach adult levels. The relationships between oVEMP characteristics and structural factors were also investigated. METHODS: In total, 15 healthy children (aged 3-13 years) and 15 healthy adults (aged 24-33 years) underwent a combined oVEMP and cVEMP test under 105 dBnHL acoustic stimulation. RESULTS: Mean nI latency, pI latency, nI-pI interval and amplitude of oVEMPs of children did not differ significantly from those of adults. In contrast to oVEMPs, a significant difference in p13 cVEMP latency existed between children and adults. Correlating the structural factors with the characteristic parameters of oVEMPs did not show significant relationship. However, p13 and n23 latencies of cVEMPs in children were significantly related to the age, head girth, body height and body weight. CONCLUSIONS: The non-invasive oVEMP test can quantitatively measure the vestibulo ocular reflex (VOR) system, which has similar characteristic parameters in children aged >3 years and adults. For children aged <3 years, modified methodologies for testing oVEMPs are warranted. SIGNIFICANCE: The oVEMP test may serve as an effective diagnostic tool for evaluating the integrity of the VOR system for those >3 years old. PMID- 19443268 TI - Physical activity in young people-assessment and methodological issues. PMID- 19443269 TI - Vertical jump in female and male basketball players--a review of observational and experimental studies. AB - The main purpose of this article was to review a series of studies (n=26; 15 observational and 11 experimental) examining vertical jump (VJ) performances in female and male basketball players. Information on the tests used in these studies and their specific protocols, and the training programs conducted to improve VJ ability in elite basketball players, was assessed. It was found that vertical jump values varied greatly, from 22 to 48 cm in female players and from 40 to 75 cm in male players. These large variations can be explained mostly by the differences in testing protocols (each VJ protocol examined different physiological pathways) and skill level of players. The variations in VJ values among studies were greatly reduced when they used the same protocol. In addition, short plyometric training sessions as part of the strength and conditioning program were found to enhance VJ performances in basketball players. Based on the reviewed studies, five limitations associated with the testing protocols and the strength and conditioning programs used in the studies were outlined, among them the use of multiple testing protocols and lack of experimental studies. Three recommendations for basketball and strength and conditioning coaches were suggested, for one of which was including plyometric training in the annual training program. PMID- 19443270 TI - From purified GPCRs to drug discovery: the promise of protein-based methodologies. AB - G-protein-coupled receptors (GPCRs), the largest family of membrane proteins, represent ideal therapeutic targets for a number of disorders and diseases. Besides cell-based assays and high throughput screening (HTS), and thanks to the availability of milligram quantities of active purified receptors, protein-based approaches focusing on soluble GPCRs are growingly being used in this drug discovery effort. Along with the exploitation of GPCRs structures, innovative biochemical and biophysical approaches open up new routes for improving the knowledge of structure-activity relationships, for the identification of novel interacting partners and for the determination of receptor behaviour in different model environments. This review summarizes the state-of-the-art methodologies that robustly allow for the production and purification of soluble and active GPCRs, as well as the main outcomes that have been recently gained in GPCR biology using a panel of such protein-based approaches. PMID- 19443271 TI - Complex interactions in the regulation of trypanosome mitochondrial gene expression. AB - Trypanosomes undergo extreme physiological changes to adapt to different environments as they cycle between hosts. Adaptation to the different environments has evolved an energy metabolism involving a mitochondrion with an unusual genome. Recently, Aphasizhev and colleagues have identified two new protein complexes, a mitochondrial polyadenylation complex and a guide RNA stabilization complex, that provide novel insights into the coordinated expression of the mitochondrial genome. PMID- 19443272 TI - Feasibility of a computerized male urethral catheterization simulator. AB - Catheterization of the male urethra might cause harm and discomfort for the patient. Computer-based simulator training might improve the skills of students as well as professional nurses. This study aims to study the feasibility of a new portable computer-based male urethral catheterization simulator, Urecath (Melerit Urecath Vision). The simulator consists of three software modules: teaching (explains the different procedures in the catheterization), learning (game settings with practice and self-assessments tests), and simulator module that is connected to a box with a model of a penis where syringes and the urinary catheter can be inserted. Registered nurses (n=23), nurse assistants (n=14), nurse students (n=12), and a nurse assistant student (n=1) participated in a simulation session and answered 30 questions about the feasibility of the simulator. The participants appreciated the different modules, particularly the teaching and learning modules. The simulator module was appreciated for its cross sectional views and feedback but was found to lack a tactile component; there was too little and no varying resistance when inserting the catheter. The participants perceived the present prototype of Urecath as a valuable education tool. The male urethral catheterization simulator prototype Urecath has advantages in its present shape but to be an alternative to existing training options for practicing male urethral catheterization, it should be complemented with a tactile mode and degrees of difficulty. PMID- 19443273 TI - Commentary to "One-stage repair of severe hypospadias using modified tubularized transverse preputial island flap with V-incision suture by K. Aoki, K. Fujimoto, K. Yoshida, Y. Hirao, K. Ueoka, J Pediatr Urol 2008;4:438-441". PMID- 19443274 TI - Pediatric renal cell carcinoma. AB - Renal cell carcinoma (RCC) comprises about 5% of pediatric renal neoplasms. It has been recognized as a second malignancy in multiple reports. It is generally symptomatic at diagnosis, and most children with RCC present with more locally advanced disease than do adults. Contemporary investigation of pediatric RCC has demonstrated that a large percentage of these tumors bear cytogenetic translocations involving the MiT family of transcription factors. Surgical therapy for these children resembles operative intervention for adult RCC, though debate continues about the precise role of lymph node dissection. There are no adequately powered studies to support conclusions about adjuvant or neoadjuvant chemotherapy for children with RCC. This may be ameliorated by a multi institutional protocol which is enrolling patients. PMID- 19443275 TI - IFNbeta therapy progressively normalizes the increased ex vivo T lymphocyte apoptosis observed in active patients with multiple sclerosis. AB - Abnormal apoptosis has been reported in circulating T lymphocytes in patients with multiple sclerosis. The effects of 12 months of IFNbeta treatment in T and B lymphocyte spontaneous ex vivo apoptosis were studied in patients with MS. Peripheral blood mononuclear cells were obtained from 48 patients before and at 1, 6 and 12 months after treatment with IFNbeta. Spontaneous ex vivo apoptosis was quantified by four-color flow cytometry. A significant reduction and normalization of the percentage of apoptotic cells was found in all T lymphocyte subsets. B cell apoptosis values were unaffected by therapy; Relapses of the clinical activity of the disease were associated to transitory upturns of lymphocyte apoptosis. In conclusion, IFNbeta therapy progressively normalizes the increased ex vivo T lymphocyte apoptosis observed in MS. However, it is not clear if this reduction in spontaneous T lymphocyte apoptosis is due to direct effect of IFNbeta or secondary to decreased clinical and sub-clinical activity. PMID- 19443277 TI - Crosstalk between peroxisome proliferator-activated receptor-gamma and angiotensin II in renal tubular epithelial cells in IgA nephropathy. AB - Our recent study suggested that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist attenuates inflammatory response in activated tubular epithelial cells in IgA nephropathy (IgAN). Here, we explore thiazolidinediones as new therapeutic additives to established treatment regime of renin angiotensin blockade in IgAN. Human proximal tubular epithelial cells (PTEC) were pretreated with PPAR-gamma agonist, rosiglitazone, and/or angiotensin II (AngII) type 1 receptor (ATR1) blocker (ARB), losartan, followed by activation with the conditioned medium collected from human mesangial cells incubated with pIgA1 (IgA HMC) from patients with IgAN. IgA-HMC conditioned medium up-regulated expression of ICAM-1, IL-6 and ATR1 and activated NF-kappaB and ERK1/2 in PTEC. Dual treatment of rosiglitazone and losartan provided synergistic effect in reducing ICAM-1, IL-6 and ATR1 expression and NF-kappaB and ERK1/2 activation induced by the conditioned media when compared with monotherapy. Our data suggest that rosiglitazone trans-represses AngII signaling and may offer additional potential when combined with ARB in treating IgAN. PMID- 19443276 TI - Treatment of patients with new onset Type 1 diabetes with a single course of anti CD3 mAb Teplizumab preserves insulin production for up to 5 years. AB - Anti-CD3 mAbs may prolong beta cell function up to 2 years in patients with new onset Type 1 diabetes (T1DM). A randomized open label trial of anti-CD3 mAb, Teplizumab, in T1DM was stopped after 10 subjects because of increased adverse events than in a previous trial related with higher dosing of drug. Teplizumab caused transient reduction in circulating T cells, but the recovered cells were not new thymic emigrants because T cell receptor excision circles were not increased. There was a trend for reduced loss of C-peptide over 2 years with drug treatment (p=0.1), and insulin use was lower (p<0.001). In 4 drug-treated subjects followed up to 60 months, C-peptide responses were maintained. We conclude that increased doses of Teplizumab are associated with greater adverse events without improved efficacy. The drug may marginate rather than deplete T cells. C-peptide levels may remain detectable up to 5 years after treatment. PMID- 19443278 TI - Nitric oxide synthesis blockade reduced the baroreflex sensitivity in trained rats. AB - OBJECTIVE: The present study has investigated the effect of blockade of nitric oxide synthesis on cardiovascular autonomic adaptations induced by aerobic physical training using different approaches: 1) double blockade with methylatropine and propranolol; 2) systolic arterial pressure (SAP) and heart rate variability (HRV) by means of spectral analysis; and 3) baroreflex sensitivity. METHODS: Male Wistar rats were divided into four groups: sedentary rats (SR); sedentary rats treated with N(omega)-nitro-l-arginine methyl ester (L NAME) for one week (SRL); rats trained for eight weeks (TR); and rats trained for eight weeks and treated with L-NAME in the last week (TRL). RESULTS: Hypertension and tachycardia were observed in SRL group. Previous physical training attenuated the hypertension in L-NAME-treated rats. Bradycardia was seen in TR and TRL groups, although such a condition was more prominent in the latter. All trained rats had lower intrinsic heart rates. Pharmacological evaluation of cardiac autonomic tonus showed sympathetic predominance in SRL group, differently than other groups. Spectral analysis of HRV showed smaller low frequency oscillations (LF: 0.2-0.75 Hz) in SRL group compared to other groups. Rats treated with L-NAME presented greater LF oscillations in the SAP compared to non-treated rats, but oscillations were found to be smaller in TRL group. Nitric oxide synthesis inhibition with L-NAME reduced the baroreflex sensitivity in sedentary and trained animals. CONCLUSION: Our results showed that nitric oxide synthesis blockade impaired the cardiovascular autonomic adaptations induced by previous aerobic physical training in rats that might be, at least in part, ascribed to a decreased baroreflex sensitivity. PMID- 19443279 TI - Evidence against a role of ketone bodies in the generation of oxidative stress in human erythrocytes by the application of reliable methods for thiol redox form detection. AB - Aim of this study was to reconsider the previously suggested contribution of ketone bodies in causing oxidative damage in human red blood cells (RBCs) in the light of our recent findings demonstrating some methodological pitfalls that can occur during detection of hematic thiols. RBCs were incubated at 37 degrees C with 20mM ketone bodies and analyzed with time for their content of glutathione, glutathione disulfide and S-glutathionylated proteins (in both the hemoglobin and membrane skeletal protein fraction). No changes in the concentrations of glutathione and its related forms were evidenced. Differently from previous reports, our results suggest that ketone bodies do not mediate generation of oxidative stress in human RBCs. PMID- 19443280 TI - [Cholestasis associated with prolonged parenteral nutrition in neonates: the role of urso-deoxycholic acid]. AB - INTRODUCTION: The morbidity associated with prematurity occasionally leads to the use of prolonged parenteral nutrition, with the subsequent development of cholestasis being one of its complications. PATIENTS AND METHODS: This is a two year retrospective study which compared biochemical markers of liver damage and cholestasis in premature babies who received or did not receive urso-deoxycholic acid for parenteral nutrition associated cholestasis. RESULTS: Of a total of 24 recruited patients 17 received urso-deoxycholic acid and 7 did not. In the treated group significant decreases (P<0.05) in gamma-glutamyltranspeptidase and conjugated bilirubin were found after four and five weeks of treatment, respectively. Moreover, a significant correlation (P<0.01) between conjugated bilirubin and duration of total parenteral nutrition was established. CONCLUSIONS: Patients who were promptly treated with urso-deoxycholic acid showed a more rapid decrease in biochemical markers of cholestasis, but not of cytotoxicity in the hepatobiliary complications secondary to prolonged parenteral nutrition. However, the present study has limitations derived from its design and therefore it would be desirable launch a randomized trial with sufficient power to evaluate the benefits derived from prophylactic or therapeutic use of urso deoxycholic acid in the hepatobiliary conditions associated with the prolonged use of parenteral nutrition in the premature infants. PMID- 19443281 TI - Preference for attractiveness and thinness in a partner: influence of internalization of the thin ideal and shape/weight dissatisfaction in heterosexual women, heterosexual men, lesbians, and gay men. AB - This study assesses whether characteristics of one's own body image influences preferences of attractiveness in a partner. The role of gender and sexual orientation is also considered. Heterosexual women (n=67), lesbian women (n=73), heterosexual men (n=61) and gay men (n=82) participated in an internet survey assessing attitudes towards the body and preferences of attractiveness in a partner. Men in particular were found to prefer attractive partners, regardless of sexual orientation. Weight/shape dissatisfaction was found to be a negative predictor for heterosexual men and women. For gay men, preferences were better explained by internalization and weight/shape dissatisfaction. No such associations were found in the lesbian group. Levels of weight/shape dissatisfaction and internalization of socio-cultural slenderness ideals influence expectations of thinness and attractiveness in a partner with this effect being modified by gender and sexual orientation. PMID- 19443282 TI - Use of macroporous gelatine spheres as a biodegradable scaffold for guided tissue regeneration of healthy dermis in humans: an in vivo study. AB - If a biodegradable scaffold is applied, the dermis can be regenerated by guided tissue regeneration. Scaffolds can stimulate in-growth of cells from the surroundings that migrate into them and start to produce autologous extracellular matrix as the scaffold is degraded. Several materials are available, but most of them are in the form of sheets and need to be laid on an open wound surface. A number of injectable fillers have been developed to correct soft-tissue defects. However, none of these has been used for guided tissue regeneration. We present a new technique that could possibly be used to correct dermal defects by using macroporous gelatine spheres as a biodegradable scaffold for guided tissue regeneration. In eight healthy volunteers, intradermal injections of macroporous gelatine spheres were compared with injections of saline and hyaluronic acid (Restylane). Full-thickness skin biopsy specimens of the implants and surrounding tissue were removed 2, 8, 12 and 26 weeks after injection, and the (immuno)histological results were analysed. The Restylane merely occupied space. It shattered the dermal tissue and compressed collagen fibres and cells at the interface between the implant and the dermis. No regeneration of tissue was found with this material at any time. The macroporous gelatine spheres were populated with fibroblasts already after 2 weeks. After 8 weeks the spheres were completely populated by fibroblasts producing dermal tissue. After 12 and 26 weeks, the gelatine spheres had been more or less completely resorbed and replaced by vascularised neodermis. There were no signs of capsular formation, rejection or adverse events in any subject. Further in vivo studies in humans are needed to evaluate the effect of the macroporous spheres fully as a matrix for guided tissue regeneration with and without cellular pre-seeding. However, the results of this study indicate the possibility of using macroporous gelatine spheres as an injectable, three-dimensional, degradable matrix for guided tissue regeneration. PMID- 19443283 TI - Cool it!!--the judicious use of liquid nitrogen for viral warts is important. PMID- 19443284 TI - The serratus anterior free flap revisited. PMID- 19443285 TI - Infant feeding in the first 12 weeks following birth: a comparison of patterns seen in Asian and non-Asian women in Australia. AB - BACKGROUND: There is a belief amongst midwives that Asian women are less likely to breastfeed compared to non-Asian women. The aim of this research was to compare the infant feeding decisions of Asian and non-Asian women on discharge from two Sydney hospitals, and at 6 and 12 weeks following birth. PARTICIPANTS: 235 Asian and 462 non-Asian first time mothers. METHODS: A secondary analysis was undertaken into data from a randomised clinical trial of a perineal management technique (perineal warm packs). Simple descriptive statistics were used for analysis and Chi-square and logistic regression was used to examine differences between women from Asian and non-Asian backgrounds. RESULTS: Compared with non Asian women, Asian women were no less likely to exclusively breastfeed on discharge from hospital (83% vs. 87%, OR 0.7, 95% CI 0.4-1.2), at 6 weeks (60% vs. 61%, OR 1, 95% CI 0.7-1.4) or 12 weeks postpartum (51% vs. 56%, OR 0.8, 95% CI 0.6-1.2). They were, however, significantly more likely to be partially breastfeeding on discharge from hospital (10% vs. 2%, OR 5.3, 95% CI 2.3-12.4), at 6 weeks (22% vs. 11%, OR 1.9, 95% CI 1.2-3.2) and 12 weeks postpartum (17% vs. 8%, OR 2.2, 95% CI 1.2-3.9). DISCUSSION: Asian women were more likely than non Asian women to be giving their baby some breast milk at 6 and 12 weeks postpartum when partial breastfeeding was taken into account. This contradicts popular beliefs amongst midwives regarding the infant feeding practices of Asian women. CONCLUSION: Further research into this important issue is needed in order to improve breastfeeding support for women from different cultural backgrounds. The issue of causes of, and variations in, the levels of partial breastfeeding between different ethnic groups needs more investigation. PMID- 19443286 TI - Total hip arthroplasty for osteoarthritis in patients aged 80 years or older: influence of co-morbidities on final outcome. AB - BACKGROUND: In osteoarthritic patients aged 80 years or older, total hip arthroplasty (THA) offers well-established benefits; however this selective group of population is known to carry a high morbidity rate. HYPOTHESIS: The higher morbidity rate carried by this group does benefit more from identification of risk factors than from improved surgical and anesthesia techniques. MATERIALS AND METHODS: Seventy-two patients, operated between October 2003 and December 2006, were retrospectively analyzed. The interventions performed on the traction table, through an anterior approach, involved implantation of a cemented total prosthesis combined to a retentive, cemented acetabular component. RESULTS: At an average delay of 31 months (minimum 5 months, maximum 54 months), no patient was lost to follow-up and no prosthesis had to be revised. In total, 19 patients presented 27 complications, which were not influenced by their American Society of Anesthesiology (ASA) score (p>0.1) nor by the presence of co-morbidities (p>0.5). No perioperative deaths or infection occurred. Twenty-eight patients required blood products transfusion. ASA score (p<0.03) and body mass index<25 (p=0.01) appeared to be risk factors for transfusion. Seventeen patients were pain-free and walked without restriction, and 19 had a Merle d'Aubigne score under 15. We noted two isolated dislocations (2.6%). Eleven patients were hindered in their walking ability by an associated orthopaedic condition and five by unrelated medical problems. Although preoperative ASA score did not seem to be of predictive value to the quality of surgical outcome (p>0.5), the occurrence of an associated orthopaedic condition (p<0.001) and, even more the patient's categorization in Charnley class B or C (p<0.001) strongly correlated to this outcome quality. DISCUSSION: While THA for the treatment of osteoarthritis in patients older than 80 years exposed them to a complication rate of 27%, no specific risk factor was identified. Other neuro-orthopaedic disorders hampered the quality of the functional outcome. The use of a retentive cup could not eliminate the occurrence of two dislocations (2.6%). LEVEL OF EVIDENCE IV: retrospective therapeutic study. PMID- 19443287 TI - Long-term outcome of the shaken baby syndrome and medicolegal consequences: a case report. AB - INTRODUCTION: Studies of long-term outcome of the shaken baby syndrome (SBS) are scarce, but they usually indicate poor outcome. OBJECTIVES: To describe long-term outcome of a child having sustained a SBS, to ascertain possible delayed sequelae and to discuss medicolegal issues. METHODS: We report a single case study of a child having sustained a SBS, illustrating the initial clinical features, the neurological, cognitive and behavioural outcomes as well as her social integration. RESULTS: The child sustained diffuse brain injuries, responsible for spastic right hemiplegia leading to secondary orthopaedic consequences, as well as severe cognitive impairment, worsening over time: the developmental quotient measured at 15 months of age was 55 and worsened as age increased. At 6 years and 8 months, the child's IQ had fallen to 40. Behavioural disorders became apparent only after several months and precluded any social integration. The child eventually had to be placed in a specialised education centre at age 5. DISCUSSION AND CONCLUSION: The SBS has a very poor outcome and major long standing sequelae are frequent. Cognitive or behavioural sequelae can become apparent only after a long sign-free interval, due to increasing demands placed on the child during development. This case report confirms severity of early brain lesions and necessity for an extended follow-up by a multi-disciplinary team. From a medicolegal point of view, signaling the child to legal authorities allows protection of the child, but also conditions later compensation if sequelae compromise autonomy. PMID- 19443288 TI - Novel treatments for men with lower urinary tract symptoms suggestive of benign prostate hyperplasia. PMID- 19443289 TI - The clinical implications of blood adiponectin in cardiometabolic disorders. AB - Adipose tissue is now accepted by the scientific and medical community to be a genuine endocrine organ, in addition to its classical role as an energy store. Adiponectin is one of the many adipocytokines that are secreted almost exclusively by adipose tissue. Alteration in blood adiponectin concentrations has been linked to many human diseases in numerous cross-sectional and prospective studies. In this review, we describe briefly the biological effects of adiponectin as revealed by basic scientific investigations. We also summarize the principles of blood adiponectin assays. Overall, lower blood adiponectin concentration is found in subjects with obesity, type 2 diabetes mellitus, dyslipidemia, and hypertension. These medical conditions are components of the metabolic syndrome and major risk factors for accelerated atherosclerosis. Plasma adiponectin levels are also expected to be lower in subjects with cardiovascular diseases, such as coronary artery disease, ischemic stroke and peripheral artery disease. Congestive heart failure (CHF) and cardiac arrhythmia are common end points in cardiovascular diseases. Surprisingly, higher blood adiponectin levels are frequently reported to predict mortality associated with CHF. Few human data regarding adiponectin and cardiac arrhythmia are available. Higher blood adiponectin level has been documented only in atrial fibrillation. We also summarize data on the role of the high molecular weight (HMW) isoforms of adiponectin and the effects of clinical treatment on the levels of total or HMW adiponectin. Whether adiponectin is a risk marker or a risk factor for the diseases reviewed in this article, and in many other human diseases, and their detailed pathogenic links awaits further investigation. PMID- 19443290 TI - Epidemiology of acute q Fever, scrub typhus, and murine typhus, and identification of their clinical characteristics compared to patients with acute febrile illness in southern taiwan. AB - BACKGROUND/PURPOSE: In Taiwan, acute Q fever, scrub typhus, and murine typhus (QSM diseases) are the most common rickettsioses, but their epidemiology and clinical characteristics have not been clarified. Diagnosis of these three diseases based on clinical manifestations is difficult, and most of their reported characteristics are identified by describing the predominant manifestations, without being compared with other diseases. METHODS: Serological tests for QSM diseases were examined simultaneously in patients suspected of the three diseases, regardless of which one was suspected. Clinical manifestations were recorded retrospectively from their charts. The characteristics of QSM diseases were identified by comparison with patients who had non-QSM diseases. RESULTS: From April 2004 to April 2007, a total of 226 cases of suspected QSM diseases were included. One hundred (44.2%) cases were serologically confirmed as QSM diseases (68 acute Q fever, 23 scrub typhus, and 9 murine typhus), and 126 (55.8%) cases were non-QSM diseases. Only 33 cases (33.0%) of QSM diseases were initially suspected at the time of hospital visit, whereas 54 cases (42.9%) of non-QSM diseases were incorrectly suspected as QSM diseases. Cases of Q fever and scrub typhus were distributed over plain and mountain areas, respectively. By multivariate analysis, relative bradycardia (OR [95% CI], 2.885 [1.3-6.4]; p = 0.009), radiographic hepatomegaly (OR [95% CI], 4.454 [1.6-12.3]; p = 0.004), and elevated serum aminotransferases (OR [95% CI], 5.218 [1.2-23.1]; p = 0.029) were independent characteristics for QSM diseases, and leukocytosis (OR [95% CI], 0.167 [0.052-0.534]; p = 0.003) was negative for the diagnosis of QSM diseases. CONCLUSION: In southern Taiwan, acute Q fever is the most common rickettsiosis. QSM diseases should be suspected in febrile patients who present with relative bradycardia, hepatomegaly, and elevated serum aminotransferases, but without leukocytosis. PMID- 19443291 TI - Assessment of changes in knowledge and stigmatization following tuberculosis training workshops in taiwan. AB - BACKGROUND/PURPOSE: There is little understanding of the depth of knowledge of health workers involved in tuberculosis (TB) control programs, and even less is known about health workers attaching stigma to TB patients. This study surveyed health workers enrolled in TB training workshops prior to the execution of the directly observed treatment, short course (DOTS) program. METHODS: All participants attended the training course and completed structured questionnaires before (pre-test) and after training (post-test). The questionnaires were collected immediately following completion and the scores were analyzed. RESULTS: Pair comparison of knowledge scores revealed that all participants made statistically significant improvements in level of TB knowledge, except those who had a history of TB (p = 0.331). Pair comparison of stigmatization scores revealed a reduction in stigmatization, with the DOTS workers attaching less stigma to TB patients. After training, caregivers, including women (p = 0.012), public health workers (p = 0.028), 40-49-year-old subjects (p = 0.035), those with an education of < 12 years (p = 0.024), those who had been a volunteer (p = 0.018), and those who had a history of TB and those who did not (p = 0.034, p = 0.036), were significantly less likely to stigmatize patients. TB knowledge was not found to be significantly correlated with stigmatization (pre-test, p = 0.298; post-test, p = 0.821). CONCLUSION: Training workshops in TB control were effective for promotion of knowledge and elimination of stigmatization in first line caregivers. DOTS workers attached less stigma to TB patients than public health workers, and older workers who had been volunteers attached the least stigma. PMID- 19443292 TI - Hospitalization for ambulatory-care-sensitive conditions in Taiwan following the SARS outbreak: a population-based interrupted time series study. AB - BACKGROUND/PURPOSE: In 2003, the severe acute respiratory syndrome (SARS) outbreak resulted in 8096 probable cases and 774 deaths in 26 countries. The purpose of this study was to explore the effect of the SARS outbreak on hospitalization for chronic ambulatory-care-sensitive conditions (ACSCs) in Taiwan. METHODS: We applied a population-based interrupted time series study design and used the time series auto-regressive integrated moving-average model to compare the actual and predicted admission rates of seven selected chronic ACSCs. The analyses were based on National Health Insurance hospital inpatient claims data from 1997 to 2003. RESULTS: The impact of SARS on ACSCs after the outbreak varied among seven selected chronic conditions. Hospitalization for respiratory conditions was significantly lower than the predicted values, whereas hospitalization for diabetes was significantly higher than the predicted values after the outbreak. CONCLUSION: Admission rates for most ACSCs, except for diabetes, did not change in the post-SARS period. The reductions in outpatient utilization during the SARS outbreak did not appear to affect adversely admissions for most ACSCs. PMID- 19443293 TI - Decline of tetanus antitoxin level with age in taiwan. AB - BACKGROUND/PURPOSE: Tetanus is caused by Clostridium tetani, and is a vaccine preventable infectious disease. The purpose of this study was to investigate the degree of protective tetanus immunity among adolescents and adults in Taiwan, which may provide valuable information for recommendations for tetanus vaccination strategy. METHODS: Individuals aged 16 years or older who were visiting a local hospital for health examinations were invited to participate in the study. Participants' serum levels of tetanus antitoxin were measured. A standard questionnaire was used to collect demographic data and information about risk factors. The prevalence of protective tetanus immunity in various age groups was described and sociodemographic factors that potentially influenced the degree of tetanus immunity were analyzed. RESULTS: Overall, 326 persons were included. Of these, 217 (67%) had never received a toxoid booster, while 109 (33%) had received a booster at least once. Among all participants, 95% had protective tetanus antitoxin levels (> or = 0.11 IU/mL), and 60% had protective antitoxin levels without the need of an immediate booster, i.e. > or = 0.51 IU/mL. Among 70 participants aged > 60 years, 89% had protective antitoxin levels > or = 0.11 IU/mL, and 31% had protective antitoxin levels > or = 0.51 IU/mL. Tetanus antitoxin levels declined with age. Male gender, birth after 1955, and prior receipt of toxoid booster(s) were independently associated with protective tetanus immunity (> or = 0.51 IU/mL) by multivariate analysis. Compared with those without tetanus toxoid boosters, individuals with a prior booster had higher antitoxin levels. The percentage of people with protective immunity declined if the interval between the last toxoid booster increased. CONCLUSION: Waning immunity to tetanus was observed after primary tetanus vaccination or toxoid booster. The public health policy that one dose of toxoid booster after primary vaccination should be emphasized for continuing protection against tetanus. PMID- 19443294 TI - Mutational spectrum of multiple endocrine neoplasia type 2 and sporadic medullary thyroid carcinoma in taiwan. AB - BACKGROUND/PURPOSE: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer predisposition syndrome, and > 95% of MEN 2 patients carry rearranged during transfection (RET) protooncogene mutants. We aimed to elucidate the genotype and phenotype relationship of RET proto-oncogene mutations in Taiwanese subjects with medullary thyroid cancer (MTC). METHODS: We genotyped the MEN-2-associated germ-line mutations by PCR-based sequencing of the RET gene. DNA was extracted from a total of 69 members from eight unrelated families with individuals affected by MTC, and from seven sporadic cases of MTC. RESULTS: RET mutations were found in four MEN 2A families, all at codon 634 (one with C>R, two with C>F, and one with C>W). One MEN 2A patient carried a de novo mutation at codon 634 (C>R). In two families of MEN 2B, all carried the mutation at codon 918 (M>T). These two cases of MEN 2B were all de novo mutations. One family of familial MTC or unclassified MEN 2 carried the codon 620 (C>F) mutation. Among the seven sporadic cases of MTC, none was found to carry any mutation in hotspot exons. Only two non-synonymous variants (T278N/exon 4 and D489N/exon 7) were found in two cases. However, these two variants were not uncommon in our elderly population. CONCLUSION: We found that all eight MTC patients with a family history or with the other phenotypes of MEN 2 had RET mutations, whereas no significant RET mutation was found in seven patients with isolated MTC without family history and other endocrine diseases. Molecular scanning of the RET gene in MEN 2 and MTC in Taiwanese patients probably should be limited to exons 10, 11 and 16, initially to be cost-effective. PMID- 19443295 TI - Unsuspected prostate cancer after cystoprostatectomy: a comparison between two periods in taiwan. AB - BACKGROUND/PURPOSE: The incidence of and mortality rate from prostate cancer have been rising rapidly in Taiwan in recent years. Prostate specimens obtained during cystoprostatectomy may play a role in the study of prostate cancer evolution. METHODS: From January 2001 to December 2005, we collected and examined retrospectively 65 prostate specimens obtained from patients during cystoprostatectomy performed for various conditions. Fourteen patients (21%) had evidence of prostate cancer and 11 (17%) had high-grade prostatic intraepithelial neoplasia. RESULTS: We compared our results with those of a previous study conducted at the same institute from 1992 to 1997. There was no statistical difference between the two groups in unsuspected prostate cancer prevalence (p = 0.263), but the prevalence declined from 32.7% to 21.5%. CONCLUSION: The results imply that the epidemiological decline in unsuspected prostate cancer in central Taiwan may be associated with the wide application of testing for prostatic specific antigen. PMID- 19443296 TI - Changing quality of life in hysterectomized women. AB - BACKGROUND/PURPOSE: Most women undergo a hysterectomy to relieve symptoms and improve their quality of life rather than to solve a life-threatening problem. We used hierarchical linear modeling to evaluate the changes, in a 6-8-week period, in the quality of life of women who had undergone hysterectomy. METHODS: This was a prospective follow-up study of 64 women who had undergone hysterectomy and 68 controls of similar age and marital status. A quasi-experimental design was used. The World Health Organization Questionnaire on Quality of Life: BREF-Taiwan Version was used to assess quality of life before surgery, at discharge, and 2 and then 6-8 weeks after surgery. The control group was measured three times: after their initial hospital visit, and 2 and then 6-8 weeks later. RESULTS: Women with hysterectomy (H-group) had significantly lower scores for the physical health dimension of quality of life at all time-points as compared with the control group, yet postoperatively, they showed a more dramatic increase in this dimension. As for the group mean trajectories, the vaginal hysterectomy (VH) subgroup had a relatively low quality of life immediately after surgery, which then gradually improved, especially in the dimension of physical health. As for the social relationships dimension, the abdominal hysterectomy (AH) subgroup showed an upward curve similar to the pattern of their physical health dimension. The psychological and environmental dimensions did not show a clear trajectory for either group. As for individual trajectories, the social relationships and environmental dimensions showed different patterns for women with hysterectomy. CONCLUSION: Hysterectomy can improve physical health. In the VH subgroup, physical health was improved significantly, especially from 6-8 weeks postoperatively. In the AH subgroup, physical health and social relationships were improved significantly postoperatively. Social relationships and environmental dimensions tended to show different patterns for women with hysterectomy. These findings may be useful to doctors and nurses, especially in counseling women who have had, or plan to have, a hysterectomy. PMID- 19443297 TI - HLA-DR-matched parental donors for allogeneic hematopoietic stem cell transplantation in patients with high-risk acute leukemia. AB - The immunomodulating effect of human leukocyte antigen (HLA)-DR and the central role of CD4 T cells in alloimmunity provide clues suggesting that HLA-DR-matched, partially mismatched related donors could be feasible alternative donors of allogeneic hematopoietic stem cells for transplantations (allo-HSCT). We describe our experience with allo-HSCT in eight patients with high-risk acute leukemia; donors included one of each of the parents. Among the eight patients, seven were identical HLA-DR matches with the donors. The stem cells were not manipulated in vitro. Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, cyclosporine, and methotrexate. All patients had successful trilineage engraftment. Only one patient had grade 2-4 acute GVHD. Two patients died before day +100 due to complications. At the end of follow-up, four patients had survived for 18-48 months and three are alive and without relapse. Our results suggest that HLA-DR fully-matched parents are feasible alternative donors for allo-HSCT in patients with high-risk acute leukemia under an intensive conditioning regimen. PMID- 19443298 TI - Human papillomavirus type and clinical manifestation in seven cases of large-cell neuroendocrine cervical carcinoma. AB - Large-cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a very rare malignancy. We aimed to investigate the role of human papillomavirus (HPV) on the survival of patients, and its correlation with clinical parameters of HPV status or survival outcomes. Only seven cases of LCNEC were retrospectively collected among 8018 (0.087%) invasive cervical carcinomas from the cancer registry systems at Mackay Memorial Hospital and Veterans General Hospital over a period of 17 years. The median survival time was 17.2 months, including only one long-term survivor (> 5 years). The 2 year and 5-year survival rates after diagnosis were 42% and 30%, respectively. The results indicated that the majority of LCNEC cases were dominated by high-risk HPV-18. No clinical parameters appeared to be associated with HPV-18 or survival outcomes of LCNEC patients. Pelvic lymph node metastasis positivity could also be considered as a prognostic factor for this disease. PMID- 19443299 TI - Inflammatory omental cyst adjacent to the transverse colon mimicking appendicitis in an adult patient. AB - Cysts of the omentum are rare and most frequently discovered in children. These cysts may cause abdominal distension, pain, or vomiting. Omental cysts with right lower quadrant pain are found even more rarely in adults. We describe a 44-year old male who had a 2-day history of abdominal pain localized in the right lower quadrant. Before surgery, acute appendicitis with intra-abdominal abscess was suspected, but during the operation, an infected cyst of the omentum, adjacent and adherent to the redundant transverse colon, was found to have been causing these symptoms. Despite the fact that cysts of the omentum have been reported rarely, the operator should be aware that the cyst is a benign entity and the surgical strategy should be different from that for malignancy. We should keep the possibility of omental cyst in mind to avoid unnecessary bowel resection and potentially harmful inappropriate treatment. PMID- 19443300 TI - Generalized parapoxvirus infection associated with increased antibody titres for varicella zoster virus and measles. AB - Human parapoxvirus infections are rare, self-limiting, zoonotic diseases. A 35 year-old veterinarian presented with a generalized rash of large umbilicated vesicles that appeared after antibiotic treatment for erysipelas on the forearm. The erysipelas arose from an erupted pustular thumb lesion that appeared after examining a sheep. An outbreak of chickenpox in the village suggested parapoxvirus or varicella zoster virus (VZV) was the most likely agent. No poxvirus was detected by electron microscopy or in cell cultures from lesion material. PCR revealed parapoxvirus DNA with a sequence similar to orf-viruses from Finland. Orf-virus immunofluorescence showed a titre increase, supporting the parapoxvirus diagnosis. VZV was not detected by PCR, but varicella antibodies increased three-fold in serum samples drawn two weeks apart. In addition, the patient had high antibody titres for measles and reported recent contact with individuals exposed to an outbreak of measles in nearby Austria. To explain the unusually generalized symptoms in this young and healthy patient, these findings could be variously interpreted as: i) a booster by community VZV infections; ii) a subclinical VZV (re)infection that was superinfected by the parapoxvirus; iii) an orf-virus mediated immune stimulation; iv) a post-infectious syndrome; or v) a temporary immunosuppression by subclinical measles. PMID- 19443301 TI - Crohn's disease: an important differential diagnosis of granulomatous skin diseases. AB - Metastatic Crohn's disease is a very rare skin manifestation of Crohn's disease. Its time of occurrence and severity do not necessarily correlate with the intestinal disease. The main characteristic is that the granulomatous skin changes occur at sites distant from the bowel. We report the case of a 65-year old woman with metastatic Crohn's disease on her right lower leg without clinical intestinal signs at the time of diagnosis. The inflammatory pustulating skin lesions resolved after systemic and topical treatment with corticosteroids. After reducing immunosuppressive therapy, fistulating lesions reappeared on the lower legs and at the mons pubis. Coloscopy now, more than five years after the onset of the first skin lesions, showed an intestinal Crohn's disease. Metastatic Crohn's disease and its differential diagnoses with granulomatous reaction pattern are discussed in this manuscript. PMID- 19443302 TI - Topical delivery of cosmetics and drugs. Molecular aspects of percutaneous absorption and delivery. AB - Percutaneous penetration/permeation is a useful tool for obtaining qualitative and/or quantitative information on the amount of a drug, a cosmetic substance, or any chemical that may enter a skin compartment or the systemic circulation of the human body for pharmaceutical or cosmetic purposes, or for toxicological studies. In the latter case, the extent entering can then be taken into consideration in order to calculate the margin of safety using the NOAEL (No Observed Adverse Effect Level) of an appropriate repeated dose toxicity study with the respective substance. This paper is a short overview of various aspects of skin penetration/permeation of drugs or cosmetic agents. The literature reports numerous studies on skin structure and skin properties influencing drug/cosmetic agent permeation profiles and kinetic parameters. The extensive research concerning the skin structure for determining the key parameters of the penetration/permeation process is therefore described first. Mathematical models of the skin absorption process for a drug are then discussed. Finally new developments in pharmaceutical and cosmetic fields to enhance drug permeation or to modify the stratum corneum structure are considered. PMID- 19443303 TI - Epidermolytic hyperkeratosis with palmoplantar keratoderma in a patient with KRT10 mutation. AB - We report the case of a 12-year-old girl presenting at birth with erythroderma, erosions and blisters scattered over the integument. By the age of 3 she presented generalized hyperkeratotic plaques with a cobblestone pattern and a pungent odour, most prominently around flexures, scalp and palmoplantar areas. Clinical, histological and ultrastructural findings confirmed the diagnosis of epidermolytic hyperkeratosis (EHK). Molecular genetic analysis revealed a mutation in the KRT10 gene. Treatment with oral acitretin was attempted but it was discontinued due to hepatic dysfunction and marked desquamation and blistering. EHK is a rare autosomal dominant disorder of keratinization, caused by mutations in either the KRT1 or KRT10 genes. Although palmoplantar keratoderma is typically found in patients with KRT1 mutation, our patient presents EHK with palmoplantar involvement and KRT10 mutation. Moreover, a poor response to systemic retinoids was observed, contrary to what is expected in patients with KRT10 mutation. Even though management is usually unsatisfactory, some patients with this lifelong and serious condition may experience improvement with age. PMID- 19443304 TI - [Cytomegalovirus infection in pregnancy]. AB - Primary and recurrent infections of human cytomegalovirus (HCMV) can occur during pregnancy. Both can result congenital infection, the leading infectious cause of mental retardation, sensorineural deafness and visual impairment. Intrauterine transmission of HCMV and adverse outcome are mainly related to primary maternal infection. However, there is an increasing evidence that incidence of symptomatic infections in infants born to immune mothers is higher than previously thought. Therefore the option of prenatal diagnosis has a crucial role in the management of pregnancy complicated by active HCMV infection. In spite of the potentially devastating consequence of congenital HCMV infection, little information is available concerning antiviral therapy as prophylactic treatment for women at high risk of the transmission of HCMV during pregnancy. Passive immunization for prevention of vertical transmission of the virus seems to be promising. Until a HCMV vaccine is available, education regarding the risk and strategies for prevention of HCMV infection during pregnancy is needed. PMID- 19443305 TI - [Free circulating DNA based colorectal cancer screening from peripheral blood: the possibility of the methylated septin 9 gene marker]. AB - DNA methylation acts in early tumorigenesis. Its detection is possible either from tissue, stool or peripheral blood. Septin 9 is a sensitive methylation marker, which has been studied in several cancers such as breast and ovarian tumors and in neurological or hematological diseases. Septin proteins have an important role from cytoskeleton organisation to development of embryonal pattern. Nowadays intensive researches are going on about the relation between the septin 9 gene hypermethylation and colorectal cancer development. PMID- 19443306 TI - [Dental aspects of general symptoms in the 18th century]. AB - In the 18th century, numerous diseases with symptoms of oral cavity were cured by chirurgien-dentist, barber-surgeons, or tooth drawer. The so called "dentitio difficilis" was blamed for the high children mortality, therefore gum cut or use of leeches was advised as a treatment. Both acute and chronic type of gum inflammation was called scurvy. It seems that the mechanical removal of plaque was enough to cure the scurvy as it was written in advertisements from that time. Syphilis was present in the everyday life throughout centuries, and assumed to cause different stigmas in the oral cavity. Today we consider theses stigmas as the toxic signs of mercury treatment. PMID- 19443307 TI - [Home ECG monitoring of high-risk post-myocardial infarction patients]. AB - In the era of acute coronary interventions, patients who suffered myocardial infarction (MI) are discharged early (after just a few days) either home or to a rehabilitation facility. However, mortality rate is the highest during the first month after MI. Most endangered patients are those who lost a significant percentage of their myocardium and have a consequential decreased left ventricular systolic function. Given the advances of telemedicine, it may be therefore important to develop new methods of home arrhythmia monitoring for these patients. OBJECTIVE: To determine the reliability of internet-based continuous home arrhythmia monitoring during the first month after discharge in patients with decreased left ventricular function who suffered an acute MI and underwent coronary intervention. METHODS: Although numerous telephone-based ECG monitoring systems exist, authors present their experiences with a new technology involving continuous, internet-based ECG monitoring which does not require activation by the patient. A mobile internet based device was developed for those patients who did not have internet access. RESULTS: We monitored 10 post-MI patients who were discharged home with an ejection fraction of less than 40 percent. Cumulative monitoring time was 170 days. The completely noise-free and error-free ECG periods amounted to 98 percent and 99 percent, respectively. Average time to response to the 66 alarms raised was 27 seconds. Average number of alarms per day was 0.39 while positive predictive value of the alarms was 0.106. Total alarm time was 29.8 minutes which works out to 10.5 seconds per day. CONCLUSIONS: The unique chest band we developed makes possible to produce error free ECG records during most of the monitoring period. Our method appears to be suitable for home monitoring of patients discharged from hospital. Low alarm time means that many patients can be monitored simultaneously without compromising patient safety. PMID- 19443308 TI - [Efficacy and safety of ezetimibe/simvastatin combination therapy in patients with type 2 diabetes and nonalcoholic fatty liver disease]. AB - Nonalcoholic fatty liver disease is commonly associated with type 2 diabetes, dyslipidemia and obesity all of which are components of the metabolic syndrome. AIM: To determine the efficacy and safety of ezetimibe/simvastatin 10/20mg combination therapy on patients with type 2 diabetes and nonalcoholic fatty liver disease. METHODS: We studied nineteen patients with type 2 diabetes and nonalcoholic fatty liver disease diagnosed and treated between 2005 and 2008 at Health Center of Budaors. After six months of ezetimibe/simvastatin (10/20mg/day) combination treatment, all patients were assessed for changes serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides. RESULTS: Six months of ezetimibe/simvastatin administration reduced significantly the serum levels of ALT (63.78+/-5.12 vs 32.57+/-3.92 U/L; p < 0.0001), AST (50.79+/-3.66 vs 23.68+/-3.42 U/L; p < 0.0001), cholesterol (6.26+/-0.46 vs 4.02+/-0.31 mmol/L; p < 0.0001) and LDL-cholesterol (4.24+/-0.37 vs 2.22+/-0,1 mmol/L; p < 0.0001). Combination therapy reduced significantly serum triglyceride level (2.62+0.48 vs 1.33+0.20 mmol/L; p < 0.0001) and increased the level of HDL cholesterol (1.02+/-0.12 vs 1.18+/-0.07 mmol/L; p < 0.0001). CONCLUSIONS: These findings indicate that ezetimibe/simvastatin combination therapy is safe and effective in patients with type 2 diabetes and nonalcoholic fatty liver disease. PMID- 19443313 TI - Integration of temperature-controlled requirements into pharmacy practice. AB - OBJECTIVES: To describe (a) Food and Drug Administration (FDA) regulations and guidelines issued by several professional organizations to ensure appropriate storage, handling, and distribution of temperature-controlled prescription drugs from manufacturer to wholesaler to pharmacy to patients; (b) pharmacy business practices that ensure the dispensing of high-quality temperature-controlled drug products; and (c) education that facilitates patients' important role in maintaining product quality. DATA SOURCES: PubMed from 1950 to 2007 using the search terms drug stability in transit, drug stability storage tablet, drug stability testing, drug stability transportation, drug stability relative humidity, and drug storage high temperature. Nonprimary sources included the FDA website (www.fda.gov), presentations from meetings or workshops, and websites of professional organizations. Additional resources were identified from bibliographies collected by the authors. DATA EXTRACTION: Relevant data were extracted independently by the authors. DATA SYNTHESIS: The important role of pharmacists in ensuring the quality of drugs dispensed to and handled/stored by patients is supported by business practices that (a) promote purchase of quality temperature-controlled drugs (including quality agreements with providers), (b) ensure appropriate handling and storage upon receipt, (c) ensure proper packaging for receipt by patients, (d) provide relevant information to patients, and (e) evaluate issues associated with possible compromised transit, handling, and storage of temperature-controlled drug products. CONCLUSION: The transit, handling, and storage of temperature-controlled drug products within complex supply chains provide opportunities for exposure of such drugs to temperatures above or below those recommended by the manufacturer. Pharmacists have opportunities to integrate business practices that facilitate the proper receipt, handling, and storage of temperature-controlled drug products. These practices will enhance the dispensing of high-quality, efficacious drug products to patients and proper handling and storage by patients. PMID- 19443314 TI - Medication interventions for fall prevention in the older adult. AB - OBJECTIVE: To review fall epidemiology, risk factors, assessments and intervention methods, and outcomes in order to provide guidance to pharmacists. DATA SOURCES: Recently published articles listed in Medline and resources on the Agency for Healthcare Research and Quality website (www.ahrq.gov) identified using the search terms falls, medications and falls, fall risk factors, and falls interventions and outcomes; personal data in preparation for publication consideration by the authors; and bibliographies from gathered articles. DATA SYNTHESIS: Falls may result from multiple risk factors that should be considered to both prevent falls and intervene when a fall has occurred. Careful consideration of the total psychoactive drug load, especially psychotropic drugs, and well-planned recommendations for tapering, discontinuing, and/or replacing drugs implicated in increasing fall risk are presented. A fall risk assessment method that incorporates fall history and risk factors, current disease states and conditions, and medications that may increase fall risk is provided. Two cases with interventions and outcomes are detailed. Because anemia may increase fall risk, adequate assessment of the cause(s) of anemia and conservative recommendations to correct it may decrease fall risk. Adequate vitamin D and calcium intake also may be essential to both decrease falls and fall-related fracture risk. Suggested alternatives and tapering for drugs implicated in increasing falls are considered. Osteoporosis risk assessment is a further area requiring delineation for possible pharmacist assistance to the patient and prescriber to reduce the risk of both fall-related and nontrauma fractures. Interventions to change medications may reduce falls by up to 70%. Additional fall-related resources on the Internet are provided. CONCLUSION: Pharmacists can play an important role by identifying patients who may have fall risk factors and history and by providing information for drug changes that may reduce fall risk. PMID- 19443316 TI - Health care reform and the role of the pharmacist. PMID- 19443317 TI - Advocacy: the essential competence. PMID- 19443318 TI - Choosing our attitudes. PMID- 19443319 TI - Perceptions of patients on Medicare Part D medication therapy management services. AB - OBJECTIVES: To determine patients' perceptions and expectations about medication therapy management (MTM) services pertaining to the core elements of an MTM service in the community pharmacy setting, and to develop educational strategies and outreach programs aimed at increasing patients' knowledge of MTM services and the expanded role of pharmacists in the community pharmacy setting. DESIGN: Multicenter, cross-sectional, anonymous study. SETTING: Four regional community chain pharmacies in Maryland and Delaware in January and February 2006. PATIENTS: 81 patients who were 18 years of age or older and able to complete the survey. INTERVENTION: Survey containing 14 questions administered within pharmacies, two of which had patient care centers that were providing clinical services. MAIN OUTCOME MEASURE: Patients' perceptions and expectations regarding MTM services. RESULTS: 49 of 81 patients (60%) had never heard of MTM services. A total of 65 patients (80%) had never had or received a medication therapy review, 63 (78%) never had or received a personal medication record, and 70 (86%) never had or received a medication action plan. Some 56% of participants (n = 45) thought that pharmacist provision of medication therapy reviews, personal medication records, medication action plans, recommendations about medications, and referral to other health care providers was very important. At least 70% of participants (n = 57) thought that having one-on-one consultation sessions with pharmacists to improve communication and relationships with their pharmacists and to improve their medication use and overall health was very important. More than 50% of participants indicated that they would like to receive brochures or talk to their pharmacist to learn more about MTM services. CONCLUSION: Patients have very limited knowledge of the core elements of an MTM service in the community pharmacy setting. Patients reported that pharmacist provision of MTM services was important, but they were concerned about privacy and pharmacists' time. Patients are also supportive of and believe that MTM services can improve communication and relationship with their pharmacist and improve medication use. Patients appear to prefer receiving brochures and talking to pharmacists to learn more about MTM services. This survey identified a key opportunity for pharmacists to inform patients about MTM services. PMID- 19443320 TI - Descriptive analysis of primary package labels from commercially available prescription solid oral dosage form drugs. AB - OBJECTIVE: To describe formats used by manufacturers to display drug names on primary package labels for prescription solid oral dosage forms. DESIGN: Cross sectional study. SETTING: Independent community pharmacy in rural Indiana. The images were collected in February 2006. PARTICIPANTS: Not applicable. INTERVENTION: High-resolution digital photos were taken of 918 primary package labels (422 brand name and 496 generic) from all solid oral dosage forms stocked in an independent community pharmacy. We coded the images for the presence or absence of specific typographical characteristics used to distinguish the name of the drug. We also coded for the presence or absence of an image of the product on the label. MAIN OUTCOME MEASURES: Frequency of various typographical characteristics used to display the drug name(s) on a primary package label. RESULTS: Manufacturers use a wide variety of techniques to increase the distinctiveness of drug names on primary package labels, including color, boldface, underlining, italics, capitalization, highlighting, use of abbreviations, and use of parentheses to differentiate the generic name of the drug, as well as use of images of the drug product. The frequency of use of the different techniques varied substantially (e.g., boldface fonts used in nearly 98% of brand-name labels, underlining used in only 0.2% of brand-name labels). The frequency of use of the techniques differed across brand and generic products. CONCLUSION: The lack of standardization in the typographical presentation of drug names on primary package labels of solid oral dosage forms in the United States appears to reflect underlying uncertainty about the relative effectiveness of the different techniques. Given the frequency and severity of wrong drug errors caused, at least in part, by the inability of clinicians to distinguish between similar labels, research is urgently needed to determine which technique or combination of techniques will minimize the risk of confusion. PMID- 19443321 TI - Expanding access to sterile syringes through pharmacies: assessment of New York's Expanded Syringe Access Program. AB - OBJECTIVES: To investigate the evolution of pharmacist practices, attitudes, and experiences with the Expanded Syringe Access Program (ESAP), which permits over the-counter sale of syringes by registered pharmacies in New York State. DESIGN: Longitudinal study. SETTING: New York State in 2002 and 2006. PARTICIPANTS: 506 (2002) and 682 (2006) managing pharmacists (response rates approximately 70%) at ESAP-registered pharmacies (n = 346 in both years). INTERVENTION: Mailed surveys (2002 and 2006). MAIN OUTCOME MEASURES: Pharmacist practices, attitudes, and experiences with ESAP over time. RESULTS: Approximately 75% of pharmacists reported that ESAP had facilitated timely/emergency access to syringes, and more than 90% in each year reported no problems or very few problems administering ESAP. The practice of placing additional requirements on the sale of syringes decreased from 2002 (51.4%) to 2006 (45.1%), while a 55% increase in syringe sales was reported between 2002 (43.3/month) and 2006 (67.1/month). The sale of sharps containers also increased between 2002 (85.2%) and 2006 (92.8%). Community independent pharmacies and those located outside New York City generally expressed more favorable attitudes and experiences with ESAP, although these differences decreased over time. CONCLUSION: Pharmacy-based syringe access is a viable harm-reduction alternative in the fight against blood-borne diseases, with ESAP now equaling the number of syringes being distributed by syringe exchange programs in New York State. Continued education/training is necessary to increase participation in ESAP and to further reduce barriers to ESAP use. PMID- 19443322 TI - Medication management in primary and secondary schools: assessing the knowledge and opinions of parents. AB - OBJECTIVES: To assess the knowledge and opinions of parents regarding medication management in their children's schools and to evaluate roles for pharmacists in this area. METHODS: Cross-sectional survey of individuals caring for children between 5 and 18 years of age who take prescription medications at five community pharmacies, one daycare center, and one university. Main outcome measures were the opinions and level of understanding of parents regarding the medication management-related policies of their children's schools and how pharmacists can help the medication behaviors of children before or during school hours. RESULTS: 86 surveys were collected. Of participants, 89.5% reported the name of at least one prescription or over-the-counter (OTC) medication that their child was taking. The most common medications mentioned (40.5%) were those for asthma and/or allergies. More than 45% of children were taking at least two medications. Almost 27% of the medications were taken at school. More than 60% of participants indicated that a nurse was present at their child's school every school day. Of parents, 28.2% and 38.8% did not know whether prescription and OTC products, respectively, were allowed on school premises. The most common relevant service reported to be offered at community pharmacies was an additional labeled prescription container (22.1%), which was also a service that many parents would like to have pharmacies offer (39.6%). Many parents also desired to have a second inhaler for their child at school (34.9%) and that the pharmacy place a label on the inhaler and not just its box (37.2%). These two services were less commonly reported as being offered at pharmacies (22.1% and 12.8%, respectively). CONCLUSION: Many participants in the current study were unaware of important school policies related to medication management. Also, the parents surveyed seemed to desire and felt they would benefit from services that community pharmacists could provide in a relatively simple way. PMID- 19443323 TI - Obtaining patient test results from clinical laboratories: a survey of state law for pharmacists. AB - OBJECTIVES: To identify states with laws that restrict to whom clinical laboratories may release copies of laboratory test results and to describe how these laws may affect pharmacists' ability to obtain patient laboratory test results. METHODS: Researchers examined state statutes and administrative codes for all 50 states and the District of Columbia at the University of Iowa Law Library between June and July 2007. Researchers also consulted with lawyers, state Clinical Laboratory Improvement Amendments officers, and law librarians. Laws relating to the study objective were analyzed. RESULTS: 34 jurisdictions do not restrict the release of laboratory test results, while 17 states have laws that restrict to whom clinical laboratories can send copies of test results. In these states, pharmacists will have to use alternative sources, such as physician offices, to obtain test results. CONCLUSION: Pharmacists must consider state law before requesting copies of laboratory test results from clinical laboratories. This may be an issue that state pharmacy associations can address to increase pharmacist access to important patient information. PMID- 19443324 TI - Exploring patient-pharmacist interaction differences between the drive-through and walk-in windows. AB - OBJECTIVE: To preliminarily determine whether interactions between pharmacists and patients during drive-through service encounters differed significantly from those observed during walk-in service encounters at one community chain pharmacy. METHODS: Two student pharmacist observers timed interactions and recorded observations on a standardized form at the drive-through and walk-in windows. RESULTS: More than 200 encounters were documented at both the drive-through and walk-in windows. Patients using the two locations were similar in terms of gender, age, and proportion of mobility impaired. Of patients using the drive through window, 35% had passengers in their car and 1% were smoking. Drive through window encounters were more likely to involve at least one "more confidential" prescription compared with walk-in window encounters (17.7% vs. 11.3%). The proportion of patients with limited English proficiency was greater at the walk-in window compared with the drive-through window. Patients were acknowledged more frequently when they came to the walk-in window and accepted counseling more often when offered. While the length of total personnel time was greater, the proportion of time with the pharmacist was significantly less with patients at the drive-through window, indicating that drive-through interactions at this pharmacy are primarily with technicians. CONCLUSION: This pilot project suggests that the interaction between pharmacists and patients may be richer and lengthier when the walk-in window is used, particularly for patients with limited English proficiency. PMID- 19443325 TI - Advertising of OTC products in a Nigerian urban setting: content analysis for indications, targets, and advertising appeal. AB - OBJECTIVE: To identify the indications for which treatments were promoted, the segments of population targeted, and the type and extent of advertising appeal used for over-the-counter (OTC) products in a Nigerian urban setting. METHODS: Using a cross-sectional design, the content of advertisements for OTC products on radio, television, and billboards in a city in southwestern Nigeria were assessed during a 3-month period. Two coders independently assessed 1,492 advertisements for 49 brands of OTC products (interrater reliability [Cohen's kappa] = 0.83 [95% CI 0.80-0.90]). RESULTS: The most frequent indications for OTC products were aches and pain (42.9%), anemia/malnutrition (34.8%), and malaria (22.2%). Of advertisements, 92% were targeted at the primary end user. Use of appeal related to efficacy (100%), psychosocial enhancement (80%), and ease of use (40%) in visual, written, and audio messages was highest in ads on billboards. Efficacy appeal had the highest frequency across the three advertising media (100%); ease of-use and safety appeal had the lowest frequency (40% and 7.4%, respectively). Nigerian movie stars were used as brand icons in advertisements of OTC products on radio (59.5%), television (52.9%), and billboards (49.6%). CONCLUSION: The majority of advertisements for OTC products in a Nigerian urban setting used advertising appeal related to efficacy and psychosocial enhancement. Promotional efforts by pharmaceutical manufacturers appear to focus on positive emotional appeal to influence drug purchase and use decisions. PMID- 19443326 TI - Managing oneself: an essential skill for managing others. AB - OBJECTIVE: To discuss the importance of self-management for student pharmacists, pharmacists, and pharmacy managers and present a series of steps that students and new pharmacists can use in managing themselves. DATA SOURCES: An English language-only literature search was conducted of the PubMed and International Pharmaceutical Abstracts databases from 1980 to 2007 using the keywords managing and career, managing oneself, and career management. Information from the search was supplemented with selected articles and books from the management and self improvement literature. STUDY SELECTION: Cited sources were chosen based on their relevance to the article's objectives. DATA EXTRACTION: By the author. DATA SYNTHESIS: Common steps associated with managing oneself and one's career consist of taking responsibility for your life, knowing yourself, deciding what you want to do and be, establishing goals to achieve the life you want to live, and taking action. A major goal of any self-management plan for managers is to develop soft interpersonal skills that help individuals manage themselves and influence the world around them. CONCLUSION: Effective self-management is necessary for success in managing others. The steps are relatively simple but take a lifetime to master. PMID- 19443327 TI - U.S. Public Health Service Commissioned Corps pharmacists: making a difference in advancing the nation's health. AB - OBJECTIVE: To describe how U.S. Public Health Service (PHS) pharmacists serving in jobs that are normal for them, but considerably different than those found in the private sector, are making a difference in advancing the nation's health. SUMMARY: Pharmacists who serve in the Commissioned Corps of PHS fill roles that are considerably different than their counterparts in the private sector. Their work takes them out from behind the counter and into the world. Pharmacy officers advance the health and safety of the nation by their involvement in the delivery of direct patient care to medically underserved people, national security, drug vigilance, research, and policy-making endeavors. PHS pharmacists fill essential public health leadership and service roles throughout the U.S. Department of Health and Human Services (HHS) and certain non-HHS federal agencies and programs. The Health Resources and Services Administration, National Institutes of Health, Federal Bureau of Prisons, Indian Health Service, Food and Drug Administration, and U.S. Coast Guard are among the many federal agencies in which pharmacy officers are assigned. CONCLUSION: In each setting, PHS pharmacists find traditional roles augmented with assignments and challenges that broaden the scope of their practice. PMID- 19443328 TI - William Shoulden Apple 1918-1983: proponent of pharmacy's independence. PMID- 19443329 TI - Vaccinations in solid-organ transplant patients: what a health professional should know. PMID- 19443330 TI - New drugs: Febuxostat, lacosamide, and rufinamide. PMID- 19443333 TI - Individualizing therapy for non-small-cell lung cancer: a paradigm shift from empiric to integrated decision-making. PMID- 19443334 TI - Genomic prognostic models in early-stage lung cancer. AB - Patients with early-stage lung cancer demonstrate significant recurrence rates and lower-than-expected survival rates after surgical resection, indicating that our current staging methods do not adequately predict outcome. Since the last revision of the TNM staging system, a number of genomic models have been proposed which more accurately predict prognosis in patients with early-stage lung cancer. A variety of prognostic genomic models based on gene-expression profiling and quantitative polymerase chain reaction (PCR) are able to stratify patients with early-stage lung cancer into high- and low-risk groups with respect to disease free and overall survival. In the future, clinical application of these models may ultimately dictate both the use of adjuvant therapy as well as the choice of surgical procedure in patients with early-stage lung cancer. An effort to develop a robust genomic model for use in the clinical setting should be prompted by encouraging results obtained by the use of a quantitative PCR-based genomic signature in the field of breast oncology. PMID- 19443335 TI - Advanced non-small-cell lung cancer in the elderly. AB - Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Elderly patients have more comorbidities and tend to tolerate more poorly aggressive chemotherapy and radiation therapy than younger individuals. Our purpose in this article is to summarize recent studies of single-agent chemotherapy and combination regimens with cytotoxic or targeted therapies in the management of elderly patients with advanced NSCLC. We have reviewed the available evidence in the literature to gauge the results of therapy for elderly patients with lung cancer. We found that single-agent chemotherapy remains the standard of care for nonselected elderly patients. Retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. Therefore, the outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally greater. PMID- 19443336 TI - Gene expression profiling and non-small-cell lung cancer: where are we now? AB - Despite new developments in molecular techniques and better knowledge on lung cancer tumor biology, many genetic alterations associated with the development and progression of lung carcinogenesis still remain unclear. Although the development of targeted agents has improved response rates and survival, lung cancer has a very high mortality rate, even for early stages. Thus, there is a greater need for other mechanisms or technologies that may help us diagnose, predict, and treat patients with lung cancer in a more effective way. One of these technologies has been the use of genomics. Some of the available genomic technologies include single-nucleotide polymorphism analysis, high-throughput capillary sequencing, serial analysis of gene expression, and gene expression arrays. DNA microarray analysis is capable of discovering changes in DNA expression within the neoplastic tumor. Thus, gene expression array could help us to decipher the complexity and interaction of different oncogenic pathways and, hence, could contribute to the selection of better targeted agents on an individual basis rather than a general and nonspecific approach as it has been done for many decades. Several studies initiated a few years ago have started to produce fruitful results. Herein, we review the role of gene expression profiling in lung cancer as a diagnostic tool, predictive and prognostic biomarker, and its potential use for a "personalized" medicine in the years to come. PMID- 19443337 TI - Management and prognosis in synchronous solitary resected brain metastasis from non-small-cell lung cancer. AB - BACKGROUND: Reports in the medical literature have described cases of extended survival of patients with non-small-cell lung cancer (NSCLC) with solitary metastatic disease who have received aggressive treatment both to the brain metastasis and to the local/regional disease. The objective of this research is to analyze prognostic factors that predict for outcome in this unique patient population. PATIENTS AND METHODS: A single-institution, retrospective chart review was performed on 35 patients with NSCLC and a synchronous solitary brain metastasis (SSBM) treated with craniotomy and whole-brain radiation therapy. Eight patients (22.9%) had chest surgery, 24 (68.6%) had chemotherapy, and 14 (40%) had thoracic radiation as part of their local management. Fourteen had stage I/II disease (42.9%), and 20 had stage III disease (57.1%). Mean age at diagnosis was 58.5 years. Eighteen patients (56.25%) had a brain metastasis < 3 cm, and 14 patients (43.75%) had a metastasis > 3 cm. RESULTS: Median survival was 7.8 months, and at last follow-up, 3 patients (8.6%) were alive and well, 6 patients (17.1%) were alive and with disease, 24 patients (68.6%) had died of disease, and 2 patients (5.7%) had died of other causes. Univariate analysis demonstrated that lung surgery (P = .0033), primary lung treatment > 8 weeks after brain surgery (P = .0128), and stage I/II disease (P = .0467) were predictive of overall survival. CONCLUSION: Survival remains poor for patients with NSCLC with an SSBM. However, patients with thoracic disease amenable to local resection should be considered for such therapy because a survival advantage could exist compared with patients with more locally advanced disease. PMID- 19443338 TI - Predictors of long-term survival in patients with lung cancer included in the randomized Spanish Lung Cancer Group 0008 phase II trial using concomitant chemoradiation with docetaxel and carboplatin plus induction or consolidation chemotherapy. AB - PURPOSE: The aim of this study was to analyze prognostic variables associated with long-term survival in patients with stage III non-small-cell lung cancer enrolled in a Spanish Lung Cancer Group (SLCG) phase II trial. PATIENTS AND METHODS: Between May 2001 and June 2006, 139 patients were enrolled. The initial design included 3 arms: sequential chemotherapy (CT) followed by standard thoracic radiation therapy (TRT; RT), concomitant CT/TRT followed by consolidation CT, or induction CT followed by CT/TRT. Based on the results of the Radiation Therapy Oncology Group 9410 trial, the sequential arm was closed. Induction or consolidation therapy comprised docetaxel plus gemcitabine. Concomitant treatment comprised docetaxel plus carboplatin plus 60 Gy TRT. A univariate and a Cox proportional hazard regression analysis of the following 11 variables were performed: age, sex, Eastern Cooperative Oncology Group performance status (PS), histology, forced expiratory volume in 1 second, disease stage, nodal status, hemoglobin level, completion of RT treatment, completion of induction or consolidation plus concomitant treatment, and RT delay. RESULTS: With a median follow-up of 23 months for living patients, median survival was 13.07 months for the consolidation arm and 14.65 months for the induction arm. The 4-year survival rates were 25.37% and 32.35%, respectively. Only RT treatment completion (P < .0001) and induction or consolidation plus concomitant treatment completion (P < .0001) were associated with longer survival. CONCLUSION: Based on this retrospective analysis of patients enrolled in the SLCG 0008 randomized phase II study, age, sex, PS, and clinical parameters are not good predictors of overall survival; however, completion of treatment is needed to achieve long-term results. PMID- 19443339 TI - Initial treatment strategies and outcomes for multifocal bronchioloalveolar carcinoma. AB - BACKGROUND: Bronchioloalveolar carcinoma (BAC) commonly presents as multifocal disease. Management of multifocal BAC remains controversial and may include surgical resection, systemic therapy, surveillance, or a combination of these strategies. Knowledge of current practice patterns and outcomes could help to inform future research. MATERIALS AND METHODS: Medical records of patients with BAC were retrospectively reviewed, and regression analyses were conducted to correlate demographic parameters, disease characteristics, and treatment modality with clinical outcomes. RESULTS: Of the 109 cases identified, 85 patients were eligible for study, 26% with unifocal and 74% with multifocal BAC. Median age at diagnosis was 65 years; the majority of the patients were female (64%), were non Asian (82%), and had a smoking history (66%). In the subset with multifocal BAC, 24% of the cases were confined to one lobe, 76% affected multiple lobes, and 40% involved both lungs. The primary treatment modality for multifocal disease included surgical resection (78%), systemic therapy (14%), and observation (8%). In multivariate analyses, extensive disease (> or = 3 lobes involved) and medical oncology assessment predicted treatment with systemic therapy (odds ratio [OR], 8.68; P = .03 and OR, 1.68; P < .01, respectively). The presence of extensive disease and the receipt of systemic therapy were associated with higher likelihood of disease progression (hazard ratio [HR], 8.62; P = .02 and HR, 8.46; P = .02, respectively). CONCLUSION: Initial treatment choices and referral patterns for multifocal BAC were diverse and influenced by clinical selection, whereby patients with extensive disease were more likely to discuss and receive systemic therapy. Surgery and surveillance were reasonable treatment options for selected patients. The precise roles of the various treatment strategies for multifocal BAC require further evaluation. PMID- 19443340 TI - PROCLAIM: A phase III study of pemetrexed, cisplatin, and radiation therapy followed by consolidation pemetrexed versus etoposide, cisplatin, and radiation therapy followed by consolidation cytotoxic chemotherapy of choice in locally advanced stage III non-small-cell lung cancer of other than predominantly squamous cell histology. AB - This clinical trial summary provides the background and rationale for a randomized trial examining the benefits of pemetrexed/ cisplatin chemotherapy combined with radiation followed by consolidation pemetrexed in patients with unresectable stage IIIA/B non-small-cell lung cancer. The rationale for the selection of the control arm is provided, and study design limitations are discussed. The primary outcome is survival, and secondary outcomes include progression-free survival, toxicities, and 1-, 2-, and 3-year survival rates. Radiation quality control is a key component of the trial. PMID- 19443342 TI - Stroke rehab down under: can Rupert Murdoch, Crocodile Dundee, and an Aboriginal elder expect the same services and care? AB - Australia is the world's sixth largest country, has a relatively small population of 21.5 million, and a blended (public and private) health system. In this article, we explain the stroke rehabilitation infrastructure including consumer organisations, research networks, data collection systems, and registries. This represents a complex but fledgling set of organisations showing great promise for coordination of care and research. The article goes on to expose the inequalities in service provision by describing the paths of stroke survivors in three settings - in the city, in the country, and in remote settings. The complexities and difficulties in treating indigenous stroke survivors are described in a culturally sensitive narrative. The article then discusses the outcomes of the first Australian audit of post acute stroke services completed in December 2008, which describes the journeys of 2,119 stroke survivors at 68 rehabilitation units throughout Australia's 6 states and 2 territories. It demonstrates an average length of stay of 26 days, with 18% of survivors requiring nursing home or other supported accommodation. The article concludes with future directions for stroke rehabilitation in Australia, which include hyperacute rehabilitation trials, studies in 7-days-a-week rehabilitation, and the potential use of robotics. PMID- 19443343 TI - Stroke rehabilitation in Canada: a work in progress. AB - Stroke rehabilitation in Canada continues to function under models and practices that have changed little in the last four decades and struggles to implement new evidence-based or best practices. Ontario, Canada's largest province, has had a coordinated stroke strategy since 2000. The Ontario Stroke System has developed an extensive infrastructure of research syntheses, consensus panel recommendations, practice guidelines, standards of care, and centralized data collection across the continuum of stroke care. This has produced a solid foundation upon which an evidence-based stroke rehabilitation system can be developed. However, failure to invest in stroke rehabilitation or provide incentives to implement change has resulted in the stroke rehabilitation system and critical outcomes remaining largely unchanged. Improvements in time to admission have been countered by rising admission FIM scores such that severe stroke patients often cannot access the stroke rehabilitation system. Many stroke patients are still rehabilitated on general rehabilitation units, therapy intensities remain unacceptably low, and many outpatient programs are being reduced or even closed. Although there are pockets of innovation, the stroke rehabilitation system continues to function more according to traditional ways of practicing. The hope is that with appropriate investments and incentives, Canadians and Ontarians can build upon the existing infrastructure to ensure stroke patients receive optimal rehabilitative care based on best evidence. In the meantime, stroke rehabilitation in Canada remains a work in progress. PMID- 19443344 TI - European comparison of stroke rehabilitation. AB - BACKGROUND: Our understanding of the components of stroke rehabilitation critical to patients' outcomes is limited. Comparing practices and outcomes across countries may give clues to how to improve rehabilitation services. METHOD: In the CERISE project (Collaborative Evaluation of Rehabilitation in Stroke across Europe), clinical and organisational aspects of stroke rehabilitation were compared among four European rehabilitation centres (United Kingdom, Belgium, Switzerland, and Germany). Main findings were summarised and interpreted. RESULTS: Gross motor and functional recovery were significantly better in the German and Swiss centres compared to the British centre, respectively. Insights in admission criteria, patients' therapy time, content of therapy, and task characteristics of physiotherapists and occupational therapists were in line with the differences in recovery. In Germany, neurorehabilitation is more structured with clearly defined phases, each linked with specific criteria and reimbursement schemes. In Belgium, more variation exists in the rehabilitation trajectories. CONCLUSION: Stroke rehabilitation services are embedded in health care systems, creating contextual constraints with various (dis)incentives. These constraints vary between countries, resulting in differences in the organisation of stroke rehabilitation. Studies on the effectiveness of stroke rehabilitation should incorporate contextual elements of the organisation of the unit. PMID- 19443345 TI - Stroke rehabilitation in the United kingdom. AB - A Consensus Conference on Stroke in 1988 concluded that rehabilitation for stroke in the United Kingdom was poorly organised, was not based on evidence, and was associated with poor outcomes compared with similar health care systems. In addition, there were significant variations in the quality of services and outcome across different areas of the country. Efforts to improve care included increased investment into services and research, development of multidisciplinary national guidelines for all aspects of stroke care, and a regular national audit of stroke rehabilitation. The last 20 years have seen dramatic improvements in the development of a coherent policy for the management of stroke patients in the United Kingdom, underpinned by well-organised services within a framework of guidelines and performance review. However, further work is needed to increase the evidence base for the nature, duration, and effectiveness of complex rehabilitation interventions and to improve multidisciplinary interactions and communications with patients and their caregivers. Of the further work required, the leading priority is to increase therapy input to make the best use of time that patients spend in rehabilitation settings. PMID- 19443346 TI - Hospital-based stroke rehabilitation in the United States. AB - In this article, we consider (1) the role of Medicare in shaping US inpatient rehabilitation facility (IRF) stroke rehabilitation, (2) admission criteria for IRF care in the United States and medical management while in IRF, (3) the organization and delivery of IRF-level nursing and therapy, (4) post-IRF rehabilitation choices, (5) monitoring of rehabilitation outcomes, and (6) the implications of a multisite stroke outcome study for stroke rehabilitation practice. Inpatient stroke rehabilitation in the United States is a team oriented, patient-centered, Medicare-driven service provided to stroke survivors. As a field of practice, it strives for continuous quality improvement to optimize patient outcomes. Stroke rehabilitation as a science, however, remains underfunded relative to the scope of the challenge in Western societies and worldwide for that matter. Worldwide sharing of best practices found in the United States and other countries will allow stroke survivors of any country improved chances for functional recovery, greater independence, and life satisfaction. PMID- 19443347 TI - Stroke rehabilitation: an international perspective. AB - There is a revolution underway in stroke rehabilitation. International comparative studies coupled with an impressive evidence base have provided a platform from which an ideal system for stroke rehabilitation can be envisioned. Using the concepts of structure and process of care, different systems of stroke rehabilitation can be compared and evaluated against best evidence. Two structures of care are examined: specialized interdisciplinary stroke rehabilitation units and outpatient programs. Although specialized interdisciplinary stroke rehabilitation units remain the "gold standard" of care, access to them is often limited. Outpatient programs are essential to stroke rehabilitation systems of care; however, while some countries are investing in outpatient programs, others are scaling back. Even though structures of care have been shown to affect processes of care, it is the processes of care that have proven to be more influential in altering patient outcomes. Four key processes of care are examined: time to admission, intensity of therapy, task-specific therapy, and discharge planning. Within international stroke rehabilitation systems, differences in these processes have resulted in significant differences in outcomes. This allows for "real-world" comparisons of how differing processes affect patient outcomes. Those systems whose structures and processes of care best reflect current best evidence appear to achieve better outcomes. PMID- 19443348 TI - The Bobath concept in contemporary clinical practice. AB - BACKGROUND: Future development in neurorehabilitation depends upon bringing together the endeavors of basic science and clinical practice. The Bobath concept is widely utilized in rehabilitation following stroke and other neurological conditions. This concept was first developed in the 1950s, based on the neuroscience knowledge of those times. PURPOSE: The theoretical basis of the Bobath concept is redefined based on contemporary neuroscience and rehabilitation science. The framework utilized in the Bobath concept for the analysis of movement and movement dysfunction is described. This framework focuses on postural control for task performance, the ability to move selectively, the ability to produce coordinated sequences of movement and vary movement patterns to fit a task, and the role of sensory input in motor behaviour and learning. The article describes aspects of clinical practice that differentiate this approach from other models of practice. Contemporary practice in the Bobath concept utilizes a problem-solving approach to the individual's clinical presentation and personal goals. Treatment is focused toward remediation, where possible, and guiding the individual towards efficient movement strategies for task performance. The aim of this article is to provide a theoretical framework on which future research into the Bobath concept can be based. PMID- 19443349 TI - Rhythmic auditory-motor entrainment improves hemiparetic arm kinematics during reaching movements: a pilot study. AB - PURPOSE: Recovery of skilled upper limb movement remains a critical focus of rehabilitation in individuals post stroke. Conventional treatments, however, have demonstrated limited capability to produce substantial improvements in poststroke quality of movement. Recently, rhythmic auditory stimulation (RAS) has emerged as efficacious in improving and normalizing limb movements in neurologically impaired populations. This pilot study examined changes in pre- to post-RAS reach kinematics and functional outcomes in survivors of stroke. METHOD: Five individuals in the chronic poststroke phase participated in a 2-week program of RAS training. Kinematic reaching variables were trunk, shoulder, and elbow segment contribution; movement time; and reach velocity. Functional outcomes were the Wolf Motor Function Test, Motor Activity Log, and Fugl-Meyer Assessment. RESULTS: Post-RAS assessment of reaching kinematics revealed a significant (p < .05) decrease in compensatory trunk movement, increase in shoulder flexion, and a slight increase in elbow extension. Movement time and velocity significantly improved post RAS. Significant gains were observed on all functional assessments. CONCLUSIONS: Post RAS, participants demonstrated substantial decreases in compensatory reaching movements. These changes in motor control strategy were paralleled by gains in functional abilities, suggesting that reduced reliance on compensatory movements may translate to improved performance of daily activities. PMID- 19443351 TI - Prosecutors making (bad) law? PMID- 19443350 TI - Predictors of resuming therapy within four weeks after discharge from inpatient rehabilitation. AB - PURPOSE: To identify the percentage of persons with stroke resuming therapy within 4 weeks of inpatient rehabilitation discharge, to compare the characteristics of those who did and did not resume therapy, and to determine the predictors of resuming physical (PT), occupational (OT), and speech (ST) therapy. METHOD: Sociodemographic, stroke-related, and therapy data for persons with stroke (N = 131) were abstracted from inpatient rehabilitation charts. FIM, Stroke Impact Scale, Geriatric Depression Scale, and data on therapy received after discharge were also collected. RESULTS: Logistic regression models demonstrated that minorities were less likely to resume PT (odds ratio [OR] = 0.30) and OT (OR = 0.25). Survivors with neglect/visual-field cut/spatial perceptual loss were 2-3 times more likely to resume PT, OT, and ST. Survivors with higher scores on the SIS Physical domain subscale were less likely to resume PT (OR = 0.98) and OT (OR = 0.97). Men were 3.3 times more likely to have OT than women. Those with comprehensive health insurance were 11.2 times more likely to receive ST. CONCLUSIONS: The benefits of outpatient therapy are not universally available to all persons with stroke. Further research needs to explore the factors that hinder the prompt resumption of therapy for minority and female persons with stroke and to test appropriate interventions. PMID- 19443352 TI - Human papillomavirus infection as a prognostic factor in oropharyngeal squamous cell carcinomas treated in a prospective phase II clinical trial. AB - The aim of this study was to determine the presence of high-risk HPV-16 in patients with HNSCC, assess the impact of HPV status on treatment response and survival in this select cohort treated with combined modality therapy and to identify the differences in HIF-1alpha and VEGF expression in HPV-positive and negative tumors. PATIENTS AND METHODS: Patients had resectable, untreated stage III, IV HNSCC of the oral cavity, oropharynx, hyopharynx or larynx, and stage II cancer of the base of tongue, hypopharynx and larynx. HPV status was determined by conventional PCR in fresh frozen biopsy samples and by Taqman PCR assay on formalin-fixed, paraffin-embedded specimens. HIF-1alpha and VEGF expression were assessed by quantitative real-time PCR (RT-PCR). Multivariate Cox proportional hazards regression analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) based on HPV status. RESULTS: HPV-16 was detected in 14 of 24 evaluable cases. There were no significant differences in response rates after neoadjuvant chemotherapy (86% vs. 90%) in HPV-positive and HPV-negative patients, respectively. There was a trend toward better progression-free (HR=0.15, 95% CI=0.002-12.54; p=0.06) and overall survival (HR=0.14, 95% CI=0.001 14.12; p=0.10) for HPV-positive patients. In a subset of 13 fresh frozen samples, RT-PCR revealed a significant increase in VEGF mRNA levels in HPV-positive tumors (p<0.01). No difference was seen for HIF-1alpha expression. CONCLUSION: HPV presence portended a better prognosis in patients with oropharyngeal SCC treated with a multimodality treatment in a prospective clinical trial. The level of VEGF mRNA was up-regulated in HPV-16-positive tumors possibly through an HIF-1 independent manner. PMID- 19443353 TI - Urokinase-type plasminogen activator and plasminogen-activator-inhibitor type 1 predict metastases in good prognosis breast cancer patients. AB - This retrospective analysis was designed to confirm the predictive role of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type I (PAI-1) in the outcome of early stage, node-negative breast cancer patients. PATIENTS AND METHODS: Node-negative patients having not received adjuvant chemotherapy, and for whom frozen samples were available, were selected. RESULTS: Among the 169 patients included, 56.8% presented with uPA >3 ng/mg of proteins and/or PAI-1 >14 ng/mg of proteins. The median follow-up was 73 months. Significant correlations were found between uPA and disease-free survival (p [univariate]=0.003; p [multivariate]=0.01), and between uPA, PAI-1, and uPA plus PAI-1 and distant relapses (p=0.002). No significant correlation was found between uPA/PAI-1 and the risk of locoregional recurrence. CONCLUSION: This study demonstrated that uPA and PAI-1 are useful predictors of distant metastases in a subset of early stage, node-negative breast cancer patients. PMID- 19443354 TI - A randomized controlled trial investigating the effects of celecoxib in patients with localized prostate cancer. AB - Cyclooxygenase-2 (COX-2) is associated with tumour promotion, inhibition of apoptosis, angiogenesis and metastasis. Celecoxib, a selective COX-2 inhibitor was investigated, in patients with clinically localized prostate cancer using immunohistochemistry. PATIENTS AND METHODS: Patients with cT1-2 prostate cancer (n=45) were randomized to celecoxib 400mg b.d. or no treatment for four weeks prior to radical prostatectomy. Histological sections of preoperative biopsy and matched radical prostatectomy specimens were stained for markers of cell proliferation (MIB-1/Ki-67), microvessel density (CD-31 with Weidner scoring), COX-2, apoptosis (TUNEL analysis), angiogenic factors (VEGF and KDR) and HIF-1. RESULTS: Celecoxib decreased tumour cell proliferation, microvessel density, angiogenesis and HIF-1 whilst enhancing apoptosis. These effects approached statistical significance in a multivariate model and the cell proliferation index approached statistical significance on univariate analysis. CONCLUSION: In this pilot study a 4 week regimen of celecoxib resulted in measurable biological effects in prostate cancer tissue. These findings warrant further investigation. PMID- 19443355 TI - ErbB 1-4 expression alterations in primary colorectal cancers and their corresponding metastases. AB - BACKGROUND: EGFR (epidermal growth factor receptor) targeted therapies are important new tools in colorectal cancer treatment. EGFR analysis of the primary tumour was previously recommended to identify patients who will benefit from the EGFR targeted therapy. Previous studies have displayed diverging results regarding the expression of EGFR in the primary tumour compared to the metastases. The present study was performed to investigate whether EGFR and ErbB2 4 expression differed between 64 primary tumours and their corresponding metastases. PATIENTS AND METHODS: EGFR and ErbB2-4 expression were analysed in the primary tumour and in the corresponding metastases using immunohistochemistry (IHC). RESULTS: In 49/64 samples (76%), the primary tumours were EGFR positive; in 33% (16/49) of EGFR positive samples, the tumours lost the EGFR expression in the metastasis compared to the primary tumour. From the primary tumours, 15/64 (23%) were negative and 5 of these (33%) developed EGFR expression in the metastasis. ErbB2, ErbB3, and ErbB4 expression was evident in 54%, 67%, and 81%, respectively. There was no significant difference between ErbB2, ErbB3, and ErbB4 expression in primary tumours and metastases. The co-expression of the ErbB family members was also analysed, with a significant increase of ErbB3/ErbB4 co expression in late stage tumours. CONCLUSION: The EGFR expression was lost in 33% of metastasising primary colorectal cancer tumours, a finding that agrees with at least one previous study. Thus, the present results clearly implicate the need for EGFR analysis of both the primary tumour and metastases to accurately determine EGFR status when considering the use of EGFR targeted therapies. PMID- 19443356 TI - Collision tumor versus multiphenotypic differentiation: a case of carcinoma with features of colonic and lung primary tumors. AB - BACKGROUND: Collision tumors are rare tumors composed of two histologically distinct neoplasms coinciding at the same location. Collision tumors need to be distinguished from tumors originating from a progenitor cell with potential for multiphenotypic differentiation. CASE REPORT: A clinically puzzling case of an intricate malignant pulmonary nodule in a patient with previous history of colorectal carcinoma is reported. A brief review of the clinical literature on collision tumor and tumor stem cells is presented. CONCLUSION: This case report emphasizes the importance of detailed histopathologic and immunohistochemical analyses, and clinical history in diagnosing a tumor composed of multiple malignant morphologies. PMID- 19443357 TI - Pathological classification of DCIS and planning of therapeutic management. AB - BACKGROUND: Ductal intraepitelial neoplasia (DIN) represents a spectrum of disease that may progress from usual hyperplasia to ductal carcinoma in situ (DCIS) grade 3. The aim of the study was to asses the correlation between the DIN classification and the surgical treatment including sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS: In this retrospective study, 229 patients with DIN had undergone conservative or radical surgical treatment and SLNB in cases of DIN1C-DIN3. RESULTS: Breast conservative surgery was the definitive treatment in 80% of the cases. The H&E evaluation of excised sentinel nodes was negative for metastatic disease; nevertheless the immunohistochemical (IHC) evaluation revealed the presence of metastatic cells in 6 patients (3.7%). CONCLUSION: In cases of DIN lesions SLNB is not indicated. The only reason SLNB should be considered is when there is an evidence of invasive foci at definitive histology or when radical mastectomy is proposed. PMID- 19443358 TI - Carbon-11-methionine PET imaging of choroidal melanoma and the time course after carbon ion beam radiotherapy. AB - The aim of this study was to assess the feasibility of MET-PET as an evaluation method of the therapeutic effect of carbon ion beam radiotherapy. PATIENTS AND METHODS: Twenty-four choroidal melanoma patients who were treated with a carbon ion beam underwent at least three MET-PET scans before and after therapy. The uptake was visually and semiquantitatively evaluated on the basis of the tumor-to brain ratio (TBR). RESULTS: The accumulation was significantly decreased at 6 months or more after therapy and disappeared in 50% of the patients at 12 months after therapy. The baseline TBR, 1, 6, 12 and 24 months after therapy averaged 1.88+/-0.65, 1.73+/-0.52, 1.08+/-0.42, 0.67+/-0.27 and 0.65+/-0.30, respectively. TBR was significantly decreased at 6 months or more after therapy. CONCLUSION: MET-PET may be an alternative method for evaluating the effect of radiotherapy. PMID- 19443359 TI - Feasibility of AC/EC followed by weekly paclitaxel in node-positive breast cancer in Japan. AB - The feasibility and efficacy of adriamycin or epirubicin in combination with cyclophosphamide followed by weekly paclitaxel (AC/EC-weekly PAC) as adjuvant chemotherapy for breast cancer was investigated. PATIENTS AND METHODS: Node positive breast cancer was treated with AC/ EC-weekly PAC, namely AC at 60/600 mg/m(2) or EC at 90/600 mg/m(2) x4 at three-week intervals, followed by weekly PAC (80 mg/m(2)) x 12, namely four cycles of single weekly administration for three weeks followed by a one-week rest (3 x 4 PAC) or single weekly administration for 12 consecutive weeks (12 PAC). RESULTS: One hundred and three of 109 consecutive patients enrolled were analyzed, of whom 96 (93.2%) completed the regimen. Grade 3/4 neutropenia occurred in 52.4% receiving AC/EC, and 10.9% of 55 receiving 12 PAC but only 2.1% of 48 receiving 3 x 4 PAC. Neuropathy disorders occurred in more than half receiving PAC, which did not improve after one-week rest in 3 x 4 PAC. CONCLUSION: AC/EC-weekly PAC is feasible and without serious complications. PMID- 19443360 TI - A phase I/II study of docetaxel and gemcitabine combination for chemotherapy resistant ovarian cancer. AB - BACKGROUND: A phase I/II study of docetaxel (DOC) and gemcitabine (GEM) combination for treatment-resistant ovarian cancer (OC) was conducted. MATERIALS AND METHODS: Eligible patients exhibited recurrent OC within 12 months after initial treatment, or after more than 2 chemotherapy regimens. Planned dose levels (DL) were as follows: DOC 70 mg/m(2), GEM 800 mg/m(2) (DL1); DOC 70 mg/m(2), GEM 1000 mg/m(2) (DL2). DOC was administered on day 1 combined with GEM on days 1 and 8 every 3 weeks. Adverse events were assessed by NCI-CTC2.0J. Response was evaluated by RECIST or Rustin's criteria. RESULTS: The recommended dose was DL1. For all enrolled patients, the median interval from last chemotherapy was 2.5 (1-11) months and 32 patients were assessable for response. One complete response, 6 partial responses and 6 stable disease were noted. Median time to progression was 4.8 months. Toxicities were mainly hematological and manageable. CONCLUSION: This combination could be an acceptable treatment option before palliation. PMID- 19443361 TI - Increased prevalence of regulatory T-cells in the peripheral blood of patients with gastrointestinal cancer. AB - BACKGROUND: Although recent studies have shown that FoxP3 represent the most specific Treg marker only a few studies have reported on the presence of FoxP3(+)Treg in peripheral blood. PATIENTS AND METHODS: Peripheral blood mononuclear cells (PBMC) were harvested from 37 healthy volunteers and 94 patients with gastrointestinal cancer. The prevalence of Treg co-expressing CD4(+)FoxP3(+) was analyzed using flow cytometry. RESULTS: The prevalence of Treg in the peripheral blood of gastrointestinal cancer patients was significantly higher than that in healthy volunteers (p=0.012). In early stage I cancer, Treg levels tended to be higher than those in healthy volunteers (p=0.069); these levels were significantly reduced after tumor resection (p=0.0027). CONCLUSION: The prevalence of Treg was increased in patients with gastrointestinal cancer, even in the early stages of the disease. Since Treg levels decreased after curative resection, it is possible that tumor cells may have induced and expanded the Treg pool. PMID- 19443362 TI - A pilot study of quality of life of patients with hormone-refractory prostate cancer after gene therapy. AB - BACKGROUND: The effects on quality of life (QOL) after a Phase I/II clinical trial of a combination of osteocalcin promoter-driven herpes simplex virus thymidine kinase (Ad-OC-TK) gene therapy and valacyclovir (VAL) were investigated for patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: The QOL of six patients was prospectively assessed after gene therapy on days 0, 14, and 28. A modified questionnaire was created based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire's prostate cancer-specific module (EORTC QLQ-PR25). RESULTS: The scores of all items significantly improved along with the total score. Further, bodily pain was significantly reduced on day 28. Moreover, the rate of change in the serum prostate-specific antigen levels from day 0 to day 28 was significantly correlated with the rate of change in bodily pain. CONCLUSION: In this clinical trial, Ad-OC-TK plus VAL treatment significantly improved the short-term QOL and bodily pain of patients with localized recurrence or bone metastases of HRPC. PMID- 19443363 TI - Assessing the size of polyp phantoms in tandem colonoscopies. AB - BACKGROUND: The size of colorectal neoplastic polyps is important for their clinical management. MATERIALS AND METHODS: The size of 12 polyp phantoms was assessed in tandem colonoscopies carried out by 7 endoscopists differing in years of clinical endoscopical experience. The endoscopists measured, with (n=5) or without (n=2) the aid of open forceps, the largest diameter of 12 polyp phantoms. Measurements in two independent trials were compared with the gold standard-size assessed at The Department of Production Engineering, The Royal Institute of Technology. RESULTS: In tandem trials, 99.4% (167/168) of the measurements underscored the gold standard size. In the 1st trial, the size in all 84 measurements was underestimated by -40% (range -34% to -45%) and in the 2nd trial the size in 83 of the 84 measurements was underestimated by -34% (range -24% to 42%). Neither the age of the participant, nor the years of experience with clinical endoscopy improved the results obtained. The participants significantly underestimated larger devices (>or=20 mm) whereas the smallest "polyps" were also underestimated, but with a lower degree of inaccuracy. The absolute difference between the golden standard size and the mean of all measurements performed on each polyp in 167 out of 168 measurements followed a regular downward trend. The volume of the devices was one of the confounding factors in size assessment. When compared to the gold standard size, the larger the "polyp" size, the higher the degree of underestimation. This may be crucial considering that the risk for colorectal adenomas to shelter an invasive growth is 46%, for adenomas measuring >or=2 cm, a limit accepted as a guideline worldwide for the management of patients with large colorectal polyps. CONCLUSION: Considering the clinical implications of the results obtained, the possibility of developing a method that would allow the assessment of the true size of polyps in clinical colonoscopy, is being explored. PMID- 19443364 TI - Gemcitabine-capecitabine plus intra-arterial epirubicin-cisplatin in pretreated pancreatic cancer patients: a phase I study. AB - BACKGROUND: Gemcitabine plus capecitabine are active in patients (pts) with advanced pancreatic cancer (APC). Intra-arterial chemotherapy showed activity and low toxicity. Combination of systemic and intra-arterial chemotherapy was investigated. PATIENTS AND METHODS: Patients with APC, progressed after a first line chemotherapy, were included. Fixed doses of epirubicin 35 mg/m(2) and cisplatin 42 mg/m(2) intra-arterially every 28 days, and capecitabine 650 mg/m(2) twice a day on days 2-15; gemcitabine systemically in increasing doses on day 2. The purpose was to find maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). RESULTS: Fifteen patients were enrolled. DLT occurred at 1300 mg/m(2) of gemcitabine and consisted of myelotoxicity (grade 4 febrile neutropenia and grade 4 thrombocytopenia). CONCLUSION: Limiting toxicity was hematological. For further studies intra-arterial epirubicin 35 mg/m(2) and cisplatin 42 mg/m(2); systemic gemcitabine at 1,000 mg/m(2) on day 2, and capecitabine at 650 mg/m(2) twice a day PO on days 2-15 are suggested. PMID- 19443365 TI - Cancer-induced hypercalcemia. AB - Cancer-induced hypercalcemia (CIH) occurs in 5% to 30% of patients with cancer during the course of their disease, depending on the type of tumor. This review provides information on the pathophysiology and treatment of CIH. Enhanced bone resorption is the primary cause of CIH and the release of tumor-derived mediators induces this increase in osteoclast-mediated resorption. The interactions between osteoclasts and cancer cells are mainly mediated by parathyroid hormone-related protein (PTHrP), that activates osteoblasts to produce receptor activator of nuclear factor-kappa ligand (RANKL) and osteoclast precursors, with subsequent bone osteolysis. Low parathyroid hormone serum levels together with high calcium levels in a cancer patient may suggest a CIH. There are two different therapeutic approaches for treating CIH, to increase the urinary excretion of calcium, or to inhibit osteoclastic bone resorption, RANKL or the action of PTHrP. In patients with CIH the first step of therapy is usually to restore renal function which is often impaired due to dehydration. Bisphosphonates administration is at present the main-stay of treatment, while calcitonin, gallium nitrate and mithramycin have limited activity and several side-effects. Anti-RANKL therapy (denosumab) and antibodies against PTHrP are promising therapies, but their clinical use should be further explored to more clearly document the effects. PMID- 19443366 TI - Changes in estrogen receptor, progesterone receptor and Her-2/neu status with time: discordance rates between primary and metastatic breast cancer. AB - BACKGROUND: Changes in the receptor profile between primary and metastatic breast cancer tissue have been suggested. The degree of hormone receptor discordance in archival paired pathological samples was evaluated. MATERIALS AND METHODS: Archival data were collected on 100 patients for whom tissue from primary and metastatic sites was available. Estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu status in the primary and metastasis were compared. RESULTS: The discordance rate for ER was 17.7% (2-sided p=0.0039) with 9.7% of tumours changing from ER-positive to ER-negative and 8.0% changing from ER-negative to ER positive. The discordance rate for PR was 37.3% (2-sided p<0.0001), with all of these tumours changing from PR-positive to PR-negative. No significant discordance for Her-2/neu was found. CONCLUSIONS: This series suggests that significant discordance exists for hormone receptor status between primary and metastatic breast cancer samples. Loss of PR was particularly frequent. PMID- 19443368 TI - Prognostic value of serum and ascites levels of estradiol, FSH, LH and prolactin in ovarian cancer. AB - The aim of this study was to investigate the influence of sex hormone levels on tumor biology and patients' outcome in ovarian cancer. PATIENTS AND METHODS: One hundred and six patients with ovarian cancer were enrolled into this prospective study. Serum and ascites samples were obtained intraoperatively. Concentrations of estradiol, FSH, LH and prolactin were measured and correlated with parameters of tumor biology, such as FIGO stage, tumor spread and postoperative tumor residual mass. Patients with primary ovarian cancer were compared to patients with recurrent disease. Influence factors on progression-free survival and overall survival were analyzed using the Kaplan-Meyer method. RESULTS: Serum FSH concentrations were significantly higher and estradiol concentrations in ascites were significantly lower in patients with recurrent disease. According the multivariate analysis, only FSH level in ascites was seen to be an independent prognostic factor for patients' survival. CONCLUSION: High level of FSH in the ascites provides prognostic information in patients with ovarian cancer and is inversely correlated with patients' survival. PMID- 19443369 TI - DNA image cytometry in the differential diagnosis of benign and malignant lesions of the bile duct, the pancreatic duct and the papilla of Vater. AB - The value of DNA image cytometry in the differential diagnosis of benign and malignant epithelial lesions was tested analyzing 174 specimens from the biliary tract, the pancreatic ducts and the papilla of Vater. PATIENTS AND METHODS: Cytologic specimens (n=45) or monolayer smears, prepared from three 50 microm thick sections by a cell separation technique (n=129), were stained according to Feulgen. The DNA content of 250 epithelial cells, chosen per random, was determined using a TV-image analysis system CM-1 (Hund, Wetzlar, Germany). The DNA content of 30 lymphocytes served as an internal standard for the normal diploid value in every individual case. Different DNA cytometric parameters and the mean nuclear area were calculated. RESULTS: In comparison with the benign cases (n=120), the mean values of all DNA cytometric variables were markedly increased in the malignant (n=54) (p<0.001). However, a certain overlay of the data distribution had to be considered. Requiring a specificity of >or=95%, sensitivity values up to 87% (mean ploidy) could be obtained. An aneuploid DNA stemline was present in 76% of the tumor cases. The occurrence of 9cEEs were completely restricted to malignant specimens (specificity: 100%), but only present in 50% of the tumor cases. As an additional finding in some benign cases, DNA polyploidy up to 8c could be demonstrated (11/120, 9.2%). CONCLUSION: DNA image cytometry represents a relevant tool in the objective identification of malignant changes of specimens of the biliary tract, the pancreatic duct or the papilla of Vater, if suitable variables are used for DNA data interpretation. However, mainly due to the fact that several cases reveal only slight ploidy changes, a well-preserved DNA ploidy profile does not exclude malignant changes. PMID- 19443370 TI - Usefulness of current risk groups in the treatment of surgically staged endometrial carcinomas; a population-based study from Western Sweden. AB - BACKGROUND: Endometrial carcinoma is the most common malignancy of the female genital tract and its incidence is increasing. However, treatment results have not improved during the last decades. PATIENTS AND METHODS: Our regional quality register was used to evaluate treatment results for the period between January 1995 and December 2003. This study includes 2211 consecutive patients, of which 1993 surgically staged patients were evaluated in detail. Of these, 831 (53%) were at low risk and were given no further treatment after primary surgery. Patients with moderate- and high-risk tumors were postoperatively treated according to the respective protocols of one Swedish and one international study. Postoperative vaginal brachytherapy +/- external radiation was given to 486 (31%) patients at moderate risk, while 234 (15%) had high-risk disease and were randomized to external radiation + brachytherapy or external radiation + brachyterapy + chemotherapy. RESULTS: Overall cause-specific 5- and 10-year survival was 83.9% and 81.3%, respectively, for all included patients. The corresponding figures for surgically staged patients were 87.4% and 84.9%, respectively. One important observation was that there was no significant difference in survival between patients at low and moderate risk. CONCLUSION: The results strongly suggest that the risk groups used during this study period were not optimal. It is recommended to use smaller, better specified groups defined by more prognostic factors for enhanced individualization of treatment. PMID- 19443371 TI - Primary abdominal wall clear cell carcinoma: case report and review of literature. AB - BACKGROUND: The development of a mass in a surgical scar poses a diagnostic dilemma due to similarities in appearance to hernias, abscesses, hematomas or desmoid tumors. Scar endometriosis is uncommon and malignant change within this ectopic tissue is rare. CASE REPORT: The case of a 55-year-old woman with an isolated clear cell adenocarcinoma in an area of scar endometriosis more than 17 years after a cesarean section is presented. Initially, this tumor was thought to be a chronic abscess, but was finally diagnosed as clear cell carcinoma. This case highlights the difficulties in preoperative diagnosis as well as the poor prognosis of these tumors. CONCLUSION: Accurate diagnosis of a lump within a scar is important to define the prognosis and treatment. Further data are needed for the management of this pathology. PMID- 19443372 TI - Tumor immune systems in esophageal cancer with special reference to heat-shock protein 70 and humoral immunity. AB - The objective of this study was to clarify the participation of heat-shock protein 70 (HSP70) and the humoral immune system in antitumor immunity in esophageal cancer. PATIENTS AND METHODS: Immunohistochemical staining for HSP 70, and CD4(+) T-, CD8(+) T-, B- and plasma cells was performed on surgical specimens obtained from 125 patients with esophageal cancer. An enzyme-linked immunosorbent assay (ELISA) was then performed to measure serum anti-HSP70 antibodies in the azygos vein. RESULTS: The expression of HSP 70 correlated inversely with depth of invasion (p<0.0001), pathological stage (p<0.0001) and blood vessel invasion (p<0.001), and there was a positive correlation between HSP70 and CD4(+) T-, CD8(+) T-, B- and plasma cells. Of these, the B- and plasma cells had the strongest correlation to HSP70 expression. Serum anti-HSP70 antibody levels in the azygos vein correlated with HSP70 expression, and B and plasma cell infiltration. Patients positive for HSP70, and B- and plasma cell infiltration had good prognosis compared to other cases. According to multivariate analyses, simultaneous occurrence of HSP70 expression, and B- and plasma cell infiltration is a stronger prognostic factor than simultaneous occurrence of HSP70 expression, and CD4(+) T- and CD8(+) T-cell infiltration. CONCLUSION: It is suggested that the HSP70-humoral immune cell system might play an important role in antitumor effects in patients with esophageal cancer. PMID- 19443373 TI - High incidence of synchronous or metachronous breast cancer in patients with malignant and benign thyroid tumor or tumor-like disorders. AB - BACKGROUND: Although many reports indicated an association between thyroid diseases and breast cancer, such an association still remains controversial. The present study was aimed to clarify the association of thyroid diseases with the breast cancer incidence. In the patients with benign and malignant thyroid tumor or tumor-like disorders, the incidence of other malignancies was surveyed, and the frequency of thyroid cancer in patients with breast cancer was also surveyed. PATIENTS AND METHODS: Between 1982 and 2005, a total of 201 female patients received surgery for tumor or tumor-like disorders, including 65 carcinoma, 68 adenoma, 61 adenomatous goiter and 7 chronic thyroiditis cases. Their outcomes were surveyed in December 2006. Furthermore, during the same periods, 340 female patients underwent breast cancer surgery and their outcomes were also surveyed in December 2006. RESULTS: The overall incidence rate of breast cancer was 16.4% (33/201) in the patients, who received thyroid surgeries and was much higher than other malignancies: 2.0% gastric cancer, 1.0% uterine and colorectal cancer. The incidence rate of breast cancer in each disease was 13.8% for thyroid cancer, 16.2% for adenoma and 21.3% for adenomatous goiter, but no incidence for chronic thyroiditis. On the other hand, in the patients with breast cancer during the same period in our department, the frequency of thyroid cancer was only 2.1% (7/340). CONCLUSION: It appears that thyroid cancer, adenoma and adenomatous goiter were associated with the risk of breast cancer, but chronic thyroiditis was not related. PMID- 19443374 TI - Mifepristone may halt progression of extensively metastatic human adenocarcinoma of the colon - case report. AB - BACKGROUND: Mifepristone, a progesterone receptor antagonist has been found to improve the length and quality of life in various spontaneous murine cancer models including tumors without progesterone receptors theoretically by inhibiting an immunomodulatory protein that suppresses natural killer cell function in the tumor microenvironment. MATERIALS AND METHODS: Mifepristone 200 mg per day by mouth was given to two patients with stage 4 colon cancer with extensive metastases. RESULTS: Both patients not only survived far longer than expected but had marked improvement in their quality of life similar to mice. Though the metastatic lesions did not disappear, no new ones appeared for a long time and the ones present did not grow. The drug was extremely well tolerated. CONCLUSION: The use of progesterone receptor antagonists may present a novel immunotherapy to help fight cancer. A larger controlled study is needed. PMID- 19443375 TI - Microsatellite instability does not predict the efficacy of chemotherapy in metastatic colorectal cancer. A systematic review and meta-analysis. AB - BACKGROUND: Microsatellite Instability (MSI) status is a good prognostic factor for colorectal cancer (CRC) but its predictive value for chemosensitivity remains controversial. A previous meta-analysis (MA) in the adjuvant setting showed that MSI-high (H) status did not predict the efficacy of chemotherapy. The predictive value of MSI status on the effect of metastatic chemotherapy was investigated by MA. PATIENTS AND METHODS: Studies were identified by electronic search through PubMed, Embase and ASCO proceedings online databases, using several key words (colorectal cancer, chemotherapy, microsatellite instability). For each study, the ratio of response rate (RR), complete (CR) and partial response (PR) divided by stable disease and progression was calculated. From 190 articles and 100 abstracts, only eight independent studies were selected. The data were analysed with a random-effect model (due to heterogeneity between studies) using EasyMA software. Statistical calculations were performed on six studies representing 964 patients (mean age 63 years; 91 MSI-H; 873 microsatellite stable (MSS) tumours). A total of 287 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 678 patients received combinations of 5FU or capecitabine with oxaliplatin and/or irinotecan. RESULTS: No benefit of metastatic chemotherapy in terms of RR for MSI H patients compared with MSS patients was found. The global hazard ratio (HR) for RR was 0.82 (95% confidence interval, CI: 0.95; 0.65-1.03; p=0.09). CONCLUSION: MSI status does not predict the effect of chemotherapy which is similar in MSI-H and MSS metastatic CRC tumours. PMID- 19443376 TI - Clinical and pathological response to primary chemotherapy in patients with locally advanced breast cancer grouped according to hormonal receptors, Her2 status, grading and Ki-67 proliferation index. AB - OBJECTIVES: Biological markers that reliably predict clinical and pathological response to primary systemic therapy may have considerable clinical potential; this study evaluated response compared to expression of ER, PgR and Her2, grading and Ki-67 proliferation index before and after neoadjuvant chemotherapy in patients with locally advanced breast cancer (LABC). PATIENTS AND METHODS: Fifty five patients received neoadjuvant chemotherapy for LABC. The incidence of clinical and pathological responses was assessed with respect to basal clinical stage, absent/low vs. high ER and PgR status, low vs. high proliferation index, grading and Her2 overexpression. RESULTS: Overall, 30 patients (54%) underwent downstaging of their primary tumor; pathological complete remission was observed in only one patient with Her2 positive breast tumor. Patients with pre-treatment Ki-67 >20%, Her2 overexpression, T2b/T3 vs. T4 clinical stage achieved higher response rate. CONCLUSION: The future of neoadjuvant therapy lies in tailoring treatment to individual patients by identifying response predictors; although the number of patients reported is small, this study confirms that clinical stage at diagnosis, Ki-67 reduction and Her2 overexpression are predictive of tumor response to neoadjuvant regimens. PMID- 19443377 TI - Management of cardiac adverse events occurring with sunitinib treatment. AB - BACKGROUND: Sunitinib malate is the reference standard of care for the first-line treatment of metastatic renal cell carcinoma (mRCC). Cardiovascular adverse events (AEs) have been observed with sunitinib treatment. Here, we present the case report of a 49-year-old male patient with mRCC in whom cardiac AEs experienced during sunitinib treatment were successfully managed. The patient was at poor prognostic risk, with an Eastern Cooperative Oncology Group performance status of 3. RESULTS: The patient was treated with sunitinib 50 mg/day (4 weeks on treatment followed by 2 weeks off treatment; Schedule 4/2) following lung and bone metastases. Cardiac AEs occurred following sunitinib initiation. These events were resolved with cardiovascular co-medication. Sunitinib improved the patient's quality of life and performance status, with a prolonged duration of treatment of 24 months. CONCLUSION: This case indicates that cardiac AEs should not be a barrier to the effective use of sunitinib in mRCC. PMID- 19443378 TI - Genetic polymorphisms in CYP1A1, CYP1B1, COMT, GSTP1 and NAT2 genes and association with bladder cancer risk in a French cohort. AB - Tobacco smoking and environmental exposures are the main known risk factors for bladder cancer (BC) via exposure to chemical carcinogens. Genetic differences in the metabolism of chemicals have been suggested to be associated with individual susceptibility to BC. Polymorphisms in genes coding to metabolising enzymes, resulting in variation of carcinogen detoxification efficiency, may therefore change the response of individuals to chemical carcinogens and be associated with an increased BC risk. PATIENTS AND METHODS: The aim of the study was to investigate the association between functional polymorphisms in CYP1A1, CYP1B1, COMT, GSTP1 and NAT2 genes and BC risk, through a hospital-based case-control study. The genotyping of 11 Single Nucleotide Polymorphisms (SNPs) was carried out on DNA of 51 bladder cancer male patients and 45 male controls. The technique of MGB (Minor Groove Binder) probes that utilize allelic discrimination with the Taqman(R) method was used. RESULTS: Individuals with NAT2 slow acetylator genotypes had a significant increase in risk of BC compared to individuals with NAT2 rapid acetylators (OR adjusted for smoking status=2.70; 95% CI, 1.10-6.61). GSTP1 Ile(105)Val variants (deletion of one - Ile/Val- and two -Val/Val-, null genotype- copies) showed a marginal increased risk of BC with OR adjusted for smoking status of 2.27 (95% CI, 0.97-5.31) compared to individuals carrying wild type genotype (Ile/Ile). No statistically significant effects on BC risk with CYP1A1, CYP11B1 and COMT genotypes were observed. CONCLUSION: The results are consistent with previous literature among Caucasian populations. PMID- 19443379 TI - Comparison of robotic-assisted versus retropubic radical prostatectomy performed by a single surgeon. AB - BACKGROUND: To compare perioperative outcomes between patients undergoing robotic assisted laparoscopic radical prostatectomy (RALP) and patients undergoing retropubic radical prostatectomy (RRP) performed by a single surgeon in Taiwan. PATIENTS AND METHODS: This study was a retrospective review of 30 consecutive patients who underwent RRP and 30 initial patients who underwent RALP. The preoperative parameters, operation parameters (operative time, vesicourethral anastomosis time, blood loss, transfusion and complication rates) and postoperative parameters (post-operative stay, catheter duration, cystography received, continence rate, sexual function and histopathologic factors) were evaluated. RESULTS: Preoperative clinical parameters were similar between groups. Vesicourethral anastomosis time was shorter in RRP group than in RALP group. RRP had higher incidence of bilateral pelvic lymph node dissection than RALP (100% vs. 73.3%), but lower incidence of neurovascular bundle preservation (6.7% vs. 53.3%). Significant differences were found in blood loss (RALP 314 mL vs. RRP 912 mL) and transfusion rates (RALP 13.3% vs. RRP 60%) between groups. A statistically significant difference was found in incidence of cystograms performed between RRP and RALP groups (93.3% vs. 43.3%) before removing urethral catheter. Positive surgical margin was 20% in RRP group vs. 50% in RALP group, demonstrating statistical significance. Shorter catheterization duration and postoperative stays were found with RALP. Three-month continence rate was higher in RALP patients than in RRP patients (76.7% vs. 36.7%, p=0.04). CONCLUSION: RALP is minimally invasive with less blood loss and lower transfusion rates than RRP. RALP had greater incidence of neurovascular bundle preservation and faster convalescence than RRP. PMID- 19443380 TI - Comparison of clofarabine activity in childhood and adult acute leukemia: individual tumor response study. AB - BACKGROUND: Clofarabine is a second-generation nucleoside analogue. The aim of the study was the analysis of ex vivo activity of clofarabine and 14 other anticancer drugs in pediatric and adult acute lymphoblastic (ALL) and myeloid (AML) leukemia. PATIENTS AND METHODS: The ex vivo drug resistance profile was analyzed in 282 patients, including 201 children with ALL de novo, 24 children with relapsed ALL, 25 children with AML de novo and 32 adults with AML. Cellular ex vivo drug resistance was tested by means of the MTT assay. RESULTS: Clofarabine had comparable ex vivo activity against lymphoblasts and myeloblasts, both on initial diagnosis and at relapse, both in children and in adults. Its activity in acute myeloid leukemia was independent of patient age. No significant differences in drug resistance to clofarabine between pediatric age-based subgroups of ALL were detected, while it was observed for most of other drugs. An activity of clofarabine in relapsed pediatric ALL patients was as good as in newly-diagnosed ones. CONCLUSION: In comparison to childhood acute lymphoblastic leukemia, lack of differences in ex vivo activity gives rationale for use of clofarabine in refractory and relapsed pediatric and adult patients with acute myeloid leukemia. PMID- 19443381 TI - The clinical significance of serum markers of bone turnover in NSCLC patients: surveillance, management and prognostic implications. AB - The purpose of this study was to investigate various serum markers of bone turnover in non-small cell lung cancer patients (NSCLC) in the presence or absence of bone metastasis. Our retrospective study included 79 newly diagnosed NSCLC patients. Group A included 51 patients with bone metastasis and group B included 28 patients that never developed bone metastasis. The measurement of bone formation markers, bone resorptive markers and osteoclastogenesis markers as well as routine biochemical analysis was determined. Patients with bone metastasis had an increase in receptor activator of nuclear factor kappaB ligand, osteopontin and osteoprotegerin. Patients who later developed bone metastasis had decreased osteocalcin and tartrate-resistant acid phosphatase isoform 5b levels (TRACP-5b). We also found an unusually low TRACP-5b/RANKL ratio for patients who have or later developed metastasis. In patients that never developed bone metastases, cross-linked carboxy-terminal telopeptide of type I collagen was increased. Positive correlations were found between osteopontin and TRACP-5b, and also between bone alkaline phosphatase with osteocalcin and TRACP-5b. In conclusion, serum markers of bone turnover may be able to determine the time-to tumor progression, metastatic potential and overall survival of the NSCLC patient. In addition, they may contribute to a more accurate follow-up and tailored treatment options. PMID- 19443382 TI - CYP17 gene polymorphism and its association in north Indian prostate cancer patients. AB - BACKGROUND: The CYP17 gene codes for the cytochrome P450c17a enzyme, which mediates two key steps in sex steroid synthesis In this study, the association between CYP17 polymorphism and the risk of prostate cancer in comparison to benign prostatic hyperplasia (BPH) in a north Indian population was investigated. PATIENTS AND METHODS: This study included 157 prostate cancer patients and 170 BPH patients as controls. A 451-bp fragment encompassing the polymorphic site was amplified by PCR and treated with the restriction enzyme MspA1. The undigested allele was recognized as A1 and the MspA1-digested variant allele was designated as the A2 allele. RESULTS: Men with the A2/A2 CYP17 genotype had an increased risk of prostate cancer (OR=3.56; 95% CI=1.49-8.53; p=0.004) compared with those with the A1/A1 genotype. A significantly increased risk of prostate cancer was also found in smokers as well as non-vegetarians by four-fold as compared to their counterparts. There was a significant association between the CYP17 genotype and the tumour status (stage) of prostate cancer. The A2 allele showed a 1.90- (95% CI=1.09-3.32; p=0.02) and a 1.51- (95% CI=1.08-2.13; p=0.017) fold increased risk of prostate cancer in localized and metastatic prostate cancer cases respectively. CONCLUSION: The A2 allele of the CYP17 polymorphism is associated with an increased risk of prostate cancer and has a role in the development of prostate cancer in smokers and non-vegetarians. PMID- 19443383 TI - Gastric perforation presenting as empyema in a patient with pancreatic cancer on bevacizumab treatment. AB - Bowel perforation is a rare but life-threatening complication of bevacizumab, a new anticancer treatment. Patients with bowel perforation usually present with acute abdominal symptoms. Here a case history is presented to highlight a pancreatic cancer patient on bevacizumab chemotherapy who developed empyema as the first manifestation of gastric perforation. This unusual presentation warns physicians that bevacizumab-related bowel perforation can arise as a thoracic complication, without typical gastrointestinal manifestations, in an advanced cancer patient. PMID- 19443384 TI - Reconstruction of periacetabular bone tumor by vascularized fibula graft and irradiated autograft. AB - BACKGROUND: Periacetabular reconstruction following malignant bone tumor resection for limb saving is extremely challenging. We attempted a new reconstruction method in two patients by combining a free vascularized fibula graft with an extracorporeally irradiated autograft. PATIENTS: A 14-year-old boy with osteosarcoma and a 44-year-old man with chondrosarcoma were treated with wide excision of the tumor, followed by periacetabular reconstruction with an autogenous, extracorporeally irradiated osteoarticular graft combined with a free vascularized fibula graft. RESULTS: Incorporation of the irradiated pelvic bone was achieved without any complications and the resulting limb function was good. Osteoarthritic changes were seen in one patient. CONCLUSION: This reconstruction method was safe and reliable for primary, limb-sparing surgery. It is best indicated when the femoral head can be preserved and the mechanical strength of the affected acetabulum is maintained. PMID- 19443385 TI - Lymphatic vessel density in correlation to lymph node metastasis in head and neck squamous cell carcinoma. AB - BACKGROUND: In head and neck squamous cell carcinoma (HNSCC), metastatic dissemination to regional lymph nodes serves as a major prognostic indicator for incipient disease progression and constitutes the guideline for subsequent therapeutic strategies. In this study, whether intratumoral (IT) and peritumoral (PT) lymphatic vessel density (LVD) might be a predictive indicator to the risk of lymph node metastasis was investigated. PATIENTS AND METHODS: Tumour lymph vessels in fresh frozen sections of 105 head and neck cancer were quantified by immunostaining for the lymphatic endothelial marker LYVE-1. These results underwent correlation with the nodal status of the patient. RESULTS: There was a significant relationship between a high IT LVD and nodal metastasis (N+) (p=0.049, Mann-Whitney test). Analysed separately by anatomic regions, a significant correlation was only shown in oral carcinoma (p=0.032, Mann-Whitney test). Intratumoral LVD was lower compared to peritumoral LVD. Logistic regression, however, showed that the only predictive parameter for the nodal status was the localisation of the primary tumour but not LVD. CONCLUSION: This study confirmed that IT LVD is low in HNSCC. In this group of tumours there was a significant correlation between IT LVD and nodal involvement. PMID- 19443386 TI - Clinicopathological features of perforated colorectal cancer. AB - The aim of this retrospective study was to determine clinicopathological factors pertinent to the prognosis of perforated colorectal cancer (PCRC). PATIENTS AND METHODS: A retrospective review of clinical records of 17 cases of emergency primary resection for PCRC (stage IIIa in 2, stage IIIb in 6 and stage IV in 9) was performed. RESULT: The 5-year survival rate was 31% (31% for stage III and 12% for stage IV). When compared with non-PCRC (533 cases) in stage III (78.8%) or stage IV (14.8%), the 5-year survival rate of stage III perforated colorectal cancer was clearly worse (p<0.01) than the non-perforated counterpart. For stage IV, however, the two groups had a similar prognosis. MST of the PCRC was 31 months for stage III and 12 months for stage IV. Approximately half of the recurrence pattern of stage III (75%), or stage IV (44%) PCRC was peritoneal carcinomatosis. As for the type of operations performed, Hartmann's procedure was the preferred technique (71%), for which mortality and morbidity rate were both low. CONCLUSION: Because of the high incidence of peritoneal carcinomatosis and low 5-year survival rate, stage III PCRC should be regarded as a stage IV disease, for which postoperative chemotherapy seems essential. PMID- 19443387 TI - Expression of matriptase and clinical outcome of human endometrial cancer. AB - BACKGROUND: Matriptase, a type II transmembrane serine protease is involved in angiogenesis, degradation of extracellular matrix and in progression of some epithelial cancers. The purpose of the present study was to examine matriptase expression and evaluate its clinicopathological significance in endometrial cancer. PATIENTS AND METHODS: Matriptase expression was examined in normal endometrium (n=20), endometrial hyperplasia (n=11) and endometrial cancer (n=65) samples. The distribution of cases that scored positive for each of the biological parameters examined was correlated with matriptase expression status obtained by immunohistochemistry. RESULTS: Matriptase was found to be significantly overexpressed in endometrial cancer as compared with normal endometrium and endometrial hyperplasia. Interestingly, matriptase expression is associated with stage (p=0.010), grade (p=0.021), depth of myometrial invasion (p=0.004), cervical involvement (p=0.021), lymph node metastasis (p=0.009), LVS involvement (p=0.041) and peritoneal cytology (p=0.045). The high matriptase expression was a significant predictor for poor prognosis when compared with low matriptase expression (Disease-free survival rate; p=0.032, Overall survival rate; p=0.011). CONCLUSION: High matriptase expression in endometrial cancer may be associated with poor prognosis. PMID- 19443388 TI - Immunohistochemical detection of WT1 protein in endometrial cancer. AB - BACKGROUND: The Wilms' tumor gene WT1 is overexpressed in various kinds of solid tumors. However, it remains unclear whether WT1 plays a pathophysiological role in endometrial cancer. PATIENTS AND METHODS: A series of 70 endometrial cancer patients who had undergone a curative resection was studied to determine the correlation between WT1 expression, clinicopathological characteristics and prognosis. Tissue specimens were evaluated for WT1 expression by immunohistochemistry. RESULTS: The expression of WT1 was strong in 31 patients (44%) and weak in 39 patients (56%). WT1 overexpression was associated with advanced FIGO stage (p=0.0266), myometrial invasion (p=0.0477) and high-grade histological differentiation (p=0.0049). The expression level of WT1 was found to be a significant predictor of disease relapse in univariate analysis (p=0.0233), but not in multivariate analysis (p=0.4757). CONCLUSION: These results suggested that tumor-produced WT1 provided additional prognostic information in endometrial cancer patients. PMID- 19443389 TI - Prognosis for isolated skin recurrence after breast cancer treated by mastectomy. AB - Isolated skin recurrence after mastectomy (ISRAM) for breast cancer is a rare event for which treatment is difficult and subject to debate. PATIENTS AND METHODS: The records of 75 patients presenting with ISRAM were reviewed retrospectively. The factors liable to affect recurrence prognosis were analyzed, and included both factors related to the primary tumor and its treatment and those related to the recurrence itself. RESULTS: The size of the primary tumor is correlated with the inflammatory nature of the recurrence as well as overall survival. Metastatic lymph node involvement also affects the risk of inflammatory recurrence and is correlated with overall survival. Salvage mastectomy for local recurrence after primary breast-conserving surgery followed by ISRAM has a poor prognosis in terms of recurrence-free survival, and chest wall radiotherapy after primary mastectomy reduces the risk of metastatic development after ISRAM. When confronted with ISRAM, 2 factors affect prognosis: the inflammatory nature of the recurrence impairs overall survival and chest wall radiotherapy reduces the risk of secondary systemic disease. CONCLUSION: these results underline the importance of good local control when treating the primary tumor (to reduce the risk of ISRAM occurrence, and improve its prognosis if it occurs) and the advantage of locoregional and systemic treatment in the presence of ISRAM and in particular its inflammatory presentation. PMID- 19443390 TI - Kinetics of HER2/neu ECD in 45 patients treated with trastuzumab (Herceptin) between January 2001 and June 2005 at the Grenoble University Hospital. AB - The aim of this study was to evaluate the utility of HER2/neu ECD concentration as a marker of the efficacity of clinical response to Herceptin. PATIENTS AND METHODS: Iterative measurements of HER2/neu ECD (ELISA c-erbB2/c-neu Rapid Format Elisa kit QIA10 Calbiochem) concentrations in 45 patients treated with Herceptin between January 2001 and June 2005 at the Grenoble University Hospital. RESULTS: Changes in HER2/neu ECD concentrations were observed in 21 patients (47%). The baseline concentration was the concentration of circulating HER2/neu ECD before treatment with Herceptin. In 15 patients, the mean baseline concentration was 52 ng mL(-1) (extreme values 13-170), which normalized no later than at the time of the 3rd administration of Herceptin. Nine patients (60%) were still alive 5 years later (p<0.05). For 6 patients, the mean baseline concentration was 800 ng mL(-1) (extreme values 140-2000) which persisted and even increased during Herceptin therapy; fewer than 25% were alive 30 months later (p<0.05). In the case of the 24 patients whose HER2/neu ECD concentration remained <5 ng mL(-1), survival time was intermediate. CONCLUSION: The study confirmed the utility of HER2/neu ECD in predicting therapeutic response. However, as in the case of other circulating tumor markers, it is only useful when there is a variation in concentration. This marker should now be evaluated in multi-center studies covering a large number of homogeneous subjects. PMID- 19443391 TI - GSTM1 and NAT2 polymorphisms and colon, lung and bladder cancer risk: a case control study. AB - BACKGROUND: Glutathione S-transferase M1 (GSTM1) and N-acetyltransferase-2 (NAT2) are phase II enzymes involved in the metabolism of xenobiotics and whose polymorphisms have been related to individual cancer risks. PATIENTS AND METHODS: A case-control study was performed including 92 colon, 75 lung and 23 bladder cancer patients and 121 corresponding controls to verify the existence of an association between the main genetic polymorphisms of GSTM1 and NAT2 and the risk to develop cancer. Genomic DNA, isolated from 5 mL whole blood, was used to study GSTM1 and NAT2 polymorphisms using multiplex PCR and a PCR-RFLP technique, respectively. RESULTS: GSTM1 homozygous null genotype was associated with an increased risk of colon cancer, especially in females and in younger patients. For NAT2 gene, the results suggest a role for the low acetylator phenotype in the development of colon and lung cancer, especially in females. In bladder cancer patients two rare NAT2 genotypes were found at a higher frequency compared with all the other groups. CONCLUSION: The results do not suggest a different distribution of GSTM1 and NAT2 polymorphisms in the studied population compared to those reported for other Caucasian populations and warrant further studies in order to evaluate their potential relationship with individual cancer risks. PMID- 19443392 TI - Lymph-vascular space involvement and outer one-third myometrial invasion are strong predictors of distant haematogeneous failures in patients with stage I-II endometrioid-type endometrial cancer. AB - The aim of this retrospective study was to assess the predictive value of different clinicopathological variables (patient age, tumour size, FIGO grade, myometrial invasion, lymph-vascular space involvement [LVSI], invasion margins, peri-tumour phlogistic infiltrate and mitotic activity) for the risk of distant haematogenous recurrences in patients with endometrioid-type stage Ib-II endometrial cancer. Between August 1990 and April 2005, 259 patients had undergone laparotomy, peritoneal washing, total abdominal hysterectomy and bilateral salpingo-oophorectomy, with or without pelvic +/- para-aortic lymphadenectomy for endometrioid-type endometrial cancer. Thirty-six (13.9%) patients had developed recurrent disease after a median time of 17 months (range, 2-128 months). The relapse had been locoregional in 9, distant in 21 and both locoregional plus distant in 6 cases. This study assessed 12 patients with FIGO stage Ib-II disease who had developed distant haematogenous recurrences and 20 randomly chosen control patients with FIGO stage Ib-II disease who had remained recurrence-free after a median follow-up of 52 months (range, 37-66 months). Adjuvant therapy had been: no further treatment in 15 patients, external pelvic irradiation in 14 patients, adjuvant external pelvic irradiation plus brachytherapy in 2 patients and platinum-based chemotherapy followed by external pelvic irradiation in 1 patient. The site of distant failure had been the lung in 9 patients, liver in 2 patients and lung plus liver in 1 patient. A concomitant locoregional relapse (vagina or lymph nodes) had occurred in 3 patients. The median interval between surgery and the development of distant failure had been 16.5 months (range, 5-113 months). On univariate analysis, a higher incidence of FIGO grade 3 (50% versus 10%, p=0.0114), outer one-third myometrial invasion (91.7% versus 35.0%, p=0.0051) and LVSI (75.0.% versus 20.0%, p=0.0022) was found in the patients who had developed distant haematogeneous metastases compared to the recurrence-free women. Multivariate analysis showed that LVSI (p=0.0264) and deep myometrial invasion (p=0.0345) were independent predictive variables for the risk of distant haematogeneous failure. Patients with these pathological findings should be enrolled in randomised trials designed to assess the role of adjuvant chemotherapy alone or combined with sequential and/or concomitant external pelvic irradiation. PMID- 19443393 TI - Comparison of antiemetic efficacy between single and repeated treatments with a 5 HT3 receptor antagonist in breast cancer patients with high-risk emetogenic chemotherapy. AB - BACKGROUND: The significance of repeated treatment with the 5-HT(3) receptor antagonist for prophylaxis of chemotherapy-induced emesis remains to be clarified. PATIENTS AND METHODS: A retrospective analysis was performed to compare the effects of single and repeated treatment with granisetron on anorexia, nausea and vomiting in patients with breast cancer who undertook anthracycline and cyclophosphamide-based cancer chemotherapy. RESULTS: The control of anorexia was significantly better in the single treatment group than in the repeated treatment group (54% versus 73%; odds ratio (OR), 0.433; 95% confidence intervals (CI), 0.226-0.828; p=0.016), although the rate of complete response to any signs of the gastrointestinal side-effects was not different between the two groups (37% versus 39%; OR, 0.911; CI, 0.489-1.700; p=0.874). However, the incidence of constipation was more frequent in the repeated treatment group (60% versus 37%; OR, 2.586; CI, 1.388-4.818; p=0.003). CONCLUSION: Repeated treatment with 5-HT(3) receptor antagonist is not likely to be beneficial to breast cancer patients who undertook anthracycline/cyclophosphamide combination chemotherapy. PMID- 19443394 TI - Phase I study of the sequential administration of S-1 and cisplatin for metastatic gastric cancer. AB - The combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) has been reported to be active against metastatic gastric cancer (MGC) and great synergy has been shown in vivo and in vitro when 5-FU precedes CDDP. The sequential combination of S-1 (tegafur, oxonic acid, 5-chloro-2,4-dihydroxypyridine) followed by CDDP for MGC was investigated. A phase I trial applying increasing doses of oral administration of S-1 (65-80 mg/m(2)) for 21 days and increasing doses of CDDP (60-80 mg/m(2)) on day 22 every 35 days was conducted in order to determine the maximum tolerated dose (MTD) and recommended phase II dose. Patients with metastatic or recurrent gastric cancer, no prior chemotherapy, measurable disease, ECOG performance status less than 3 and adequate organ functions were eligible for the study. Three patients were treated at each dose level with escalation based on toxicity. Fifteen patients were included and evaluated for dose-limiting toxicity (DLT) and MTD. DLT included NCICTC grade 3 anorexia and fatigue in patients treated at S-1 80 mg/m(2) and CDDP 80 mg/m(2) (dose level 5). The other toxicities, grade 3 or higher, included neutropenia (grade 3) and nausea/vomiting (grade 3). Non-hematological toxicities were grade 1/2 and included diarrhea, nausea and stomatitis. There was no treatment-related mortality. Therefore, the recommended dose was a combination of S-1 at 80 mg/m(2) and CDDP at 70 mg/m(2). This sequential administration of S-1 and CDDP every 35 days is tolerable and warrants a phase II trial. A multicenter phase II study is currently under way. PMID- 19443395 TI - Phase II study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer. AB - BACKGROUND: To date, no phase II trial of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer (NSCLC) has been published. The safety and efficacy of the combination of nedaplatin and weekly paclitaxel in patients with NSCLC was examined. PATIENTS AND METHODS: Patients with previously untreated NSCLC, either stage IIIB with pleural effusion or stage IV, were eligible if they had a performance status of 0 to 2, were 75 years or younger and had adequate organ function. Patients were treated with nedaplatin (80 mg/m(2) on day 1) and weekly paclitaxel (90 mg/m(2) on days 1, 8 and 15). RESULTS: From March 2005 through March 2008, 47 patients (31 men and 16 women; median age, 66 years; age range, 38 to 75 years) were enrolled. The overall response rate was 53.2% (95% confidence interval, 38.1% to 67.9%). The median survival time was 13 months (range, 1 to 36 months), the 1-year survival rate was 62% and the median time to disease progression was 5 months (range, 1 to 19 months). Grade 3 to 4 hematologic toxicities included neutropenia in 38.3% of patients, thrombocytopenia in 2.1% and anemia in 23.4% . Although frequent non-hematologic toxicities were nausea, hepatic dysfunction and peripheral neuropathy, all cases were of only mild to moderate severity. Although 1 patient had grade 3 pulmonary toxicity due to drug-induced pneumonia, this patient recovered after receiving steroid therapy. CONCLUSION: This combination chemotherapy is effective and well tolerated and is an acceptable therapeutic option for patients with untreated advanced NSCLC. PMID- 19443396 TI - Genetic alterations in the PI3K pathway in prostate cancer. AB - Alterations in the PIK3CA and PTEN genes were assessed in 40 prostate tumors (radical prostatectomy samples). Genetic analyses in glands of the highest Gleason pattern within each tumor revealed PIK3CA amplification in 13%, PIK3CA mutations in 3%, PTEN homozygous deletion in 13% and PTEN hemizygous deletion in 8% of the cases analyzed. Supporting the view that PTEN and PIK3CA act in the same PI3K signaling pathway, genetic alterations in the PIK3CA and PTEN genes were mutually exclusive, except in one tumor. Overall, 13 of the 40 (33%) prostate tumors had alterations in the PI3K pathway. For cases with genetic alterations, other tumor areas with lower Gleason patterns as well as non tumorous prostate glands were also analyzed. Of nine tumors with Gleason score 7, five cases contained the same genetic alterations in tumor areas of Gleason patterns 3 and 4, whereas in another four cases, genetic alterations were detected only in tumor areas of Gleason 4 but not Gleason 3 patterns. There were no alterations in non-tumorous glands. These results suggest that genetic alterations in the PI3K pathway are common in prostate cancer, and occur mainly through PIK3CA amplification and PTEN hemizygous or homozygous deletion. Glands of Gleason pattern 3 are genetically heterogeneous, some containing the same genetic alterations observed in glands of Gleason pattern 4. PMID- 19443397 TI - Different biological materials are found in neoplastic glands with pores at the invading edge of sporadic colonic carcinomas. AB - BACKGROUND: Studying the invading edge of colorectal carcinomas it was previously noticed that the neoplastic glands with pores could contain mucin, inflammatory cells and/or necrotic material. AIMS: To systematically record the type of intraglandular materials found in the neoplastic glands with pores at the invading edge of sporadic colonic carcinomas. MATERIALS AND METHODS: Histological sections from 12 adenocarcinomas were selected when the following materials were predominantly found in the neoplastic glands with pores at the invading tumor edge: mucin (3 cases, group I), neutrophilic granulocyes (3 cases, group II), necrotic material (3 cases, group III) and invaginated stroma (3 cases, group IV). Surgical histological sections were stained with hematoxylin and eosin (H&E) and analyzed at 20 magnifications. The length of the invading edge was measured with a translucent millimetre ruler and the number of glands with pores per mm was calculated in each case. RESULTS: Two hundred and ninety-five glands with pores were analyzed in the 12 cases. Mucus was found in 68% (n=55) of the 81 glands with pores in group I, granulocytes in 95% (n=41) of the 43 glands with pores in group II, necrotic material in 72% (n=84) of the 117 glands with pores in group III and stromal invaginations in 61% (n=33) of the 54 glands with pores in group IV. The mean number of glands with pores per mm was 1.02 (55 glands/54 mm) in group I, 0.93 (41 glands/44 mm) in group II, 1.22 (84 glands /69 mm) in group III and 0.62 (33 glands /53 mm) in group IV. DISCUSSION AND CONCLUSION: Neoplastic glands with pores at the invading front of colonic adenocarcinomas may predominantly contain various biological materials. These materials may differ in different individuals. While tumor mucins harbour proteolytic enzymes able to digest the juxtaposed stroma of the host, the possible significance of the other intraglandular materials contributed by the host, such as neutrophils, necrotic material and/or stromal invaginations on tumor growth, is still poorly understood. Further studies are necessary to assess whether each one of these intraglandular materials has any bearing on the progression of colonic carcinomas. PMID- 19443398 TI - Efficacy and feasibility of IDEA therapy for refractory or relapsed non-Hodgkin's lymphoma. AB - BACKGROUND: The effects of a novel salvage regimen, IDEA (ifosfamide, cytosine arabinoside, etoposide and dexamethasone), which does not include anthracycline or platinum, in patients with non-Hodgkin's lymphoma (NHL) were examined. PATIENTS AND METHODS: Thirty-four patients with refractory or relapsed NHL were treated with IDEA. RESULTS: The overall remission and complete remission rates were 67.6% and 35.3%, respectively. The toxicity of IDEA was tolerable. With a median follow-up of 14 months, one-year overall survival (OS) and progression free survival rates were 75.1% and 43.7%, respectively. Adequate numbers of CD34(+) cells were obtained in 77.8% of the patients assigned to receive autologous peripheral blood stem cell (PBSC) transplantation. High-dose chemotherapy with autologous PBSC transplantation was carried out in 14 patients; their 3-year OS was 75.0%, with a median follow-up of 38 months. CONCLUSION: IDEA is an effective second-line chemotherapy regimen for NHL patients and has an excellent PBSC-mobilizing effect. PMID- 19443399 TI - Carboplatin and vinorelbine combined with subcutaneous interleukin-2 in metastatic melanoma with poor prognosis. AB - BACKGROUND: The treatment results of metastatic melanoma are miserable if the tumor has spread beyond the soft tissue and lung, in particular, if dacarbazine (DTIC)-based therapy has failed. Platinum analogs and vinca alkaloids have shown some activity in melanoma. Interleukin-2 (IL-2) may augment the efficacy of chemotherapy. PATIENTS AND METHODS: A prospective phase II pilot study was conducted to evaluate the efficacy and tolerability of a regimen which contained carboplatin (450 mg/m(2) on day 1), vinorelbine (30 mg/m(2) on day 1) and IL-2 (9 MU subcutaneously once daily on days 2-5 and 9-12) in metastatic melanoma. Twenty two patients (11 men, 11 women; median age 56 years) were eligible, of whom 13 had cutaneous, 6 ocular and 3 unknown primary melanoma. Seventeen patients (77%) had liver metastases and an equal number had received prior chemotherapy and/or interferon-alfa for recurrent disease. RESULTS: One partial response was recorded, yielding a response rate of 4.5% . Nine patients had stable disease for a median of 6.0 months (range 3.0-8.6 months). The median time to progression for all patients was 1.8 months (range 0.7-8.6 months) and the median survival was 7.2 months (range 1.4-42.0 months). Toxicity was moderate but manageable. Myelosuppression was the most significant adverse event. CONCLUSION: This regimen may offer clinical benefit for melanoma patients with poor prognosis as second line therapy after DTIC has failed. PMID- 19443400 TI - Topotecan-induced long-term remission of an advanced endometrial cancer after treatment with cisplatinum, an anthracycline and paclitaxel. AB - BACKGROUND: The optimal palliative chemotherapy in endometrial cancer is unknown. CASE REPORT: A patient was diagnosed to have primary endometrioid endometrial cancer metastatic to the pelvic, paraaortic and right inguinal lymph nodes (FIGO IVb). After radical surgery, she received 6 adjuvant cycles of cisplatin and epirubicin. Twelve months later, she developed a pelvic recurrence and received second-line paclitaxel chemotherapy. Three months thereafter, computed tomography showed diffuse peritoneal carcinomatosis with lesions up to 2 cm in diameter. She received eighteen weekly cycles of topotecan which led to a complete clinical response confirmed by CT. Forty-three months after the start of third-line chemotherapy with topotecan, the patient is alive with no evidence of disease. CONCLUSION: Long-term survival with NED may be achievable by topotecan in selected patients with an initial diagnosis of extensive endometrial cancer despite repeated relapses and previous exposure to cisplatinum, an anthracycline and a taxane. PMID- 19443401 TI - Clinical outcomes of unrelated donor umbilical cord blood transplantation for 30 adults with hematological malignancies. AB - BACKGROUND: Umbilical cord blood transplantation (CBT) has increasingly been used as a therapeutic option for adult patients for whom allogeneic stem-cell transplantation is not indicated, due to the availability of cord blood. However, myeloablative conditioning regimens are associated with significant mortality, and high relapse rates in reduced-intensity regimens may result in a poor rate of disease-free survival for those with advanced stages of hematological malignancies. Therefore, it remains unknown whether CBT is a truly effective option for such adults with high-risk disease, as well as for those with standard risk disease. PATIENTS AND METHODS: Thirty adult patients with a median age of 45 years (range: 16-67) with standard or high-risk disease underwent CBT from unrelated donors at Okayama University Hospital between October 2002 and May 2007. Twenty-one patients had diseases classified as high-risk for transplantation. The median number of nucleated cells in infused cord blood was 2.65 x 10(7)/kg (range: 1.73-4.87). RESULTS: Twenty-three patients achieved neutrophil engraftment at a median time of 22 days (range: 13-42) after CBT. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 53.6% . Out of the 30 patients, 11 were alive and disease-free at a median time of 446 days (range: 124-1153) after CBT. The cumulative 1-year overall survival in patients with standard-risk or high-risk disease was 63.5% and 15.4%, respectively (p=0.01). CONCLUSION: Although from a retrospective study, these results suggest that unrelated donor CBT could be safe and effective for adult patients with standard-risk disease who cannot find a suitable HLA-matched volunteer marrow or peripheral blood donor. PMID- 19443402 TI - Correlation of nuclear morphometry of breast cancer in histological sections with clinicopathological features and prognosis. AB - BACKGROUND: The relation of nuclear morphometry measurements with clinicopathological features was evaluated along with prognosis in invasive female breast carcinoma in Libyan patients. Data was compared with corresponding results on Finnish, and Nigerian female breast cancer patients. PATIENTS AND METHODS: Histological samples from 131 patients of breast carcinoma were retrospectively studied by computerized nuclear morphometry. In each case, 50 nuclei were measured and the mean nuclear morphometric features were calculated and compared with different clinicopathological features, and patient's survival. RESULTS: There was statistically significant correlation between the mean nuclear area (MNA) and most clinicopathological features, with the strongest association observed for nuclear grade (p<0.0001). There was also correlation between nuclear area and tumor stage (p<0.04), tumor size (p<0.03) and lymph node (LN) status (p<0.001). A corresponding relationship was found between other size related features and clinical factors. The univariate analysis and survival analysis indicated that short survival time was associated with high nuclear morphometric values. MNA had negative correlation with length of survival (Pearson's test r= 0.29, p=0.019). Morphometric shape features did not show significant association with clinical features or survival. CONCLUSION: The results indicated that nuclear size features are reliable prognostic indicators in Libyan female breast carcinomas, as they were among Finnish and Nigerian females. The nuclear morphometric parameters can identify the aggressive tumor phenotype and provide significant prognostic information in predicting survival and tumors at risk of progression. The cut-off (71.0 mum(2)) of MNA might be applied as quantitative criterium for Libyan nuclear grading to separate patients into good and poor prognosis groups. PMID- 19443403 TI - Significant association of an XRCC4 single nucleotide polymorphism with bladder cancer susceptibility in Taiwan. AB - BACKGROUND: The DNA repair gene XRCC4, a member of NHEJ for double strand breaks, is very important in maintaining the overall genome stability, and may play an important role in carcinogenesis. To reveal the relationship between XRCC4 and bladder cancer, seven polymorphic variants of XRCC4, including C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317) were investigated and analyzed for their association with bladder cancer susceptibility. PATIENTS AND METHODS: In this case-control study, the association of these variants of XRCC4 with bladder carcinogenesis in Taiwan was investigated. Bladder cancer patients (158) and 158 age- and gender-matched healthy controls were recruited and their genotypes were analyzed by PCR-based restriction fragment length polymorphism method. RESULTS: It was found that XRCC4 G-1394T is a significant SNP in bladder carcinogenesis after analyzing the frequencies of each variant in both bladder cancer and control groups. The data indicated that the heterogeneous G of G-1394T is an obvious risk factor of bladder cancer susceptibility (p=0.005) and the data of G allele also showed a similar situation (p=0.0099). As for the other six polymorphisms, there was no difference between the bladder cancer and control groups. CONCLUSION: These findings suggest that the G allele of XRCC4 G-1394T may be involved in bladder carcinogenesis and useful in early detection of bladder cancer. PMID- 19443404 TI - Treatment of patients with unresectable advanced carcinoma of biliary tract - chemotherapy and surgical resection. AB - BACKGROUND: The results of 12 consecutive patients with unresectable advanced biliary tract carcinoma treated with first line chemotherapy of S1/cisplatin, combined surgical resection and second line chemotherapy of gemcitabine are evaluated. PATIENTS AND METHODS: Eight patients with intrahepatic cholangiocarcinoma, 1 with extrahepatic cholangiocarcinoma and 3 with gallbladder carcinoma were included in the study. All patients were treated with S1/cisplatin. Two of the patients underwent combined surgical resection before and 2 after therapy. Second line chemotherapy of gemcitabine was administered in 6 patients. RESULTS: MST of the patients was 14.9 months. With S1/cisplatin therapy, 6 patients had PR and 4 had SD. Two patients with surgical resection after the therapy survived more than 3 years. Second line chemotherapy of gemcitabine with moderate effects and mild adverse effects was well tolerable. CONCLUSION: S1/cisplatin showed considerable anti-cancerous effects. Employing surgical resection for patients with good response may lead to the chance of long term survival. PMID- 19443405 TI - Influence of catumaxomab on tumor cells in bone marrow and blood in ovarian cancer. AB - The trifunctional antibody catumaxomab with bispecificity for the epithelial cell adhesion molecule EpCAM and the T-cell antigen CD3, is a new therapeutic strategy for ovarian cancer patients with symptomatic malignant ascites. Whether or not intraperitoneal (i.p.) catumaxomab-therapy has influence on disseminated and circulating tumor cells was investigated by analyzing cytokeratin-positive (CK+) cells in bone marrow (BM) and peripheral blood (PB). Fourteen ovarian cancer patients with symptomatic ascites were treated with catumaxomab (up to 5 i.p. infusions; increasing dosages (10-200 microg)). CK+-cells were isolated before and after antibody-therapy by density gradient centrifugation and immunocytochemistry (anti-CK antibody A45-B/B3). Catumaxomab-treatment resulted in the sustained reduction of ascites flow and arrested ascites reaccumulation. The mean overall survival was 8 months. CK+-cells in the BM were found in 70% before and 83% after therapy (in the PB 57% and 42%, respectively). A marked reduction of CK+-cells occurred in the BM in 2 and in the PB in 4 patients. Catumaxomab shows a strong intraperitoneal effect and possibly also systemic effects on tumor cells in the BM and PB. PMID- 19443406 TI - Differences in cytokine levels in melanoma patients with and without redness (Brenner sign). AB - BACKGROUND: In view of several studies highlighting an observation of an erythematous eruption in the vicinity of or distant from the lesion in melanoma patients (The Brenner sign), this study sought to assess whether this phenomenon might be related to the blood level of cytokines IL-6 and IL-8. PATIENTS AND METHODS: Sera specimens obtained from 27 patients with melanoma, of which 15 had erythematous eruptions and 12 did not, were studied by immunohistochemistry for the expression of IL-6 and IL-8. RESULTS: IL-6 was detected in all melanoma patients in both groups. The mean level of IL-6 in the redness group (2.41 pg/L) was significantly higher than in the group without redness (1.25 pg/L). IL-8 was detected in all 27 melanoma patients in the two groups. The serum level was less than 5 pg/L in only 1 patient (6.7%) in the redness group, and in 6 patients (50%) in the group without redness, a statistically significant difference. CONCLUSION: The Brenner sign appears to reflect a more advanced disease and herald a poor prognosis according to its correlation with the IL-8 and IL-6 blood level. However, in view of the biphasic effect of IL-8 level on tumor progression, and IL-6's ability to inhibit early stage melanoma, redness in melanoma patients could be a sign of a better prognosis of the melanoma. PMID- 19443407 TI - Continuous finasteride therapy for benign prostate hypertrophy upgrades both neuroendorcine differentiation and aggressive prostate cancer. AB - Finasteride has been recognized as a drug suitable for the chemoprevention of prostate cancer (PC) by reducing intracellular dihydrotestosterone (DHT) levels. The Prostate Cancer Prevention Trial (PCPT) database on continuous finasteride treatment of almost 19 thousands patients indicated the reduction in cancer prevalence by about 25% . However, in this same study more than a twofold increase in high grade aggressive prostate tumors was recorded when compared to controls thus arising serious doubts upon the real benefits of the protocol. Here, our investigation was performed three years on a continuous versus intermittent (six month treatment followed by 6 months resting period) finasteride treatment in 125 BPH patients (pts) each. The overall PC prevalence in both finasteride-treated groups was lower that in untreated controls and thus being in accordance with the PCPT data. However, continuous therapy gave significantly higher incidence in Gleason score (GS)>6 carcinomas compared to intermitted therapy and controls (44.5%, 25% and 18.2% of total acquired PC, respectively). In addition, the acquired elevated chromogranin A (CgA) values were also more than doubled in pts treated continuously compared to the other two groups (13.6%, 5.6% and 6.4%, respectively). Acquired PC GS>6 recorded in pts with a raise in CgA was higher in continuously treated pts (50%) than in the other two studied groups (20% and 25%, respectively). In pts with the retained normal CgA concentration highest PC incidence was found in controls (5.1%) and lower prevalence was recorded in continuously (2.8%) and intermittently treated pts (2.5%) while the respective PC GS>6 incidence was lower in controls than in treated pts. Seemingly, finasteride treatment reduces PC prevalence in pts free of NED but elevates the number of aggressive carcinomas in CgA-positive pts only if continuous treatment is applied. In conclusion, current chemoprevention protocols need to be carefully reconsidered prior to the selection between continuous and discontinued finasteride treatment. PMID- 19443408 TI - Mutation status of K-ras, p53 and allelic losses at 9p and 18q are not prognostic markers in patients with pancreatic cancer. AB - BACKGROUND: K-ras mutations and allelic losses of tumor suppressors p16 and DPC4 are perceived as potential markers for screening of pancreatic malignancy. In this study, molecular data is compared with survival statistics of the patients and whether they correlate with patients' prognosis is questioned. PATIENTS AND METHODS: Fifty three consecutive patients with advanced pancreatic cancer (stage III and IV) who underwent EUS-guided fine needle aspiration (FNA) were enrolled into the study (28 males, 25 females, 63+/-10.5 years). Samples were evaluated on site for presence of malignant cells. DNA was extracted from Giemsa stained smears using laser microdissection, and mutation status of K-ras and p53 was tested by cycling-gradient capillary electrophoresis (CGCE). In addition, allelic losses of tumor suppressor genes p16 (INK4, CDKN2A) and DPC4 (MADH4, SMAD4) were detected by monitoring the loss of heterozygosity (LOH) at 9p and 18q loci. Molecular data were compared with survival statistics using Kaplan-Meier method. RESULTS: The median survival in K-ras positive group was 7.0+/-2.4 months (95% CI 2.3-11.7) and in K-ras negative group was 10.0+/-0.6 months (95% CI 8.7-11.3). The median survival in p53 positive group was 10.0+/-2.2 months (95% CI 5.6-14.4) and in p53 negative group was 6.0+/-2.5 months (95% CI 1.1-10.9). The median survival in LOH 9p positive group was 9.0+/-5.1 months (95% CI 0-18.9), in LOH 9p negatives was 10.0+/-5.0 months (95% CI 0.2-19.8). The median survival in LOH 18q positive group was 10.0+/-4.2 months (95% CI 1.8-18.2) and in LOH 18q negative group was 3.0+/-1.3 months (95% CI 0.5-5.5). After the adjustment for age using Cox proportional hazards model, none of the evaluated molecular markers was shown to be an independent prognostic marker for survival of patients with pancreatic cancer. CONCLUSION: None of the studied molecular markers was identified as an independent factor determining survival prognosis. PMID- 19443409 TI - Mutation analysis of IgVH genes in splenic marginal zone lymphomas: correlation with clinical characteristics and outcome. AB - BACKGROUND: To determine the immunoglobulin variable heavy chain (IgVH) gene usage and somatic mutation patterns in a series of SMZL patients and to correlate these findings with the clinical features and outcome. PATIENTS AND METHODS: IgVH genes were amplified and sequenced from 22 SMZL cases. Clinical and laboratory data of these patients were recorded. RESULTS: A biased usage of IgVH gene was found with overrepresentation of VH3 in 16/22 cases. A total of 13/22 (59%) of cases were found to have mutated IgVH genes, whereas 9/22 (41%) were unmutated. Positive antigen selection process was identified in two cases. Treatment was different between the cases with mutation and those without. No differences in clinical and laboratory characteristics, or survival were found between the mutated and unmutated cases. CONCLUSION: SMZL are characterized by marked molecular heterogeneity. A biased usage of certain sequences suggests antigen selection. Prognostic significance of mutational status was not confirmed in this study. However further studies are needed in order to confirm these results. PMID- 19443410 TI - Clinicopathological implications of EpCAM expression in adenocarcinoma of the lung. AB - BACKGROUND: The frequency of epithelial cell adhesion molecule (EpCAM) expression was investigated in non-small cell lung cancer (NSCLC) cells and human tissues, and its clinicopathological significance in adenocarcinoma of the lung was evaluated. MATERIALS AND METHODS: EpCAM expression was analysed by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry in human NSCLC cells. EpCAM protein expression was evaluated in 234 adenocarcinoma tissues using immunohistochemistry. RESULTS: A high expression level of EpCAM was observed in human NSCLC cells by flow cytometry and RT-PCR. EpCAM overexpression was detected in 120/234 (51.3%) surgically resected adenocarcinoma tissues. EpCAM overexpression occurred significantly more frequently in adenocarcinoma than in bronchioloalveolar carcinoma (p=0.02). The overall survival did not differ significantly between EpCAM-overexpressing and EpCAM-negative patients (p=0.40). CONCLUSION: These findings suggest EpCAM plays a role in the carcinogenesis of adenocarcinoma of the lung and might provide a promising molecule for targeted therapy in NSCLC. PMID- 19443411 TI - Molecular imaging of tumor blood vessels in prostate cancer. AB - In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of tumor vascular remodelling. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not necessarily result in the reduction of tumor diameter. The basis for the molecular imaging of tumor blood vessels is the remodelling of the tumor vessels under anti-angiogenic therapy which obviously occurs at an early stage and seems to be a convincing parameter. Beside the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodelling of the micro tumor vessels. New imaging approaches combining specific molecular markers for tumor vessels with the different imaging techniques are needed to overcome this issue as exemplarily discussed for prostate cancer in this review. Molecular contrast agents targeting the vasculature will allow clinicians the visualization of vascular remodelling processes taking place under anti-angiogenic therapy and improve tumor diagnosis and follow-up. PMID- 19443412 TI - Clinical correlations between treatment with anticoagulants/antiaggregants and late rectal toxicity after radiotherapy for prostate cancer. AB - AIM: To assess variables related to grade 2 or higher late rectal toxicity (LRT) in prostate cancer treated with external radiotherapy. PATIENTS AND METHODS: A retrospective analysis was carried out of 232 patients with T1-T3 prostate cancer treated with 3-dimensional conformal radiotherapy (3DCRT) (106 patients) or intensity modulated radiotherapy (IMRT) (126 patients) between June 2000 and May 2007. One hundred and seventy-seven patients received androgen deprivation therapy (ADT); fifty patients used anticoagulants/antiaggregants for vascular disease. RESULTS: The median follow-up was 31 months (range, 6-79). At 5 years, the cumulative incidence of grade 2 or 3 LRT was 5.6% . On multivariate analysis, medication with anticoagulants/antiaggregants was correlated with grade 2 or 3 LRT (p=0.027), whereas age, National Comprehensive Cancer Network risk group classification, use of ADT, radiotherapy technique (3DCRT vs. IMRT) and total irradiated dose were not. CONCLUSION: Treatment with anticoagulants/antiaggregants appears to be a factor in grade 2 or 3 LRT. PMID- 19443413 TI - Single nucleotide polymorphisms and clinical outcome in patients with biliary tract carcinoma treated with epirubicin, cisplatin and capecitabine. AB - BACKGROUND: Biliary tract carcinoma (BTC) is a rare highly malignant neoplasia. Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross complementing group-1 (ERCC1) and X-ray repair cross complementing group 1 (XRCC1) genes were evaluated and correlated with clinical outcome. PATIENTS AND METHODS: Thirty-three patients with BTC were treated with intravenous or intra arterial cisplatin and epirubicin and oral capecitabine. The ERCC1-C118T, XPD Asp312Asn, XPD-Lys751Gln and XRCC1-Arg399Gln polymorphisms were studied. RESULTS: A partial response (PR) occurred in 6 patients. The median progression-free (PFS) and overall survival (OS) were 4.8 and 18.9 months, respectively. No significant correlations were observed between response, PFS and OS in patients grouped according to all the studied polymorphisms. The analysis of survival starting from diagnosis resulted in a significant association of the XRCC1-Arg399Arg variant with a shorter survival. CONCLUSION: A role of the XRCC1-Arg399Gln polymorphism as a possible prognostic factor in patients affected by BTC is suggested. PMID- 19443414 TI - Multicenter phase II trial of first-line docetaxel/gemcitabine in advanced breast cancer pretreated with adjuvant anthracyclines. AB - The aim of this study was to evaluate activity and tolerability of docetaxel gemcitabine combination as first-line treatment in patients with metastatic breast cancer previously treated with adjuvant anthracyclines. PATIENTS AND METHODS: Sixty-eight women received gemcitabine 1,000 mg/m(2) as 30-minute infusion on days 1 and 8, and docetaxel 80 mg/m(2) as 1-hour infusion on day 8, with cycles repeated every 3 weeks. RESULTS: Objective responses were observed in 32 out of 68 evaluable patients (45%; 95% confidence interval, 35.2-58.8%). Responses were 44%, 42%, 49% in soft tissue, bone and visceral lesions, respectively, 50% /52% in HER2-positive/-negative tumors, and 50% in both ER- positive/-negative tumors. Median time to progression and overall survival were 6 and 16 months, respectively. Treatment was usually well tolerated, with grade 3-4 neutropenia in 32% - 7% of the patients, and neutropenic fever, grade 3 vomiting, mucositis and peripheral neurotoxicity in 3% of the patients. CONCLUSION: Gemcitabine-docetaxel combination is effective and well tolerated as first-line treatment in advanced breast cancer previously treated with adjuvant anthracyclines. PMID- 19443415 TI - Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. AB - BACKGROUND: Several clinical studies have clearly demonstrated that the immune status is one a major prognostic factor for the survival time in cancer patients. However the main clinical problem is to identify the most prognostically important index within the great number of immune parameters. Recently the evaluation of regulatory T (T-reg) (CD4CD25) lymphocyte count and function with respect to the T helper (TH) (CD4) number has been shown to represent the main immune parameters capable of representing the functional status of the anticancer immunity in cancer patients. This study evaluated the influence of the four main conventional anticancer therapies (surgery, chemotherapy, radiotherapy, immunotherapy) on the CD4/CD4CD25 ratio. PATIENTS AND METHODS: The study included 70 patients. The oncological treatments consisted of surgery in 14, chemotherapy in 36, radiotherapy in 12 and immunotherapy (subcutaneous low-dose, S.C.-low, interleukin, IL-2) in 8 patients. The normal value of the CD4/CD4CD25 ratio was greater then 4.0. RESULTS: Surgery induced a significant decline in the CD4/CD4CD25 mean ratio. Radiotherapy also induced also a dramatic significant decrease in the CD4/CD4CD25 ratio, whereas the effect of both chemotherapy and immunotherapy reflected the clinical response to the treatments. The CD4/CD4CD25 mean ratio was significantly enhanced in the patients who obtained control of the neoplastic growth, whereas it diminished in progressing patients. CONCLUSION: The commonly used anticancer therapies profoundly modify the levels of amounts of T reg lymphocytes. Because of the fundamental role of T-reg cells in suppressing the anticancer immunity, thus diminishing survival, the monitoring of the CD4/CD4CD25 ratio could constitute an important clinical index during conventional anticancer therapies to predict the prognosis of cancer patients. PMID- 19443416 TI - Local recurrence following adjuvant chemotherapy without radiotherapy in completely resected stomach and gastroesophageal junction adenocarcinoma. AB - BACKGROUND: The gold standard of adjuvant treatment after surgical resection of adenocarcinoma of the stomach or gastroesophageal junction (GEJ) is chemoradiotherapy. We retrospectively evaluated chemotherapy without radiotherapy in stomach and GEJ adenocarcinoma, using a combination of etoposide, adriamycin and cisplatin (modified EAP). PATIENTS AND METHODS: Sixty-five patients with completely resected gastric or GEJ adenocarcinoma and positive regional lymph nodes were treated with modified EAP over an 8-year period. RESULTS: Recurrent disease was diagnosed in 38/58 (69%) patients evaluable for analysis. Only two (5%) had locoregional recurrence. The main toxicity was hematological, with 22 (34%) patients developing neutropenic fever and 12 (18%) anemia requiring blood transfusion. The median survival for the entire group was 20 months, with a median time to recurrence of 11 months. Seventeen (26%) patients are alive for a median of 7+ years, with no evidence of recurrent disease. CONCLUSION: Our data cast doubt on the benefit of radiotherapy adjuvant to chemotherapy. PMID- 19443417 TI - An integrated transcriptomics and proteomics analysis of the secretome of the helminth pathogen Fasciola hepatica: proteins associated with invasion and infection of the mammalian host. AB - To infect their mammalian hosts, Fasciola hepatica larvae must penetrate and traverse the intestinal wall of the duodenum, move through the peritoneum, and penetrate the liver. After migrating through and feeding on the liver, causing extensive tissue damage, the parasites move to their final niche in the bile ducts where they mature and produce eggs. Here we integrated a transcriptomics and proteomics approach to profile Fasciola secretory proteins that are involved in host-pathogen interactions and to correlate changes in their expression with the migration of the parasite. Prediction of F. hepatica secretory proteins from 14,031 expressed sequence tags (ESTs) available from the Wellcome Trust Sanger Centre using the semiautomated EST2Secretome pipeline showed that the major components of adult parasite secretions are proteolytic enzymes including cathepsin L, cathepsin B, and asparaginyl endopeptidase cysteine proteases as well as novel trypsin-like serine proteases and carboxypeptidases. Proteomics analysis of proteins secreted by infective larvae, immature flukes, and adult F. hepatica showed that these proteases are developmentally regulated and correlate with the passage of the parasite through host tissues and its encounters with different host macromolecules. Proteases such as FhCL3 and cathepsin B have specific functions in larvae activation and intestinal wall penetration, whereas FhCL1, FhCL2, and FhCL5 are required for liver penetration and tissue and blood feeding. Besides proteases, the parasites secrete an array of antioxidants that are also highly regulated according to their migration through host tissues. However, whereas the proteases of F. hepatica are secreted into the parasite gut via a classical endoplasmic reticulum/Golgi pathway, we speculate that the antioxidants, which all lack a signal sequence, are released via a non-classical trans-tegumental pathway. PMID- 19443418 TI - Endogenous processing and presentation of T-cell epitopes from Chlamydia trachomatis with relevance in HLA-B27-associated reactive arthritis. AB - Chlamydia trachomatis triggers reactive arthritis, a spondyloarthropathy linked to the human major histocompatibility complex molecule HLA-B27, through an unknown mechanism that might involve molecular mimicry between chlamydial and self-derived HLA-B27 ligands. Chlamydia-specific CD8(+) T-cells are found in reactive arthritis patients, but the immunogenic epitopes are unknown. A previous screening of the chlamydial genome for putative HLA-B27 ligands predicted multiple peptides that were recognized in vitro by CD8(+) T-lymphocytes from patients. Here stable transfectants expressing bacterial fusion proteins in human cells were generated to investigate the endogenous processing and presentation by HLA-B27 of two such epitopes through comparative immunoproteomics of HLA-B27 bound peptide repertoires. A predicted T-cell epitope, from the CT610 gene product, was presented by HLA-B27. This is, to our knowledge, the first endogenously processed epitope involved in HLA-B27-restricted responses against C. trachomatis in reactive arthritis. A second predicted epitope, from the CT634 gene product, was not detected. Instead a non-predicted nonamer from the same protein was identified. Both bacterial peptides showed very high homology with human sequences containing the HLA-B27 binding motif. Thus, expression and intracellular processing of chlamydial proteins into human cells allowed us to identify two bacterial HLA-B27 ligands, including the first endogenous T-cell epitope from C. trachomatis involved in spondyloarthropathy. That human proteins contain sequences mimicking chlamydial T-cell epitopes suggests a basis for an autoimmune component of Chlamydia-induced HLA-B27-associated disease. PMID- 19443419 TI - Functional walking capacity as an outcome measure of laparoscopic prostatectomy: the effect of lidocaine infusion. AB - BACKGROUND: Intravenous lidocaine infusion has been shown to affect postoperative pain intensity. This present study was performed to assess the effect of intra- and postoperative lidocaine infusion on postoperative functional walking capacity, as a measure of surgical recovery. METHODS: Forty patients undergoing laparoscopic prostatectomy were randomized to receive an i.v. infusion of either lidocaine 2 mg kg(-1) h(-1) during surgery and 1 mg kg(-1) min(-1) for the first 24 postoperative hours (lidocaine group) or an equivalent volume of saline 0.9% (control group). All patients received postoperative patient-controlled analgesia with i.v. morphine. Primary outcome was functional walking capacity, as assessed by distance attained during the 2 min walking test (2MWT), recorded daily for the first 3 postoperative days. Morphine consumption and pain intensity were recorded. RESULTS: 2MWT distance decreased by an average of 60% (P<0.01) in both groups on postoperative day 1 (from 150 m before surgery to 53 m), but the decrease was 26 m less in the lidocaine group (P=0.009). During postoperative days 2 and 3, the 2MWT distance increased to an average of 96 m, still 30% less than the preoperative values. There was a significant negative correlation on postoperative days 1 and 2 between the 2MWT distance, pain intensity and fatigue, and morphine consumption. Lidocaine infusion was an independent predictor of the degree of postoperative decrease in 2MWT distance. More patients in the lidocaine group were free from PCA on the second postoperative day (P=0.011). CONCLUSIONS: Infusion of lidocaine during surgery and for the first postoperative day attenuated the deterioration in functional walking capacity, and had an opioid sparing effect. PMID- 19443420 TI - Development of atelectasis and arterial to end-tidal PCO2-difference in a porcine model of pneumoperitoneum. AB - BACKGROUND: Intraperitoneal insufflation of carbon dioxide (CO2) may promote collapse of dependent lung regions. The present study was undertaken to study the effects of CO2-pneumoperitoneum (CO2-PP) on atelectasis formation, arterial oxygenation, and arterial to end-tidal PCO2-gradient (Pa-E'(CO2)). METHODS: Fifteen anaesthetized pigs [mean body weight 28 (SD 2) kg] were studied. Spiral computed tomography (CT) scans were obtained for analysis of lung tissue density. In Group 1 (n=5) mechanical ventilation (V(T)=10 ml kg (-1), FI(O2)=0.5) was applied, in Group 2 (n=5) FI(O2) was increased for 30 min to 1.0 and in Group 3 (n=5) negative airway pressure was applied for 20 s in order to enhance development of atelectasis. Cardiopulmonary and CT data were obtained before, 10, and 90 min after induction of CO2-PP at an abdominal pressure of 12 mmHg. RESULTS: Before CO2-PP, in Group 1 non-aerated tissue on CT scans was 1 (1)%, in Group 2 3 (2)% (P<0.05, compared with Group 1), and in Group 3 7 (3)% (P<0.05, compared with Group 1 and Group 2). CO2-PP significantly increased atelectasis in all groups. PaO2/FI(O2) fell and venous admixture ('shunt') increased in proportion to atelectasis during anaesthesia but CO2-PP had a varying effect on PaO2/FI(O2) and shunt. Thus, no correlation was seen between atelectasis and PaO2/FI(O2) or shunt when all data before and during CO2-PP were pooled. Pa E'(CO2), on the other hand correlated strongly with the amount of atelectasis (r2=0.92). CONCLUSIONS: Development of atelectasis during anaesthesia and PP may be estimated by an increased Pa-E'(CO2). PMID- 19443421 TI - Quality of life assessment after percutaneous aortic valve implantation. AB - AIMS: To assess the NYHA class and the quality of life (QoL) scores after percutaneous aortic valve implantation (PAVI) with the 18-Fr CoreValve prosthesis. METHODS AND RESULTS: From April 2007 until August 2008, 57 consecutive patients with aortic stenosis were evaluated for PAVI. Of these, 30 patients with successfully prosthesis implantation had more than 5-month follow up. QoL assessment was realized with the SF-12v2 Health-Survey, a simple questionnaire designed for self-administration that provides easily interpretable scales for physical [physical component summary (PCS)] and mental [mental component summary (MCS)] health. The questionnaire was administered before and 5 months after PAVI. All 30 patients had a marked upgrading in haemodynamic and echocardiographic parameters (peak-to-peak gradient from 64 +/- 23 to 2 +/- 0.4; P < 0.001; aortic valve area index from 0.3 +/- 0.1 to 0.9 +/- 0.3; P < 0.001), with an improvement in New York Heart Association (NYHA) class at discharge and after 5 months. Mean pre-operative SF-12v2 scores showed a severe impairment of perceived quality of life compared with general Italian population >75 years, both for physical (PCS-baseline 28.5 vs. 37.9, P < 0.001) and mental scores (MCS baseline 37.8 vs. 45.4, P < 0.001). After 5 months, a striking improvement in both scores (PCS 41.3-MCS 48.3; P < 0.001) was observed. CONCLUSION: Our preliminary results show a marked short-term improvement in functional status and physical and mental health in patients underwent PAVI. PMID- 19443422 TI - The ambitions and goals of the National Heart, Lung, and Blood Institute at The National Institute of Health. PMID- 19443423 TI - Chlamydia heat shock protein 60 decreases expression of endothelial nitric oxide synthase in human and porcine coronary artery endothelial cells. AB - AIMS: Clinically, Chlamydia pneumoniae infection and its heat shock protein 60 (cHSP60) may contribute to atherogenesis; however, its underlying mechanisms are largely unknown. The objective of this study was to determine whether cHSP60 could cause endothelial dysfunction in human coronary artery endothelial cells (HCAECs) and porcine coronary arteries. METHODS AND RESULTS: When HCAECs were treated with recombinant cHSP60, endothelial nitric oxide synthase (eNOS) mRNA and protein levels, enzyme activities, cellular NO levels, mRNA stability, and promoter activities were significantly decreased. Superoxide anion production was significantly increased due to the inhibition of mitochondrial membrane potential and catalase and superoxide dismutase (SOD) activities as well as activation of NADPH oxidase. Antioxidant seleno-l-methionine (SeMet) or SOD mimetic MnTBAP effectively blocked cHSP60-induced eNOS downregulation. In addition, cHSP60 activated mitogen-activated protein kinases (MAPKs) including p38, c-Jun-N terminal kinase/stress-activated protein kinase, and extracellular signal regulated kinases. Specific chemical inhibitors or their dominant-negative mutant forms of these MAPKs effectively blocked cHSP60-induced eNOS downregulation. cHSP60-induced eNOS downregulation and oxidative stress were also demonstrated in porcine coronary artery rings in vitro. Functionally, endothelium-dependent vasorelaxation was significantly reduced in cHSP60-treated vessels. CONCLUSION: cHSP60 directly induces eNOS downregulation through oxidative stress and MAPK activation in both HCAECs and porcine coronary arteries, thereby causing endothelial dysfunction. PMID- 19443424 TI - Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. AB - AIMS: Members of the vascular endothelial growth factor (VEGF) family are among the most promising cytokines to induce neovascularization of ischaemic tissues; however, their unregulated expression often results in major undesired effects. Here, we describe the properties of inducible vectors based on the adeno associated virus (AAV), allowing precise control of VEGF expression, and exploit these vectors to define the kinetics of the angiogenic response elicited by the factor. METHODS AND RESULTS: Based on a tetracycline-inducible transactivator, we designed an AAV vector system allowing the pharmacological regulation of VEGF production in vivo and tested its efficacy in inducing functional neoangiogenesis in both normoperfused and ischaemic skeletal muscle in mice by a combination of histological, immunofluorescent, and molecular imaging techniques. We observed that a prolonged expression of VEGF was required to determine the formation of stable vessels, able to persist upon withdrawal of the angiogenic stimulus. However, the vessels formed in the presence of continuous VEGF expression consisted mainly of dilated and leaky capillaries. As determined after pinhole scintigraphy, this abnormal vasculature accounted for a significant drop in functional tissue perfusion. In contrast, transient VEGF expression, followed by a period of VEGF withdrawal, allowed maintenance of functional perfusion under resting conditions and during exercise. This VEGF-inducible system was highly effective in improving vascularization and function in a hind-limb ischaemia model. CONCLUSION: Together, these results clearly indicate that the fine tuning of VEGF expression is required to achieve the formation of a stable vasculature able to sustain functional neovascularization. PMID- 19443425 TI - PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats. AB - AIMS: Oxidative stress followed by abnormal signalling can play a critical role in the development of long-term, high blood pressure-induced cardiac remodelling in heart failure (HF). Since oxidative stress-induced poly(ADP-ribose)polymerase (PARP) activation and cell death have been observed in several experimental models, we investigated the possibility that inhibition of nuclear PARP improves cardiac performance and delays transition from hypertensive cardiopathy to HF in a spontaneously hypertensive rat (SHR) model of HF. METHODS AND RESULTS: SHRs were divided into two groups: one received no treatment (SHR-C) and the other (SHR-L) received 5 mg/kg/day L-2286 (PARP-inhibitor) orally for 46 weeks. A third group was a normotensive age-matched control group (CFY) and a fourth was a normotensive age-matched group receiving L-2286 treatment 5 mg/kg/day (CFY+L). At the beginning of the study, systolic function was similar in both CFY and SHR groups. In the SHR-C group at the end of the study, eccentric hypertrophy with poor left ventricular (LV) systolic function was observed, while PARP inhibitor treatment preserved systolic LV function. Due to these favourable changes, the survival rate of SHRs was significantly improved (P < 0.01) by the administration of the PARP inhibitor (L-2286). The PARP inhibitor used did not affect the elevated blood pressure of SHR rats, but moderated the level of plasma-BNP (P < 0.01) and favourably influenced all the measured gravimetric parameters (P < 0.05) and the extent of myocardial fibrosis (P < 0.05). The inhibition of PARP increased the phosporylation of Akt-1/GSK-3beta (P < 0.01), ERK 1/2 (P < 0.01), and PKC epsilon (P < 0.01), and decreased the phosphorylation of JNK (P < 0.05), p-38 MAPK (P < 0.01), PKC pan betaII and PKC zeta/lambda (P < 0.01), and PKC alpha/betaII and delta (P < 0.05). CONCLUSION: These data demonstrate that chronic inhibition of PARP induces long-term favourable changes in the most important signalling pathways related to oxidative stress. PARP inhibition also prevents remodelling, preserves systolic function, and delays transition of hypertensive cardiopathy to HF in SHRs. PMID- 19443426 TI - Low-level laser irradiation inhibits abdominal aortic aneurysm progression in apolipoprotein E-deficient mice. AB - AIMS: Increased early detection of abdominal aortic aneurysm (AAA) and the severe complications of its current treatment have emphasized the need for alternative therapeutic strategies that target pathogenetic mechanisms of progression and rupture. Recent in vitro studies from our laboratory have shown that low-level laser irradiation (LLLI) (780 nm) modifies cellular processes fundamental to aneurysm progression. The present study was designed to determine whether LLLI retards the progression of suprarenal AAA in vivo. METHODS AND RESULTS: High frequency ultrasonography (0.01 mm resolution) was used to quantify the effect of LLLI on aneurysmatic aortic dilatation from baseline to 4 weeks after subcutaneous infusion of angiotensin II by osmotic minipumps in the apolipoprotein E-deficient mouse. At 4 weeks, seven of 15 non-irradiated, but none of the 13 LLLI, mice had aneurysmal dilatation in the suprarenal aneurysm prone segments that had progressed to >or=50% increase in maximal cross-sectional diameter (CSD) over baseline (P = 0.005 by Fisher's exact test). The mean CSD of the suprarenal segments (normalized individually to inter-renal control segments) was also significantly lower in irradiated animals (LLLI vs. non-irradiated: 1.32 +/- 0.14 vs. 1.82 +/- 0.39, P = 0.0002 by unpaired, two-tailed t-test) with a 94% reduction in CSD at 4 weeks compared with baseline. M-mode ultrasound data showed that reduced radial wall velocity seen in non-treated was significantly attenuated in the LLLI mice, suggesting a substantial effect on arterial wall elasticity. CONCLUSION: These in vivo studies, together with previous in vitro studies from this laboratory, appear to provide strong evidence in support of a role for LLLI in the attenuation of aneurysm progression. Further studies in large animals would appear to be the next step towards testing the applicability of this technology to the human interventional setting. PMID- 19443430 TI - Acute effects of complex fractionated atrial electrogram ablation on dominant frequency and regulatory index for the fibrillatory process. AB - AIMS: The purpose of our study was to determine the acute effects of complex fractionated electrograms (CFAE) ablation guided by automated detection on dominant frequency (DF) and regulatory index (RI) for the fibrillatory process. METHODS AND RESULTS: The study included 41 patients (21 paroxysmal and 20 persistent) referred for catheter ablation of atrial fibrillation (AF). Our ablation strategy included pulmonary vein isolation (PVI) as first step, CFAE ablation as second step, roof line ablation as next, and mitral isthmus ablation as last step. On the CFAE map, we were targeting only points outside the previous PVI lines. Simultaneously, we evaluated DF and RI changes in the coronary sinus after each step of ablation. The termination rate by CFAE ablation was low (12.5% in paroxysmal and 10% in persistent AF). Changes in DF and RI after CFAE ablation were not significant (<0.25 Hz and max. 0.02 increase for RI) compared with other ablation steps. Pulmonary vein isolation, roof line, and mitral isthmus ablation resulted in significant changes in DF and RI. CONCLUSION: On the basis of our results, CFAE ablation guided by a dedicated software algorithm and performed after standard PVI without CFAE remapping does not influence the fibrillatory process significantly. Application of a modified algorithm with different settings warrants further investigations. PMID- 19443431 TI - Baseline apnoea/hypopnoea index and high-sensitivity C-reactive protein for the risk of recurrence of atrial fibrillation after successful electrical cardioversion: a predictive model based upon the multiple effects of significant variables. AB - AIMS: We tested apnoea/hypopnoea index (AHI), high-sensitivity (hs) C-reactive protein and clinical/instrumental variables as predictors of atrial fibrillation (AF) recurrence over 1-year follow-up after successful electrical cardioversion. METHODS AND RESULTS: We enrolled 158 consecutive patients. Apnoea/hypopnoea index was assessed with standard overnight polysomnography and hs-C-reactive protein with immunonephelometry assay the day before electrical cardioversion. Atrial fibrillation recurrences occurred in 81 patients (51%). Predictors at univariate analysis were: AHI > or = 15 events/h (P = 0.001), hs-C-reactive protein >0.30 mg/dL (P = 0.009), AF duration >3 days (P = 0.008), diabetes (P = 0.03), and ongoing anti-arrhythmic therapy at the time of electrical cardioversion (P = 0.03). Survival analysis confirmed that patients with AHI > or = 15 events/h and hs-C-reactive protein > 0.30 mg/dL had a higher recurrence rate of AF (log rank P = 0.0006 and P = 0.01, respectively). Predictors at multivariate analysis were: AHI > or = 15 events/h (P = 0.003), hs-C-reactive protein > 0.30 mg/dL (P = 0.01) and ongoing anti-arrhythmic therapy (P = 0.04). A predictive model based upon the multiple effects of significant variables plus age as a continuous variable stratified the risk of AF recurrence, more than tripled with all dichotomized variables altered with respect to normal variables (85 vs. 27%). CONCLUSION: AHI > or = 15 events/h and hs-C-reactive protein > 0.30 mg/dL are the strongest predictors of the predictors chosen of AF recurrence after successful electrical cardioversion over 1-year follow-up. PMID- 19443432 TI - A rare case of late right ventricular perforation by a passive-fixation permanent pacemaker lead. AB - The present paper is an interesting and rare complication of implantation of a permanent pacemaker lead. The rarity of the case is based upon that ventricular perforation is usually present during implantation, whereas in our case, it was presented late--1 month after implantation. Furthermore, in our case, the pacemaker lead had migrated through the left hemidiaphragm into the peritoneal cavity. PMID- 19443433 TI - Antiarrhythmic therapy and risk of death in patients with atrial fibrillation: a nationwide study. AB - AIMS: To examine the risk of death associated with antiarrhythmic drug (AAD) therapy in a nationwide unselected cohort of patients with atrial fibrillation (AF). METHODS AND RESULTS: All patients admitted with AF in Denmark from 1995 to 2004 and their subsequent use of AADs were identified by individual-level linkage of nationwide registries. Multivariable Cox proportional-hazard models with time dependent covariates were used to analyse the risk of death associated with AAD therapy. A total of 141,500 patients were included in the study; of these 3356 (2.4%) patients received treatment with flecainide, 3745 (2.6%) propafenone, 23,346 (16.5%) sotalol, and 10,376 (7.3%) amiodarone. Annualized mortality rates were 2.54, 4.25, 5.29, and 7.42 per year per 100 person years for flecainide, propafenone, sotalol, and amiodarone, respectively. Multivariable Cox proportional-hazard models did not show increased risk of death associated with any of the AADs. Hazard ratio (95% confidence interval) for flecainide 0.38 (0.32 0.44), propafenone 0.65 (0.58-0.71), sotalol 0.65 (0.63-0.67), and amiodarone 0.94 (0.89-1.00). CONCLUSION: In an unselected cohort of patients with AF, antiarrhythmic treatment with flecainide, propafenone, sotalol, or amiodarone was not associated with increased risk of death. From a safety perspective, this indicates appropriate selection of patients for AAD therapy. PMID- 19443434 TI - EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). PMID- 19443435 TI - Inappropriate shocks or inappropriate programming? A review of Guidant's reconfirmation algorithm. AB - Ventricular tachycardia episodes terminating during or immediately after device charging are not expected to be treated by current implantable cardioverter defibrillators as shocks are non-committed. For proper troubleshooting, the reconfirmation algorithm will be reviewed. PMID- 19443436 TI - Does child gender determine household decision for health care in rural Thatta, Pakistan? AB - BACKGROUND: In South Asia, gender disparity in child mortality is highest in Pakistan. We examined the influence of child gender on household decision regarding health care. METHODS: Prevalence ratios were calculated for 3740 children aged 1-59 months from 92 randomly selected villages of rural Pakistan using a cluster-adjusted log-binomial model. Level 1 variables included child and household characteristics and level 2 included village characteristics. RESULTS: There were 25 more girl deaths than boys per 1000 live births (95% CI: 13.9, 48.6) among post-neonates and 38 more among children aged 12-59 months (95% CI: 10.5, 65.5). However, in adjusted analysis, gender was not a significant predictor of illness reporting, visit to health facilities, choice of provider, hospitalization and health expenditure. Significant predictors of health care were child's age, illness characteristics, number of children in the family, household socio-economic status and absence of girls' school in the village. CONCLUSIONS: Differential care seeking for boys and girls is not seen in Thatta despite clear differences in mortality ratios. This calls for more creative research to identify pathways for gender differential in child mortality. Factors identified as influencing child health care and amenable to modification include poverty alleviation and girls' education. PMID- 19443437 TI - Process of neonatal tetanus elimination in Nepal. AB - BACKGROUND: In late 2005, Nepal demonstrated through surveys that it had reached the World Health Organization criterion for having eliminated neonatal tetanus (NT), i.e. NT cases occurred at a rate of less than 1 per 1000 live births in every district. This paper summarizes how a combination of strategies contributed to this success. METHODS: For each of the 4 strategies (clean delivery, routine immunization, supplemental immunization campaigns, and surveillance) activities before and after 2000 are described and achievements are summarized using published and unpublished data. RESULTS: Through routine immunization of pregnant women with tetanus toxoid (TT), NT cases had decreased substantially by 1999, but the final push was provided through the national TT supplemental immunization activities in 2000-2004, which raised the proportion of children protected at birth against tetanus to above 80%. Fewer than 20% of deliveries take place with trained assistance. Although NT surveillance has improved since the extensive Acute Flaccid Paralysis/Polio surveillance infrastructure in Nepal was made available for the NT elimination initiative, it is likely that a number of cases still occur without being reported, particularly in rural areas. CONCLUSIONS: NT elimination was achieved in 2005 in Nepal, but activities must continue and be strengthened to ensure that NT incidence will not increase in the future. The introduction and further expansion of school-based immunization will, in combination with diphtheria-tetanus-pertussis vaccine given in infancy, reduce the need for future cohorts of childbearing age women to be immunized at every pregnancy. However, booster doses will still need to be given in early adulthood to ensure ongoing protection. PMID- 19443438 TI - Using encounters versus episodes in syndromic surveillance. AB - BACKGROUND: Automated electronic medical records may be useful for syndromic surveillance to quickly detect infectious disease outbreaks. Some syndromic surveillance systems include every encounter in the analysis, whereas others exclude individuals' repeat encounters within the same syndrome occurring within a short period of time, with the rationale that these represent follow-up visits rather than new episodes of illness. METHODS: We evaluate the effect of keeping all encounters as compared with removing repeat encounters. Using the prospective space-time permutation scan statistic, we performed daily analyses on all encounters versus on episodes defined as encounters new within 2, 6 or 12 weeks. Data were taken from a Massachusetts Health Maintenance Organization (HMO) for the calendar year 1999 for four different syndromes. RESULTS: We found extensive disagreement in the number of signals detected: 70, 68, 21 and 15 signals when using all encounters versus 15-20, 3, 4-5 and 0 signals when using only new episodes for lower respiratory, lower gastrointestinal, upper gastrointestinal and neurologic syndromes, respectively. CONCLUSION: Using all encounters in syndromic surveillance may not only create too many signals but may also miss some signals by masking the anomalies generated by actual episodes. However, it is also possible to miss signals when using episodes. PMID- 19443439 TI - Inhibition of translesion DNA polymerase by archaeal reverse gyrase. AB - Reverse gyrase is a unique DNA topoisomerase endowed with ATP-dependent positive supercoiling activity. It is typical of microorganisms living at high temperature and might play a role in maintenance of genome stability and repair. We have identified the translesion DNA polymerase SsoPolY/Dpo4 as one partner of reverse gyrase in the hyperthermophilic archaeon Sulfolobus solfataricus. We show here that in cell extracts, PolY and reverse gyrase co-immunoprecipitate with each other and with the single strand binding protein, SSB. The interaction is confirmed in vitro by far-western and Surface Plasmon Resonance. In functional assays, reverse gyrase inhibits PolY, but not the S. solfataricus B-family DNA polymerase PolB1. Mutational analysis shows that inhibition of PolY activity depends on both ATPase and topoisomerase activities of reverse gyrase, suggesting that the intact positive supercoiling activity is required for PolY inhibition. In vivo, reverse gyrase and PolY are degraded after induction of DNA damage. Inhibition by reverse gyrase and degradation might act as a double mechanism to control PolY and prevent its potentially mutagenic activity when undesired. Inhibition of a translesion polymerase by topoisomerase-induced modification of DNA structure may represent a previously unconsidered mechanism of regulation of these two-faced enzymes. PMID- 19443440 TI - jpHMM: improving the reliability of recombination prediction in HIV-1. AB - Previously, we developed jumping profile hidden Markov model (jpHMM), a new method to detect recombinations in HIV-1 genomes. The jpHMM predicts recombination breakpoints in a query sequence and assigns to each position of the sequence one of the major HIV-1 subtypes. Since incorrect subtype assignment or recombination prediction may lead to wrong conclusions in epidemiological or vaccine research, information about the reliability of the predicted parental subtypes and breakpoint positions is valuable. For this reason, we extended the output of jpHMM to include such information in terms of 'uncertainty' regions in the recombination prediction and an interval estimate of the breakpoint. Both types of information are computed based on the posterior probabilities of the subtypes at each query sequence position. Our results show that this extension strongly improves the reliability of the jpHMM recombination prediction. The jpHMM is available online at http://jphmm.gobics.de/. PMID- 19443441 TI - CUGBP2 directly interacts with U2 17S snRNP components and promotes U2 snRNA binding to cardiac troponin T pre-mRNA. AB - CUGBP2 (ETR-3/NAPOR/BRUNOL3) promotes inclusion of cardiac troponin T (cTNT) exon 5 via binding between positions 21 and 74 of the downstream intron. The molecular mechanism by which CUGBP2 activates cTNT exon 5 inclusion is unknown. Our results suggest that CUGBP2 promotes exon inclusion by a novel mechanism in which CUGBP2 directly interacts with components of the activated U2 snRNP and enhances binding of U2 snRNP to the branch site located upstream of the exon. Using an in vitro splicing assay, we show that recombinant CUGBP2 enhances complex A formation of a cTNT pre-mRNA. Enhanced complex A assembly requires both the upstream and downstream introns consistent with dual requirements for the downstream CUGBP2 binding site and an upstream branch site for U2 snRNP binding. We also show that CUGBP2 enhances binding of U2 snRNA to the cTNT pre-mRNA consistent with enhanced complex A assembly. Purification of CUGBP2-interacting proteins using tandem affinity purification leads to the demonstration that the core 17S U2 snRNP components, SF3b145 and SF3b49 bind directly to CUGBP2. We conclude that CUGBP2 activates exon inclusion by forming direct interactions with components of the 17S snRNP complex and recruits and/or stabilizes binding of U2 snRNP. PMID- 19443442 TI - iCODEHOP: a new interactive program for designing COnsensus-DEgenerate Hybrid Oligonucleotide Primers from multiply aligned protein sequences. AB - PCR amplification using COnsensus DEgenerate Hybrid Oligonucleotide Primers (CODEHOPs) has proven to be highly effective for identifying unknown pathogens and characterizing novel genes. We describe iCODEHOP; a new interactive web application that simplifies the process of designing and selecting CODEHOPs from multiply-aligned protein sequences. iCODEHOP intelligently guides the user through the degenerate primer design process including uploading sequences, creating a multiple alignment, deriving CODEHOPs and calculating their annealing temperatures. The user can quickly scan over an entire set of degenerate primers designed by the program to assess their relative quality and select individual primers for further analysis. The program displays phylogenetic information for input sequences and allows the user to easily design new primers from selected sequence sub-clades. It also allows the user to bias primer design to favor specific clades or sequences using sequence weights. iCODEHOP is freely available to all interested researchers at https://icodehop.cphi.washington.edu/i-codehop context/Welcome. PMID- 19443443 TI - MM-align: a quick algorithm for aligning multiple-chain protein complex structures using iterative dynamic programming. AB - Structural comparison of multiple-chain protein complexes is essential in many studies of protein-protein interactions. We develop a new algorithm, MM-align, for sequence-independent alignment of protein complex structures. The algorithm is built on a heuristic iteration of a modified Needleman-Wunsch dynamic programming (DP) algorithm, with the alignment score specified by the inter complex residue distances. The multiple chains in each complex are first joined, in every possible order, and then simultaneously aligned with cross-chain alignments prevented. The alignments of interface residues are enhanced by an interface-specific weighting factor. MM-align is tested on a large-scale benchmark set of 205 x 3897 non-homologous multiple-chain complex pairs. Compared with a naive extension of the monomer alignment program of TM-align, the alignment accuracy of MM-align is significantly higher as judged by the average TM-score of the physically-aligned residues. MM-align is about two times faster than TM-align because of omitting the cross-alignment zone of the DP matrix. It also shows that the enhanced alignment of the interfaces helps in identifying biologically relevant protein complex pairs. PMID- 19443444 TI - p53-dependent antiviral RNA-interference facilitates tumor-selective viral replication. AB - RNA-interference (RNAi) is a potent tool for specific gene silencing. In this study, we developed an adenovirus for conditional replication in p53 dysfunctional tumor cells that uses p53-selective expression of a microRNA network directed against essential adenoviral genes. Compared to a control virus that expressed a scrambled microRNA-network, antiviral RNAi selectively attenuated viral replication in cells with transcriptionally active p53, but not in p53-dysfunctional tumor cells where both viruses replicated equivalently. Since these results were confirmed by an in vivo comparison of both viruses after infection of p53-knockout and normal mice, we could demonstrate that attenuated replication was indeed a result of p53-selective exhibition of antiviral RNAi. Addressing the therapeutic applicability, we could show that the application of RNAi-controlled virus efficiently lysed p53-dysfunctional tumors in vitro and in vivo but resulted in drastically reduced load of virus-DNA in the liver of treated mice. We have generated a broadly applicable adenovirus for selective destruction of p53-dysfunctional tumors and thereby demonstrate that virus encoded RNAi-networks represent an efficient and versatile tool to modify viral functions. RNAi-networks can be applied to all transcriptionally regulated DNA viruses to remodulate viral tropism and thus provide means to generate specifically replicating vectors for clinical applications. PMID- 19443445 TI - Histone H2a mRNA interacts with Lin28 and contains a Lin28-dependent posttranscriptional regulatory element. AB - Lin28 has been shown to block the processing of let-7 microRNAs implicated in the regulation of cell growth and differentiation. Here, we show that Lin28 also specifically associates with ribonucleoprotein particles containing the replication-dependent histone H2a mRNA in mouse embryonic stem cells. We further show that the coding region of H2a mRNA harbors high affinity binding sequences for Lin28 and that these sequences stimulate the expression of reporter genes in a Lin28-dependent manner. We suggest that a key function of Lin28 in the maintenance of pluripotency is to promote the expression of the H2a gene (and perhaps also other replication-dependent histone genes) at the posttranscriptional level in order to coordinate histone production with the unique proliferative properties of embryonic stem cells. PMID- 19443446 TI - Robust methods for purification of histones from cultured mammalian cells with the preservation of their native modifications. AB - Post-translational modifications (PTMs) of histones play a role in modifying chromatin structure for DNA-templated processes in the eukaryotic nucleus, such as transcription, replication, recombination and repair; thus, histone PTMs are considered major players in the epigenetic control of these processes. Linking specific histone PTMs to gene expression is an arduous task requiring large amounts of highly purified and natively modified histones to be analyzed by various techniques. We have developed robust and complementary procedures, which use strong protein denaturing conditions and yield highly purified core and linker histones from unsynchronized proliferating, M-phase arrested and butyrate treated cells, fully preserving their native PTMs without using enzyme inhibitors. Cell hypotonic swelling and lysis, nuclei isolation/washing and chromatin solubilization under mild conditions are bypassed to avoid compromising the integrity of histone native PTMs. As controls for our procedures, we tested the most widely used conventional methodologies and demonstrated that they indeed lead to drastic histone dephosphorylation. Additionally, we have developed methods for preserving acid-labile histone modifications by performing non-acid extractions to obtain highly purified H3 and H4. Importantly, isolation of histones H3, H4 and H2A/H2B is achieved without the use of HPLC. Functional supercoiling assays reveal that both hyper- and hypo-phosphorylated histones can be efficiently assembled into polynucleosomes. Notably, the preservation of fully phosphorylated mitotic histones and their assembly into polynucleosomes should open new avenues to investigate an important but overlooked question: the impact of mitotic phosphorylation in chromatin structure and function. PMID- 19443447 TI - Tissue-specific regulatory network extractor (TS-REX): a database and software resource for the tissue and cell type-specific investigation of transcription factor-gene networks. AB - The prediction of transcription factor binding sites in genomic sequences is in principle very useful to identify upstream regulatory factors. However, when applying this concept to genomes of multicellular organisms such as mammals, one has to deal with a large number of false positive predictions since many transcription factor genes are only expressed in specific tissues or cell types. We developed TS-REX, a database/software system that supports the analysis of tissue and cell type-specific transcription factor-gene networks based on expressed sequence tag abundance of transcription factor-encoding genes in UniGene EST libraries. The use of expression levels of transcription factor encoding genes according to hierarchical anatomical classifications covering different tissues and cell types makes it possible to filter out irrelevant binding site predictions and to identify candidates of potential functional importance for further experimental testing. TS-REX covers ESTs from H. sapiens and M. musculus, and allows the characterization of both presence and specificity of transcription factors in user-specified tissues or cell types. The software allows users to interactively visualize transcription factor-gene networks, as well as to export data for further processing. TS-REX was applied to predict regulators of Polycomb group genes in six human tumor tissues and in human embryonic stem cells. PMID- 19443448 TI - @TOME-2: a new pipeline for comparative modeling of protein-ligand complexes. AB - @TOME 2.0 is new web pipeline dedicated to protein structure modeling and small ligand docking based on comparative analyses. @TOME 2.0 allows fold recognition, template selection, structural alignment editing, structure comparisons, 3D-model building and evaluation. These tasks are routinely used in sequence analyses for structure prediction. In our pipeline the necessary software is efficiently interconnected in an original manner to accelerate all the processes. Furthermore, we have also connected comparative docking of small ligands that is performed using protein-protein superposition. The input is a simple protein sequence in one-letter code with no comment. The resulting 3D model, protein ligand complexes and structural alignments can be visualized through dedicated Web interfaces or can be downloaded for further studies. These original features will aid in the functional annotation of proteins and the selection of templates for molecular modeling and virtual screening. Several examples are described to highlight some of the new functionalities provided by this pipeline. The server and its documentation are freely available at http://abcis.cbs.cnrs.fr/AT2/ PMID- 19443449 TI - Characterization of sINR, a strict version of the Initiator core promoter element. AB - The proximal promoter consists of binding sites for transcription regulators and a core promoter. We identified an overrepresented motif in the proximal promoter of human genes with an Initiator (INR) positional bias. The core of the motif fits the INR consensus but its sequence is more strict and flanked by additional conserved sequences. This strict INR (sINR) is enriched in TATA-less genes that belong to specific functional categories. Analysis of the sINR-containing DHX9 and ATP5F1 genes showed that the entire sINR sequence, including the strict core and the conserved flanking sequences, is important for transcription. A conventional INR sequence could not substitute for DHX9 sINR whereas, sINR could replace a conventional INR. The minimal region required to create the major TSS of the DHX9 promoter includes the sINR and an upstream Sp1 site. In a heterologous context, sINR substituted for the TATA box when positioned downstream to several Sp1 sites. Consistent with that the majority of sINR promoters contain at least one Sp1 site. Thus, sINR is a TATA-less-specific INR that functions in cooperation with Sp1. These findings support the idea that the INR is a family of related core promoter motifs. PMID- 19443450 TI - Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5' exonuclease activities of human Ape2 in repair of oxidative DNA damage. AB - Human Ape2 protein has 3' phosphodiesterase activity for processing 3'-damaged DNA termini, 3'-5' exonuclease activity that supports removal of mismatched nucleotides from the 3'-end of DNA, and a somewhat weak AP-endonuclease activity. However, very little is known about the role of Ape2 in DNA repair processes. Here, we examine the effect of interaction of Ape2 with proliferating cell nuclear antigen (PCNA) on its enzymatic activities and on targeting Ape2 to oxidative DNA lesions. We show that PCNA strongly stimulates the 3'-5' exonuclease and 3' phosphodiesterase activities of Ape2, but has no effect on its AP-endonuclease activity. Moreover, we find that upon hydrogen-peroxide treatment Ape2 redistributes to nuclear foci where it colocalizes with PCNA. In concert with these results, we provide biochemical evidence that Ape2 can reduce the mutagenic consequences of attack by reactive oxygen species not only by repairing 3'-damaged termini but also by removing 3'-end adenine opposite from 8-oxoG. Based on these findings we suggest the involvement of Ape2 in repair of oxidative DNA damage and PCNA-dependent repair synthesis. PMID- 19443451 TI - ROS1 5-methylcytosine DNA glycosylase is a slow-turnover catalyst that initiates DNA demethylation in a distributive fashion. AB - Arabidopsis ROS1 belongs to a family of plant 5-methycytosine DNA glycosylases that initiate DNA demethylation through base excision. ROS1 displays the remarkable capacity to excise 5-meC, and to a lesser extent T, while retaining the ability to discriminate effectively against C and U. We found that replacement of the C5-methyl group by halogen substituents greatly decreased excision of the target base. Furthermore, 5-meC was excised more efficiently from mismatches, whereas excision of T only occurred when mispaired with G. These results suggest that ROS1 specificity arises by a combination of selective recognition at the active site and thermodynamic stability of the target base. We also found that ROS1 is a low-turnover catalyst because it binds tightly to the abasic site left after 5-meC removal. This binding leads to a highly distributive behaviour of the enzyme on DNA substrates containing multiple 5-meC residues, and may help to avoid generation of double-strand breaks during processing of bimethylated CG dinucleotides. We conclude that the biochemical properties of ROS1 are consistent with its proposed role in protecting the plant genome from excess methylation. PMID- 19443452 TI - INTREPID: a web server for prediction of functionally important residues by evolutionary analysis. AB - We present the INTREPID web server for predicting functionally important residues in proteins. INTREPID has been shown to boost the recall and precision of catalytic residue prediction over other sequence-based methods and can be used to identify other types of functional residues. The web server takes an input protein sequence, gathers homologs, constructs a multiple sequence alignment and phylogenetic tree and finally runs the INTREPID method to assign a score to each position. Residues predicted to be functionally important are displayed on homologous 3D structures (where available), highlighting spatial patterns of conservation at various significance thresholds. The INTREPID web server is available at http://phylogenomics.berkeley.edu/intrepid. PMID- 19443453 TI - PhyloPars: estimation of missing parameter values using phylogeny. AB - A wealth of information on metabolic parameters of a species can be inferred from observations on species that are phylogenetically related. Phylogeny-based information can complement direct empirical evidence, and is particularly valuable if experiments on the species of interest are not feasible. The PhyloPars web server provides a statistically consistent method that combines an incomplete set of empirical observations with the species phylogeny to produce a complete set of parameter estimates for all species. It builds upon a state-of the-art evolutionary model, extended with the ability to handle missing data. The resulting approach makes optimal use of all available information to produce estimates that can be an order of magnitude more accurate than ad-hoc alternatives. Uploading a phylogeny and incomplete feature matrix suffices to obtain estimates of all missing values, along with a measure of certainty. Real time cross-validation provides further insight in the accuracy and bias expected for estimated values. The server allows for easy, efficient estimation of metabolic parameters, which can benefit a wide range of fields including systems biology and ecology. PhyloPars is available at: http://www.ibi.vu.nl/programs/phylopars/. PMID- 19443454 TI - Focal spermatogenesis originates in euploid germ cells in classical Klinefelter patients. AB - BACKGROUND: Klinefelter syndrome is the most frequent chromosome abnormality in human males. This paper aims to investigate the ploidy of meiotic and pre-meiotic germ cells found in spermatogenic foci, and furthermore, the sex chromosome constitution of Sertoli cells which surround these germ cells in non-mosaic Klinefelter patients. METHODS AND RESULTS: A survey of 11 adult patients diagnosed with classical, non-mosaic Klinefelter syndrome who underwent testicular biopsies, showed that six of them had spermatogenesis foci. The topographical study of the biopsies showed that tubuli with germ cells are a minor fraction (8-24%) of all tubuli, although the overwhelming majority is devoid of germ cells. Using fluorescence in situ hybridization (FISH) with probes for the X-centromere and immunolocalization of meiotic proteins, the present work shows that all the 92 meiotic spermatocytes analyzed with FISH were euploid, 46,XY, and thus can form normal, haploid gametes. On the other hand, Sertoli cells show two marks for the X chromosome, meaning that they are 47,XXY. CONCLUSIONS: These results provide a rationale for the high rate of success in the testicular sperm extraction plus ICSI procedures when applied to Klinefelter patients. It is also in agreement with previous studies in the XXY-mouse model. These spermatogenic foci most probably originate from clones of spermatogonia that have randomly lost one of the X chromosomes, probably during periods of life when high spermatogonial mitotic activity occurs. PMID- 19443455 TI - Interactions between apoptotic signal transduction and capacitation in human spermatozoa. AB - BACKGROUND: Capacitation of sperm is a prerequisite for successful fertilization, determined by hyperactivated motility, increased tyrosine phosphorylation (TyrP) and membrane changes. However, the exact molecular mechanism is not fully clarified. The calpain-calmodulin-system is essential for membrane fusion during capacitation. Recently, interactions with caspase (CP) activation, a main feature of apoptotic cells, were postulated. The objective of our study was to examine interactions between apoptosis signalling and the calpain-calmodulin-system during capacitation. METHODS: Semen samples from 20 healthy donors were incubated in human tubal fluid at 37 degrees C, 5% CO(2) for 3 h without additives (control), with 3% BSA (capacitation), 10 microM calpain-inhibitor III, 20 microM CP-1 inhibitor or 20 microM calmodulin-antagonist. Capacitation was monitored by computer assisted sperm motion analyzer, chlortetracycline (CTC)-assay and western blot (TyrP). Activation of caspases and integrity of transmembrane mitochondrial potential (TMP) were evaluated by flow cytometry. RESULTS: Capacitation, as measured by CTC assay, increased TyrP levels and hyperactivation, resulted in inactivation of CP-9, CP-3 and improved integrity of the TMP. Inhibition of calpain and CP-1 during capacitation reduced the capacitation-related parameters, but did not lead to apoptosis. Inhibition of calmodulin resulted in blocking of capacitation and stimulation of apoptosis. CONCLUSION: Interaction of the capacitation and apoptosis signalling systems seems to enable the capacitation process by prevention of apoptosis. PMID- 19443456 TI - Does a testicular dysgenesis syndrome exist? AB - The concept of an increasingly common Testicular Dysgenesis Syndrome (TDS) has been widely adopted with little epidemiological appraisal. In this paper we critically review the epidemiologic evidence of the existence of a non-genetic TDS. We systematically assess and discuss the evidence of all six possible associations between the four defining conditions of TDS: impaired spermatogenesis, undescended testis, hypospadia and testicular cancer. We also evaluate whether there are common risk factors for these four conditions. We conclude that epidemiologic studies provide little support for existence of a widespread TDS because there are no consistent non-causal associations between its different manifestations. There is furthermore little evidence of shared causes between the alleged components of the syndrome. PMID- 19443457 TI - Is there an association between endometriosis and the risk of pre-eclampsia? A population based study. AB - BACKGROUND: An association between endometriosis and reduced risk of pre eclampsia has recently been reported. Longitudinally-linked electronic hospital records are a valuable resource for investigating such findings in a large, population-based sample. Our aim was to determine whether women with a history of endometriosis were at modified risk for pregnancy hypertension or pre-eclampsia. METHODS: A population-based, longitudinal study of all women in the Australian state of New South Wales, aged from 15 to 45 years of age with a singleton birth during the period 2000-2005. Endometriosis was identified using ICD-10 codes. Endometriosis subgroups were analysed based on: (i) site of endometriosis (ovary or peritoneum), (ii) multiple (i.e. two or more) sites affected and (iii) infertility. To investigate the association between pregnancy hypertension and endometriosis, number of weeks gestation at birth and maternal age, we used logistic regression. RESULTS: In the 3239 (1.6%) women with endometriosis diagnosed before their first birth, 352 (10.9%) had a diagnosis of pregnancy hypertension compared with 23,186/205,640 (11.3%) in women with no endometriosis diagnosis (OR 0.96; 95% CI 0.9-1.3). The frequency of pregnancy hypertension and pre-eclampsia was not significantly different in women with more severe endometriosis or endometriosis in conjunction with infertility when compared with those with no endometriosis. After adjusting for maternal age and weeks gestation there was still no altered risk. CONCLUSIONS: We have found no evidence for an association between endometriosis and subsequent risk of either pregnancy hypertension or pre-eclampsia in this large population-based dataset. PMID- 19443458 TI - Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction. AB - BACKGROUND: A poor quality of oocytes and embryos and a low fertilization rate have been found in polycystic ovary syndrome (PCOS) patients. An inverse association between follicular fluid homocysteine (Hcy) levels and oocyte and embryo quality has also been demonstrated. We examined the relationship between follicular fluid Hcy concentrations and oocyte and embryo quality in PCOS patients undergoing assisted reproduction. METHODS: Fifty-two PCOS patients were included in the study, and underwent GnRH agonist/recombinant FSH treatment. The Hcy, folate, vitamin B(12), malonyldialdehyde (MDA) and estradiol (E(2)) levels were measured in follicular fluid from single oocytes at time of retrieval. One follicle per ovary was sampled and 94 were analysed. Plasma hormones were also measured. Oocytes and embryos were graded (1-3) using standard approaches. RESULTS: The concentrations of Hcy, E(2), vitamin B(12), folate and MDA in plasma were higher than in follicular fluid (all P < 0.001). Significant differences were observed in follicular Hcy levels between Grade 3 and Grade 2 oocytes (P < 0.001). Hcy levels were lower in Grade 1-2 embryos than that in Grade 3 embryos; follicular fluid vitamin B(12) levels were lower in patients showing high concentrations of follicular fluid Hcy (P < 0.01). The follicular fluid Hcy levels were negatively correlated with follicular fluid vitamin B(12) (r = 0.44), folate (r = -0.68) and fertilization rate (r = -0.85), and positively correlated with follicular fluid MDA (r = 0.51). CONCLUSIONS: Concentrations of Hcy in follicular fluid on the dOPU may be a useful marker for fertilization rate, and oocyte and embryo quality in PCOS patients undergoing assisted reproduction. PMID- 19443459 TI - Effects of a warmer climate on seed germination in the subarctic. AB - BACKGROUND AND AIMS: In a future warmer subarctic climate, the soil temperatures experienced by dispersed seeds are likely to increase during summer but may decrease during winter due to expected changes in snow depth, duration and quality. Because little is known about the dormancy-breaking and germination requirements of subarctic species, how warming may influence the timing and level of germination in these species was examined. METHODS: Under controlled conditions, how colder winter and warmer summer soil temperatures influenced germination was tested in 23 subarctic species. The cold stratification and warm incubation temperatures were derived from real soil temperature measurements in subarctic tundra and the temperatures were gradually changed over time to simulate different months of the year. KEY RESULTS: Moderate summer warming (+2.5 degrees C) substantially accelerated germination in all but four species but did not affect germination percentages. Optimum germination temperatures (20/10 degrees C) further decreased germination time and increased germination percentages in three species. Colder winter soil temperatures delayed the germination in ten species and decreased the germination percentage in four species, whereas the opposite was found in Silene acaulis. In most species, the combined effect of a reduced snow cover and summer warming resulted in earlier germination and thus a longer first growing season, which improves the chance of seedling survival. In particular the recruitment of (dwarf) shrubs (Vaccinium myrtillus, V. vitis-idaea, Betula nana), trees (Alnus incana, Betula pubescens) and grasses (Calamagrostis lapponica, C. purpurea) is likely to benefit from a warmer subarctic climate. CONCLUSIONS: Seedling establishment is expected to improve in a future warmer subarctic climate, mainly by considerably earlier germination. The magnitudes of the responses are species-specific, which should be taken into account when modelling population growth and migration of subarctic species. PMID- 19443460 TI - Pollination syndromes in African Marantaceae. AB - BACKGROUND AND AIMS: The Marantaceae (550 spp.) is the most derived family in the order Zingiberales and exhibits a complex explosive pollination mechanism. To understand the evolutionary significance of this unique process of pollen transfer, comparative morphological and ecological studies were conducted in Gabon. METHODS: During a total stay of 11 months, 31 species of Marantaceae were investigated at different sites in Gabon. The study included analyses of floral diversity, observations on the pollinator spectrum as well as ecological measurements (e.g. nectar sugar concentration and volume). KEY RESULTS: Analyses reveal five flower types based on flower size and pigmentation, spatial arrangement of the floral tube and presence/absence of nectar guides and conspicuous outer staminodes. Each type is associated with a specific functional pollinator group leading to the description of distinct pollination syndromes. The 'small (horizontal)' flowers are predominantly pollinated by small bees (Thrinchostoma spp., Allodapula ornaticeps), the 'large (horizontal)' and 'medium sized (horizontal)' flowers by medium-sized bees (Amegilla vivida, Thrinchostoma bicometes), the 'locked (horizontal)' flowers by large bees (Xylocopa nigrita, X. varipes) and the '(large) vertical' flowers by sunbirds. CONCLUSIONS: The longevity of Marantaceae individuals and the omnipresence of their pollinators allowed the specialization to a given functional pollinator group. Intermediate ecological values, however, make occasional pollinator overlaps possible, indicating potential pathways of pollinator shifts. Similar radiation tendencies observed on other continents hint at similar selective pressures and evolutionary constraints. PMID- 19443461 TI - The association between the COL12A1 gene and anterior cruciate ligament ruptures. AB - BACKGROUND: Anterior cruciate ligament (ACL) ruptures are among the most severe musculoskeletal soft tissue injuries. However, the exact mechanisms which cause these acute injuries are unknown. Recently, sequence variants within two genes, namely COL1A1 and COL5A1, which code for the alpha1 chains of types I and V collagen respectively, were shown to be associated with ACL ruptures. Type XII collagen, similarly to types I and V collagen, is a structural component of the ligament fibril and is encoded by a single gene, COL12A1. OBJECTIVE: The aim of this study was to investigate whether sequence variants within COL12A1 are associated with ACL ruptures. METHODS: One hundred and twenty-nine (38 female) participants with clinically and surgically diagnosed ACL ruptures, as well as 216 (83 female) physically active controls participants (CON) without any history of ACL injury were included in this case-control genetic association study. All participants were genotyped for the AluI and BsrI restriction fragment length polymorphisms (RFLPs) within COL12A1. RESULTS: The AA genotype of the COL12A1 AluI RFLP was significantly over-represented in the female (OR=2.4, 95% CI 1.0 to 5.5, p=0.048), but not male (p=0.359) ACL participants. There were no genotype differences between the ACL and CON group for the BsrI RFLP. CONCLUSION: The COL12A1 AluI RFLP is associated with ACL ruptures among female participants in this study. The results suggest that females with an AA genotype are at increased risk of ACL ruptures. These initial genetic association studies should be explored further and, if repeated, incorporated into multifactorial models developed to identify predisposed individuals. PMID- 19443462 TI - Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. AB - BACKGROUND: Neovascular age-related macular degeneration (AMD) has a poor prognosis if left untreated, frequently resulting in legal blindness. Ranibizumab is approved for treating neovascular AMD. However, further guidance is needed to assist ophthalmologists in clinical practice to optimise treatment outcomes. METHODS: An international retina expert panel assessed evidence available from prospective, multicentre studies evaluating different ranibizumab treatment schedules (ANCHOR, MARINA, PIER, SAILOR, SUSTAIN and EXCITE) and a literature search to generate evidence-based and consensus recommendations for treatment indication and assessment, retreatment and monitoring. RESULTS: Ranibizumab is indicated for choroidal neovascular lesions with active disease, the clinical parameters of which are outlined. Treatment initiation with three consecutive monthly injections, followed by continued monthly injections, has provided the best visual-acuity outcomes in pivotal clinical trials. If continued monthly injections are not feasible after initiation, a flexible strategy appears viable, with monthly monitoring of lesion activity recommended. Initiation regimens of fewer than three injections have not been assessed. Continuous careful monitoring with flexible retreatment may help avoid vision loss recurring. Standardised biomarkers need to be determined. CONCLUSION: Evidence-based guidelines will help to optimise treatment outcomes with ranibizumab in neovascular AMD. PMID- 19443463 TI - CARD8 p.C10X polymorphism is associated with inflammatory activity in early rheumatoid arthritis. AB - OBJECTIVES: CARD8 and NLRP3 are constituents of the inflammasome which regulates interleukin 1beta production. The influence of polymorphisms in CARD8 and NLRP3 on rheumatoid arthritis (RA) susceptibility and severity were evaluated. METHODS: CARD8 p.C10X and NLRP3 p.Q705K genotypes were assessed in >500 controls and patients with early RA from northern Sweden. The patients were monitored regularly over a 2-year period. The 28-joint disease activity score (DAS28) and its separate components were compared across genotypes. RESULTS: Patients with one or more variant alleles in CARD8 (CARD8-X) had increased DAS28, tender joint count and erythrocyte sedimentation rate during the 2-year follow-up period despite receiving disease-modifying antirheumatic drugs to a greater extent. CARD8-X was significantly over-represented among patients who received anti tumour necrosis factor therapy during the first 2 years. CARD8 and NLRP3 genotypes did not influence radiological joint damage and were not associated with an increased susceptibility. CONCLUSIONS: Carriage of CARD8-X is associated with a worse disease course in early RA. PMID- 19443464 TI - New surfactant protein C gene mutations associated with diffuse lung disease. AB - BACKGROUND: Mutations in the surfactant protein C gene (SFTPC) have been recently associated with the development of diffuse lung disease, particularly sporadic and familial interstitial lung disease (ILD). OBJECTIVE: We have investigated the prevalence and the spectrum of SFTPC mutations in a large cohort of infants and children with diffuse lung disease and suspected with surfactant dysfunction. METHOD AND RESULTS: 121 children were first screened for the common SFTPC mutation, p.Ile73Thr (I73T). Ten unrelated patients were shown to carry this mutation. The I73T mutation was inherited in six cases, and appeared de novo in four. The 111 patients without the I73T mutation were screened for the entire coding sequence of SFTPC. Of these, eight (seven unrelated) subjects were shown to carry a novel mutant allele of SFTPC. All these seven new mutations are located in the BRICHOS domain except the p.Val39Ala (V39A) mutation, which is in the surfactant protein C (SP-C) mature peptide. CONCLUSIONS: Our results confirm that SFTPC mutations are a frequent cause of diffuse lung disease, and that I73T is the most frequent SFTPC mutation associated with diffuse lung disease. PMID- 19443465 TI - SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. AB - OBJECTIVE: Mutations of the SPRED1 gene, one of a family of Sprouty (Spry)/Spred proteins known to "downregulate" mitogen activated protein kinase (MAPK) signalling, have been identified in patients with a mild neurofibromatosis type 1 (NF1) phenotype with pigmentary changes but no neurofibromas (Legius syndrome).To ascertain the frequency of SPRED1 mutations as a cause of this phenotype and to investigate whether other SPRED/SPRY genes may be causal, a panel of unrelated mild NF1 patients were screened for mutations of the SPRED1-3 and the SPRY1-4 genes. METHODS: 85 patients with a mild NF1 phenotype were screened for SPRED1 mutations. 44 patients negative for both NF1 and SPRED1 mutations were then screened for SPRED2-3 and SPRY1-4 mutations. Complexity analysis was applied to analyse the flanking sequences surrounding the identified SPRED1 mutations for the presence of direct and inverted repeats or symmetric sequence elements in order to infer probable mutational mechanism. RESULTS: SPRED1 mutations were identified in 6 cases; 5 were novel and included 3 nonsense (R16X, E73X, R262X), 2 frameshift (c.1048_c1049 delGG, c.149_1152del 4 bp), and a single missense mutation (V44D). Short direct or inverted repeats detected immediately adjacent to some SPRED1 mutations may have led to the formation of the microdeletions and base pair substitutions. DISCUSSION: The identification of SPRED1 gene mutation in NF1-like patients has major implications for counselling NF1 families. PMID- 19443466 TI - Pulmonary valve papillary fibroelastoma diagnosed by echocardiography: a case report. AB - Papillary fibroelastomas (PFEs) are rare cardiac valve tumours with reported incidence of <0.03% according to autopsy studies. Among them, pulmonary valve PFEs are extremely rare. With wider use of echocardiography, they are being increasingly recognized premortem. We describe a case of a 32-year-old Caucasian woman with PFE of pulmonic valve diagnosed by echocardiography. The patient underwent surgery due to high mobility of the tumour and high risk of embolic complications. The surgery was done with complete tumour resection and total preservation of valve function. This case report discusses diagnostics of PFEs, their characteristic echocardiographic and histological features, and possible complications and suggests treatment options in this rare cardiac tumour. PMID- 19443467 TI - Unusual cause of rapidly progressive right-sided heart failure: aortic sinus of Valsalva aneurysm causing ball valve obstruction of the tricuspid valve. AB - A rare presentation with rapidly progressive right heart failure due to tricuspid inflow obstruction (simulating right-sided valvular heart disease) caused by a non-coronary cusp sinus of Valsalva aneurysm with small perforation is reported. The aneurysm was causing ball valve obstruction at the tricuspid valve, leading to dilated right atrium and back pressure changes which were relieved after successful aneurysectomy. PMID- 19443468 TI - Right ventricular function in patients with preserved and reduced ejection fraction heart failure. AB - AIMS: To determine the prevalence of right ventricular (RV) dysfunction in patients with preserved left ventricular (LV) ejection fraction (EF) heart failure (HF) and to compare RV function between patients with preserved EF HF and those with reduced EF HF. METHODS AND RESULTS: Hundred patients (72 +/- 14 years, 59% male) with HF were prospectively enrolled. Fifty-one had preserved EF HF (LVEF > 50%). The prevalence of RV systolic dysfunction in patients with preserved EF HF was 33, 40, and 50%, by using RV fractional area change (FAC), tricuspid annular motion (TAM), and peak systolic tricuspid annular tissue velocity (S') criteria, respectively. Tricuspid S' and TAM correlated the best with LVEF (r = 0. 48, P < 0.01). Patients with preserved EF HF had higher RV FAC (54 +/- 18 vs. 36 +/- 20%, P < 0.01), TAM (17 +/- 1 vs.11 +/- 1 mm, P < 0.01), and tricuspid S' (14 +/- 6 vs. 9 +/- 4 cm/s, P < 0.01) compared with those with reduced EF HF. Of those 51 patients, 34% had tricuspid E/e' > 6 suggestive of elevated RV filling pressures. Early tricuspid inflow (E), early diastolic tricuspid annular tissue (e'), tricuspid E/e', and hepatic vein systolic velocities were also higher in patients with preserved EF HF. CONCLUSION: The prevalence of RV systolic and diastolic dysfunctions was not uncommon in patients with preserved EF HF. However, patients with preserved EF HF had milder degree of RV systolic and diastolic dysfunctions compared with those with reduced EF HF. PMID- 19443469 TI - Atrial reservoir function by strain rate imaging in asymptomatic mitral stenosis: prognostic value at 3 year follow-up. AB - AIMS: Assessment of left and right systolic atrial reservoir function in asymptomatic mitral stenosis (MS) by strain and strain rate imaging (SRI) and their prognostic power at 3 year follow-up was the purpose of this study. There is clear indication to treat (by surgery or percutaneous valvotomy) symptomatic patients with MS, whereas for the asymptomatic ones, the question is much debated. So, we need new echocardiographic parameters helpful for the management of asymtomatic patients. Atrial reservoir function by SRI could help in evaluation of these patients. METHODS AND RESULTS: Fifty-three asymptomatic patients with MS and 53 healthy controls were evaluated by the standard echo Doppler study [mitral valve (MV) area, mean gradient, systolic pulmonary pressure, left atrial (LA) width, LA volumes, LA compliance index] and by Doppler myocardial imaging (velocity, strain, and SR of both atria). The endpoint at 3 year follow-up was symptoms, hospitalization for cardiac cause, atrial fibrillation, thrombo-embolic events, valvular surgery, or percutaneous commissurotomy. LA width, volumes, and systolic pulmonary pressure were significantly increased in MS patients (P < 0.001). Atrial myocardial velocities and deformation indices were significantly compromised in MS patients (P < 0.0001). Significant correlation was found between atrial myocardial velocity and MV area (by pressure half-time method: P = 0.019, R = 0.41; by planimetric method: P = 0.016, R = 0.43). Peak systolic LA myocardial strain and SR were significantly correlated with atrial volumes (strain: P = 0.03, R = -0.28; SR: P = 0.0008, R = -0.42), with atrial compliance index (strain: P = 0.04, R = 0.26; SR: P = 0.04, R = 0.16), with atrial ejection fraction (strain: P < 0.0001, R = 0.56; SR: P = 0.03, R = 0.43). At 3 year follow-up, 22 (41%) patients had events. Comparing the MS patients who had events during the 3 year follow-up with those who did not, the former had bigger LA volumes, although these parameters did not reached a significant value, whereas atrial myocardial systolic SR was significantly impaired in patients with events. In multivariate analysis, the best predictor of adverse events was LA peak systolic SR average (P = 0.04; coefficient: 0.113; SE: 0.055; cut-off value of 1.69 s(-1) for LA peak systolic SR average) with a sensitivity of 88%, specificity of 80.6%, area under the receiver operating characteristic curve of 0.852 (SE: 0.048; 95% CI: 0.74-0.93, P = 0.0001). CONCLUSION: Atrial myocardial deformation properties, assessed by SRI, are abnormal in asymptomatic patients with rheumatic MS. The degree of this impairment is predictor of events in a 3 year follow-up. SRI could be helpful in decision-making of asymtomatic patients with MS. PMID- 19443470 TI - Comparative epidemiology of stroke and acute myocardial infarction: the Dijon Vascular project (Diva). AB - BACKGROUND: Despite a common pathophysiological mechanism (ie, atherosclerosis) and similar vascular risk factors, few reliable studies have compared the epidemiology of stroke and acute myocardial infarction (AMI). METHODS: All first ever cases of stroke and AMI in Dijon, France (151 846 inhabitants) from 2001 to 2006 were prospectively recorded. The 30 day case fatality rates (CFRs) and vascular risk factors were assessed in both groups. RESULTS: Over the 6 years, 1660 events (1020 strokes and 640 AMI) were recorded. Crude incidence of stroke was higher than that of AMI (112 vs 70.2/100 000/year; p<0.001). With regard to sex, the relative incidence of stroke compared with AMI was 0.88 (95% CI 0.60 to 1.29; p = 0.51) in women <65 years and 2.32 (95% CI 1.95 to 2.75; p<0.001) in those >65 years whereas it was 0.60 (95% CI 0.42 to 0.86; p<0.001) in men below 55 years, 1.01 (0.81 to 1.24, p = 0.96) in those between 55 and 75 years and 2.01 (95% CI 1.48 to 2.71; p<0.001) at 75 years and older. CFRs at 30 days were similar for stroke and AMI (9.80% vs 9.84%; p = 0.5). Hyperglycaemia (>7.8 mmol/l) at onset was significantly associated with higher CFR in both stroke and AMI patients. The prevalence of male sex, hypercholesterolaemia and diabetes was higher in AMI patients whereas hypertension was more frequent in stroke patients. CONCLUSION: These findings will help health care authorities to evaluate future needs for stroke and AMI services, and to develop secondary prevention strategies. PMID- 19443471 TI - Responsiveness of patient reported outcome measures in multiple sclerosis relapses: the REMS study. AB - OBJECTIVES: To assess the responsiveness of the three most used patient reported multiple sclerosis (MS) specific questionnaires: the Functional Assessment of MS (FAMS), the MS Impact Scale (MSIS-29) and the 54 item MS Quality of Life (MSQOL 54). DESIGN: Prospective multicentre longitudinal study on 104 MS patients treated with intravenous steroids for clinical exacerbation. METHODS: Patient reported data, Expanded Disability Status Scale (EDSS) score and clinical information were collected at admission and 8 weeks later. "Internal" (distribution based) responsiveness was assessed by standardised response means (SRM). "External" (anchor based) responsiveness was assessed by receiver operating characteristic (ROC) curves in relation to corresponding changes in a pre-specified reference measure (anchor). The pre-specified anchor was patients' self-reported recovery assessed on a 5 point Likert scale. RESULTS: SRM was 0.39 for FAMS, 0.58 for MSIS-29 physical scale, 0.45 for MSIS-29 psychological scale, 0.71 for MSQOL-54 physical health composite and 0.57 for MSQOL-54 mental health composite. Seventy-three patients (70%) reported they had improved; physicians agreed substantially with patient assessments (kappa statistic 0.70, 95% CI 0.54 to 0.85). Areas under ROC curves differed significantly from 0.50 only for the MSIS-29 and MSQOL-54 scales where areas ranged from 0.65 (95% CI 0.53 to 0.76) for the MSIS-29 psychological scale to 0.70 (95% CI 0.58 to 0.81) for the MSQOL 54 mental health composite. Areas under ROC curves assessed using a physician based anchor were similar to the patient based areas. CONCLUSIONS: The responsiveness of the MS specific instruments was less than ideal. The MSIS-29 and MSQOL-54 were significantly more responsive, using both distribution based and anchor based approaches, than FAMS, and should be preferred in longitudinal studies. PMID- 19443472 TI - Focal atrial tachycardia. AB - Focal atrial tachycardia is a relatively uncommon arrhythmia. Nevertheless, the management of highly symptomatic patients with focal atrial tachycardia can be problematic owing to the poor response to medical treatment. Moreover, focal atrial tachycardia can trigger other atrial arrhythmias like atrial fibrillation and flutter. Radiofrequency ablation of focal atrial tachycardia is extremely successful and this approach is becoming the preferred treatment for symptomatic patients.In this review, we describe the pathophysiology, anatomical localisation, clinical features, diagnosis and therapeutic options for the management of focal atrial tachycardia. PMID- 19443473 TI - The case for fetal cardiac intervention. AB - Surgery for congenital heart disease is now often performed in the first months of life because mortality is higher and myocardial damage more serious in unoperated children or those undergoing delayed surgery. Fetal cardiac intervention may prove a logical extension and has been proposed for fetuses with critical semilunar valve stenosis or atresia. Early ventricular decompression may halt disease progression, alter the natural history and improve postnatal outcomes either by preserving a two-ventricle circulation or by improving the outlook for single-ventricle candidates because of a healthier myocardium and pulmonary bed. Without intervention, fetuses with a closed interatrial septum may develop circulatory failure resulting in hydrops and intrauterine death, whereas in utero balloon atrial septostomy may stabilise the situation and increase duration of pregnancy. PMID- 19443474 TI - Fetal cardiac interventions: worth it? PMID- 19443475 TI - Prognosis of patients with ischaemic cardiomyopathy after coronary revascularisation: relation to viability and improvement in left ventricular ejection fraction. AB - BACKGROUND: In patients with ischaemic cardiomyopathy and viable myocardium, left ventricular ejection fraction (LVEF) does not always improve after revascularisation. Whether this may affect prognosis is unclear. OBJECTIVE: To evaluate the prognosis of viable patients with and without improvement of LVEF after coronary revascularisation. METHODS: Before revascularisation, radionuclide ventriculography (RNV) and dobutamine stress echocardiography were performed to assess LVEF and myocardial viability, respectively. Nine to 12 months after revascularisation, LVEF improvement was assessed by RNV. Patients were divided into three groups: group 1, viable patients with LVEF improvement (n = 27); group 2, viable patients without LVEF improvement (n = 15), group 3, non-viable patients (n = 48). Cardiac events were evaluated during a 4-year follow-up. RESULTS: After revascularisation, the mean (SD) LVEF improved from 32 (9)% to 42 (10)% in group 1, but did not change significantly in group 2 and in group 3, p<0.001 by analysis of variance (ANOVA). Heart failure symptoms improved in both groups 1 (mean (SD) NYHA class from 3.1 (0.9) to 1.7 (0.7)) and 2 (from 3.2 (0.7) to 1.7 (0.9)), but not in group 3 (from 2.8 (1.0) to 2.7 (0.5)), p<0.001 by ANOVA. During follow-up, the cardiac event rate was low (4%) in group 1, intermediate (21%) in group 2 and high (33%) in group 3 (p = 0.01). CONCLUSION: The best prognosis after revascularisation may be expected in those viable patients whose LVEF improves. Conversely, viable patients without functional improvement have an intermediate prognosis. PMID- 19443476 TI - Aetiology of sudden cardiac death in athletes in the United Kingdom: a pathological study. AB - OBJECTIVE: To characterise the demographics and aetiology of sudden cardiac death (SCD) in athletes referred to a tertiary cardiac pathology centre in the UK. DESIGN: Retrospective non-case controlled analysis. SETTING: Cardiac pathology centre at the National Heart and Lung Institute and Royal Brompton Hospital. SUBJECTS: Between 1996 and 2008, the hearts of 118 athletes were referred for pathological assessment to ascertain the precise aetiology of SCD. RESULTS: The majority of athletes (n = 113; 96%) were male and most (107; 91%) were amateurs participating predominantly in football, rugby and running. The mean (SD) age of death was 28 (12) years (range 7-59); 75% athletes were aged < or =35 years. Most deaths (81%) occurred during or immediately after exercise. Antecedent symptoms of cardiac disease were reported in 21 (18%) subjects, and 20 (17%) had a family history of premature cardiovascular disease and/or SCD. 25 (21%) athletes had relevant past medical history which included a known history of cardiac disease. Cardiomyopathy was the commonest cause of death and accounted for 62% of all the SCDs. A significantly high proportion of athletes (23%) exhibited a morphologically normal heart. Atherosclerotic coronary disease accounted for only 3% of cases and was confined to athletes aged >35 years. CONCLUSIONS: SCD in sport is largely due to clinically silent cardiomyopathies or primary electrical disorders (morphologically normal heart). Antecedent symptoms and family history are absent in over 80% of cases, and therefore clinical screening with health questionnaires will fail to identify most athletes with potentially sinister cardiac disorders. PMID- 19443477 TI - What does it cost physician practices to interact with health insurance plans? AB - Physicians have long expressed dissatisfaction with the time they and their staffs spend interacting with health plans. However, little information exists about the extent of these interactions. We conducted a national survey on this subject of physicians and practice administrators. Physicians reported spending three hours weekly interacting with plans; nursing and clerical staff spent much larger amounts of time. When time is converted to dollars, we estimate that the national time cost to practices of interactions with plans is at least $23 billion to $31 billion each year. PMID- 19443478 TI - Peering into the black box: billing and insurance activities in a medical group. AB - Billing and insurance-related functions have been reported to consume 14 percent of medical group revenue, but little is known about the costs associated with performing specific activities. We conducted semistructured interviews, observed work flows, analyzed department budgets, and surveyed clinicians to evaluate these activities at a large multispecialty medical group. We identified 0.67 nonclinical full-time-equivalent (FTE) staff working on billing and insurance functions per FTE physician. In addition, clinicians spent more than thirty-five minutes per day performing these tasks. The cost to medical groups, including clinicians' time, was at least $85,276 per FTE physician (10 percent of revenue). PMID- 19443479 TI - A case of sudden cardiac arrest associated with early repolarisation. PMID- 19443481 TI - What is the role of the aorta in directing coronary blood flow? PMID- 19443483 TI - Lipoprotein levels and the progression of aortic valvular disease. PMID- 19443484 TI - Cardiac resynchronisation in congenital heart disease. PMID- 19443485 TI - Prosthesis-patient mismatch: myth or reality? PMID- 19443486 TI - Segmental duplications mediate novel, clinically relevant chromosome rearrangements. AB - Copy number studies have led to an explosion in the discovery of new segmental duplication-mediated deletions and duplications. We have analyzed copy number changes in 2419 patients referred for clinical array comparative genomic hybridization studies. Twenty-three percent of the abnormal copy number changes we found are immediately flanked by segmental duplications > or =10 kb in size and > or =95% identical in direct orientation, consistent with deletions and duplications generated by non-allelic homologous recombination. Here, we describe copy number changes in five previously unreported loci with genomic organization characteristic of NAHR-mediated gains and losses; namely, 2q11.2, 7q36.1, 17q23, 2q13 and 7q11.21. Deletions and duplications of 2q11.2, deletions of 7q36.1 and deletions of 17q23 are interpreted as pathogenic based on their genomic size, gene content, de novo inheritance and absence from control populations. The clinical significance of 2q13 deletions and duplications is still emerging, as these imbalances are also found in phenotypically normal family members and control individuals. Deletion of 7q11.21 is a benign copy number change well represented in control populations and copy number variation databases. Here, we discuss the genetic factors that can modify the phenotypic expression of such gains and losses, which likely play a role in these and other recurrent genomic disorders. PMID- 19443487 TI - Predisposition to relapsing nephrotic syndrome by a nephrin mutation that interferes with assembly of functioning microdomains. AB - Minimal-change disease (MCD) is the most common cause of nephrotic syndrome (NS) and is characterized only by minor morphological alterations in podocytes. A subtype of MCD arises from mutations in nephrin, a major component of the slit diaphragm (SD). Idiopathic MCD is a complex trait where interactions of genetic and immunological factors are implicated. However, the pathogenic mechanisms remain unclear. Here we studied the molecular basis for familial NS characterized by frequent relapses and minimal-change histology. Our previous mutational analysis revealed that the two affected children were compound heterozygotes for nephrin variants C265R and V822M (Kidney Int., 2008). When heterologously expressed, these variants exhibited normal metabolic half-life and raft binding. C265R exhibited substantial ER retention, reflecting an intracellular trafficking defect. In contrast, V822M was able to reach the plasma membrane, but was restricted in lateral diffusion as well as trafficking at the cell surface. Clustering of V822M failed to evoke a maximum tyrosine-phosphorylation and actin reorganization, suggesting the inability to assemble into functioning membrane microdomains. Our results suggest that C265R and V822M compose a dysfunctional SD complex due to their mixed defects comprising reduced cell surface targeting and ineffective assembly of signaling microdomains. The defective SD likely confers a susceptibility to immunogenic stimuli and predisposes to a relapsing phenotype. PMID- 19443488 TI - The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g. the liver) and causes devastating neuronal degeneration. Metabolic defects resulting from Htt aggregates in peripheral tissues also contribute to HD pathogenesis. Simultaneous improvement of defects in both the CNS and peripheral tissues is thus the most effective therapeutic strategy and is highly desirable. We earlier showed that an agonist of the A(2A) adenosine receptor (A(2A) receptor), CGS21680 (CGS), attenuates neuronal symptoms of HD. We found herein that the A(2A) receptor also exists in the liver, and that CGS ameliorated the urea cycle deficiency by reducing mHtt aggregates in the liver. By suppressing aggregate formation, CGS slowed the hijacking of a crucial transcription factor (HSF1) and two protein chaperons (Hsp27 and Hsp70) into hepatic Htt aggregates. Moreover, the abnormally high levels of high-molecular mass ubiquitin conjugates in the liver of an HD mouse model (R6/2) were also ameliorated by CGS. The protective effect of CGS against mHtt-induced aggregate formation was reproduced in two cells lines and was prevented by an antagonist of the A(2A) receptor and a protein kinase A (PKA) inhibitor. Most importantly, the mHtt-induced suppression of proteasome activity was also normalized by CGS through PKA. Our findings reveal a novel therapeutic pathway of A(2A) receptors in HD and further strengthen the concept that the A(2A) receptor can be a drug target in treating HD. PMID- 19443490 TI - Left ventricular performance in aortic valve replacement. AB - We analyzed the mid-term left ventricular (LV) performance after aortic valve replacement (AVR). We measured LV contractility (end-systolic elastance: Ees), afterload (effective arterial elastance: Ea) and efficiency (ventriculoarterial coupling: Ea/Ees; ratio of stroke work and pressure-volume area: SW/PVA) based on transthoracic echocardiography data obtained before, after and approximately 1 year after isolated AVR in 263 patients with aortic stenosis (AS group; n=116), aortic regurgitation (AR group; n=93) or aortic stenosis and regurgitation (ASR group; n=54). The LV volume was calculated by the Teichholz M-mode method. Ees and Ea were approximated as follows: Ees=mean blood pressure/minimal LV volume; Ea=systolic blood pressure/(maximal LV volume-minimal LV volume). Thereafter, Ea/Ees and SW/PVA were calculated. Arterial blood pressure was measured using manchette methods. Ees and Ea decreased after AVR in the AS group, but increased in the AR group. Ea/Ees and SW/PVA worsened after AVR in the AR group, but improved during a 1-year period after AVR in all groups. Contrasting effects of AVR on LV contractility and afterload between AS and AR were clearly demonstrated. The mid-term LV contractility and efficiency after AVR were excellent and satisfactory. However, LV efficiency worsened early after AVR in AR patients. PMID- 19443489 TI - Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. AB - Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression. PMID- 19443491 TI - Pneumonectomy for bronchogenic carcinoma: analysis of factors predicting short- and long-term outcome. AB - The objective of this study was to analyse predictive factors for postoperative and long-term outcome after pneumonectomy. From 1 January 2000 to 1 January 2005 a total of 91 (31%) pneumonectomies were performed. Multivariable analysis for postoperative morbidity, mortality, and long-term survival was performed. Patients over 70 years had 1.5 times higher risk of dying (HR=1.5, 95% CI=1.1 2.0) within five years compared to younger patients, those with co-morbidity had 1.8 times higher risk compared to no co-morbidity (HR=1.8, 95% CI=1.3-2.7) and those with stage IIIA had 2.3 times higher risk of dying compared to stage I (HR=2.3, 95% CI=1.5-3.6). Overall postoperative mortality within 30 days in patients undergoing pneumonectomy was 10% (n=9). Most patients who died postoperatively were 70 years or older, had cardiovascular comorbidity and underwent right-sided pneumonectomy (n=6). Patients over 70 years had three times higher risk of complications compared to younger patients (OR=3.1, 95% CI=1.1 8.2), and patients undergoing right-sided pneumonectomy had 2.4 times higher risk compared to left-sided pneumonectomy (OR=2.4, 95% CI=0.9-6.4). Pneumonectomy is accompanied by high postoperative mortality and morbidity rates, the highest risk in patients over 70 years and right-sided pneumonectomy, and consequently should lead to meticulous patient selection and perioperative care. PMID- 19443492 TI - Pseudo-aneurysm formation post apico-aortic conduit. AB - Apico-aortic conduit (AAC) is an alternative to conventional aortic valve replacement (AVR) in selected high-risk patients. It involves the interposition of a vascular graft with a prosthetic valve from the left ventricular (LV) apex to the descending thoracic aorta. Its use is uncommon but increasing. We describe the complication of pseudo-aneurysm formation following an apico-aortic procedure and its subsequent management. PMID- 19443493 TI - eComment: Stress levels of the surgeon within and beyond the operating room. PMID- 19443494 TI - eComment: Non-invasive ultrasonic cardiac output monitoring in the surgical operating room. PMID- 19443495 TI - eComment: Selective antegrade cerebral perfusion and metabolic suppression. PMID- 19443496 TI - eComment: Islets technique to reduce endarterectomized area included into graft during left anterior descending coronary artery endarterectomy. PMID- 19443497 TI - eComment: Costs of percutaneous coronary intervention versus coronary artery bypass surgery. PMID- 19443498 TI - eComment: Biventricular pacing improves cardiac function compared to univenticular pacing alone in postoperative patients. PMID- 19443499 TI - eComment: Improving reporting quality in meta-analyses--endorsement of the QUOROM statement. PMID- 19443500 TI - eComment: Surgical technique can prevent saphenous vein wall damage during coronary artery bypass graft surgery. PMID- 19443501 TI - eComment: Saphenous graft aneurysms. PMID- 19443502 TI - 150 years beyond Darwin's Origin of species: finding new approaches to reconstruct early animal phylogeny. AB - The conference 'Celebrating Darwin: From the Origin of Species to Deep Metazoan Phylogeny' was held at the Humboldt University in Berlin, from 3 to 6 March 2009. Specialists from the fields of bioinformatics, molecular biology, developmental biology, comparative morphology and paleontology joined forces to present and discuss novel approaches in reconstructing the still unresolved early branching patterns of the metazoan tree of life. PMID- 19443503 TI - The kin structure of sexual interactions. AB - The origin of sexual reproduction involved the evolution of zygotes from separate genomes and, like other social processes, should therefore be amenable to analysis using kin selection theory. I consider how kin structure affects sexual interactions in three contexts--the evolution of sexual reproduction, sex allocation and sexual conflict. Kin structure helps explain the even-handed replication of paternal and maternal genes under outbreeding. Under inbreeding, it predicts altruistic failure to replicate by one half of the diploid genome. Kin structure predicts optimal sex ratios and potential conflicts over sex ratio within social groups and individuals. Sexual conflict predictably occurs as a function of (i) the probability that current sexual partners will reproduce together in future and (ii) between-partner relatedness. I conclude that systematically analysing the kin structure of sexual interactions helps illuminate their evolution. PMID- 19443504 TI - Coincidence or evidence: was the sabretooth cat Smilodon social? PMID- 19443505 TI - Social structure of primate interaction networks facilitates the emergence of cooperation. AB - Animal cooperation has puzzled biologists for a long time as its existence seems to contravene the basic notion of evolutionary biology that natural selection favours 'selfish' genes that promote only their own well-being. Evolutionary game theory has shown that cooperators can prosper in populations of selfish individuals if they occur in clusters, interacting more frequently with each other than with the selfish. Here we show that social networks of primates possess the necessary social structure to promote the emergence of cooperation. By simulating evolutionary dynamics of cooperative behaviour on interaction networks of 70 primate groups, we found that for most groups network reciprocity augmented the fixation probability for cooperation. The variation in the strength of this effect can be partly explained by the groups' community modularity-a network measure for the groups' heterogeneity. Thus, given selective update and partner choice mechanisms, network reciprocity has the potential to explain socially learned forms of cooperation in primate societies. PMID- 19443506 TI - Does a predatory insect contribute to the divergence between cave- and surface adapted fish populations? AB - Immigrant inviability, where individuals from foreign, ecologically divergent habitats are less likely to survive, can restrict gene flow among diverging populations and result in speciation. I investigated whether a predatory aquatic insect (Belostoma sp.) selects against migrants between cave and surface populations of a fish (Poecilia mexicana). Cavefish were more susceptible to attacks in the light, whereas surface fish were more susceptible in darkness. Environmentally dependent susceptibility to attacks may thus contribute to genetic and phenotypic differentiation between the populations. This study highlights how predation-in this case in conjunction with differences in other environmental factors-can be an important driver in speciation. PMID- 19443508 TI - Climate change effects on migration phenology may mismatch brood parasitic cuckoos and their hosts. AB - Phenological responses to climate change vary among taxa and across trophic levels. This can lead to a mismatch between the life cycles of ecologically interrelated populations (e.g. predators and prey), with negative consequences for population dynamics of some of the interacting species. Here we provide, to our knowledge, the first evidence that climate change might disrupt the association between the life cycles of the common cuckoo (Cuculus canorus), a migratory brood parasitic bird, and its hosts. We investigated changes in timing of spring arrival of the cuckoo and its hosts throughout Europe over six decades, and found that short-distance, but not long-distance, migratory hosts have advanced their arrival more than the cuckoo. Hence, cuckoos may keep track of phenological changes of long-distance, but not short-distance migrant hosts, with potential consequences for breeding of both cuckoo and hosts. The mismatch to some of the important hosts may contribute to the decline of cuckoo populations and explain some of the observed local changes in parasitism rates of migratory hosts. PMID- 19443509 TI - Missing the rarest: is the positive interspecific abundance-distribution relationship a truly general macroecological pattern? AB - Lepidopterists have long acknowledged that many uncommon butterfly species can be extremely abundant in suitable locations. If this is generally true, it contradicts the general macroecological pattern of the positive interspecific relationship between abundance and distribution, i.e. locally abundant species are often geographically more widespread than locally rare species. Indeed, a negative abundance-distribution relationship has been documented for butterflies in Finland. Here we show, using the Finnish butterflies as an example, that a positive abundance-distribution relationship results if the geographically restricted species are missed, as may be the case in studies based on random or restricted sampling protocols, or in studies that are conducted over small spatial scales. In our case, the abundance-distribution relationship becomes negative when approximately 70 per cent of the species are included. This observation suggests that the abundance-distribution relationship may in fact not be linear over the entire range of distributions. This intriguing possibility combined with some taxonomic biases in the literature may undermine the generalization that for a given taxonomic assemblage there is a positive interspecific relationship between local abundance and regional distribution. PMID- 19443510 TI - Macrogeographical variation in the song of a widely distributed African warbler. AB - The songs of oscine passerine birds vary on many spatial scales, reflecting the actions of diverse evolutionary pressures. Here we examine the songs of Cisticola erythrops, which effectively signal species identity across a geographical area spanning 6500 km in sub-Saharan Africa. Selection for species identification should promote stability in song traits, while sexual selection and geographical segregation should promote diversity. Cisticola erythrops share syllable types across the entire range of species and structure songs similarly, but individuals sing highly variable songs through improvisational recombination of syllables. Patterns of syllable use change gradually across the range of the species and do not show distinct breaks at subspecies boundaries. The acoustic properties of the most common syllable type also change gradually with distance. The results illustrate how songs can be simultaneously species-specific and highly variable at an individual level. At a larger level, patterns of variation indicate that cultural drift has generated song diversity through an isolation by distance mechanism. PMID- 19443511 TI - Sexual conflict as a partitioning of selection. AB - Sexual conflict appears to be a powerful force in evolution. We suggest that selection theory can readily be adapted for cases of sexual conflict and illustrate how it can provide a new perspective on what traits cause conflict and might respond to its presence. Use of selection theory resolves some terminological confusion, provides operational measures of conflict and generates a conceptual tool for parsing the causes and consequences of conflict in complex systems of male-female interactions. PMID- 19443512 TI - A role for single-pill triple therapy in hypertension. AB - Hypertension remains the most prevalent chronic disease in the world, and its adequate treatment results in predictable reductions in cardiovascular morbidity and mortality. However, most hypertensive subjects do not achieve goal blood pressure despite availability of multiple antihypertensive agents with various pharmacological mechanisms of action and relatively few side effects. We review the reasons for low hypertension control rates, including factors that affect patients' adherence to therapy, number of agents required to achieve goal blood pressure, pathophysiology-based selection of therapy and diagnosis of resistant hypertension. Within this framework, we discuss the possible impact of a single pill, triple-therapy combination with an antagonist of the renin-angiotensin system, a calcium-channel blocker and a diuretic. We focus on possible differential diagnostic implications in terms of refractoriness to treatment, and therapeutic implications in terms of successful blood pressure control. We conclude that a single-pill, triple-therapy combination may improve control of hypertension by enhancing compliance, by achieving blood pressure goal rapidly and by reducing physician inertia in prescribing adequate antihypertensive therapy. We also suggest that such a combination may lead to improved accuracy in diagnosing resistant hypertension in general practice, avoiding unnecessary further workup and referrals to hypertension specialists. PMID- 19443513 TI - A heart full of stem cells: the spectrum of myocardial progenitor cells in the postnatal heart. AB - Influencing cellular regeneration processes in the heart has been a long-standing goal in cardiovascular medicine. To some extent, this has been successful in terms of vascular regeneration as well as intercellular connective tissue remodeling processes. Several components of today's routine heart failure medication influence endothelial progenitor cell behavior and support collateral vessel growth in the heart, or have been shown to prevent or reverse fibrosis processes. Cardiomyocyte regeneration, however, has so far escaped therapeutic manipulation strategies. Delivery of exogenous cells of bone marrow origin to the human myocardium may improve heart function, but is not associated with relevant neomyogenesis. However, accumulating evidence indicates that the myocardium contains resident cardiac progenitor cells (CPC) that may be therapeutically useful. This notion indeed represents a paradigm shift but is still controversial. The purpose of this review is to summarize the rapidly expanding current knowledge on CPC, and to assess whether it may be translated into solid therapeutic concepts. PMID- 19443514 TI - Antihypertensive treatment and stroke prevention: are angiotensin receptor blockers superior to other antihypertensive agents? AB - Stroke remains a common vascular event with high mortality and morbidity. After heart disease, stroke is the second leading cause of death worldwide in adult persons. Silent or subclinical stroke is likely to occur with even greater frequency than clinical stroke and increases the risk of subsequent cerebrovascular events. Hypertension is by far the single most important controllable risk factor for stroke. The relationship between blood pressure (BP) and stroke mortality is strong, linear, and continuous in subjects with levels of BP higher than 115/75 mm Hg. Blood pressure reduction by antihypertensive treatment is clearly efficacious in the prevention of stroke (both primary and secondary). Although meta-analyses suggest that BP reduction, per se, is the most important determinant for stroke risk reduction, the question is if specific classes of antihypertensive drugs offer special protection against stroke is still controversial. Some studies have suggested that angiotensin receptors blockers (ARBs) appear to offer additional protection against stroke. This has been hypothesized in studies in hypertensives, such as LIFE and SCOPE, and especially in the only comparative trial focused on secondary stroke prevention. In the MOSES trial, the comparison of eprosartan versus nitrendipine in patients with a previous stroke resulted, despite a similar BP reduction, in a significant reduction in the primary composite endpoint of total mortality plus cardiovascular and cerebrovascular events, including recurrent events. These results may suggest a blood pressure-independent effect of ARBs, which can be mediated through several mechanisms, including their ability to counteract other markers of target organ damage, but also through a direct neuroprotective effect. PMID- 19443515 TI - Atrial fibrillation: cure or treat? AB - Controversies exist with regard to the optimal management of atrial fibrillation (AF). Restoration and maintenance of sinus rhythm is a desirable goal in AF patients because the prevention of recurrences may improve cardiac function, relieve symptoms and should reduce the likelihood of adverse events. Pharmacological therapy for AF has been disappointing with unacceptable rates of AF recurrence and other proarrhythmic sequelae. Recent studies suggested that potential benefit of sinus-rhythm maintenance with respect to mortality may have been neutralized by harmful effects of currently available antiarrhythmic therapies. Because of the inefficacy and dangers with nonablative therapies currently available for maintaining sinus rhythm, alternative treatments are certainly desirable. Curative treatment of atrial fibrillation with catheter ablation is now a legitimate option for a large number of patients. In several studies AF ablation has consistently been demonstrated to be superior to antiarrhythmic medications for the maintenance of sinus rhythm. Nevertheless, many aspects of the therapy are still controversial and large-scale prospective studies are needed to confirm the efficacy and safety of this approach. PMID- 19443516 TI - Nitric oxide mechanisms of nebivolol. AB - beta-blockers are among the most widely used drugs in the prevention and treatment of cardiovascular disease, although they are associated with increased peripheral resistance. Third-generation beta-blockers avoid this adverse effect by inducing vasodilation through different mechanisms. In particular, nebivolol, a highly selective blocker of beta(1)-adrenergic receptors, is the only beta blocker known to induce vascular production of nitric oxide, the main endothelial vasodilator. The specific mechanism of nebivolol is particularly relevant in hypertension, where nitric oxide dysfunction occurs. Indeed, nebivolol is able to reverse endothelial dysfunction. Nebivolol induces nitric oxide production via activation of beta(3)-adrenergic receptors, which can explain the good metabolic profile observed after treatment with this drug. Moreover, nebivolol can also stimulate the beta(3)-adrenergic receptor-mediated production of nitric oxide in the heart, and this stimulation can result in a greater protection against heart failure. In conclusion, nebivolol has a unique profile among antihypertensive drugs, adding to a very high selectivity against beta(1) adrenergic receptors, and an agonist action on beta(3) receptors and nitric oxide (NO), which has led to clinically significant improvements in hypertensive patients. PMID- 19443517 TI - Evaluation of a 24-hour emergency bronchoscopy service in a tertiary care hospital. AB - BACKGROUND: Flexible bronchoscopy has become an important diagnostic and therapeutic tool for the management of patients with various diseases of the chest. Availability of a 24-hour bronchoscopy service equipped with experienced personnel is becoming increasingly important especially for intensive care patients. However, such services have been implemented only in a few medical centres. The aim of this study was to evaluate the usage of a 24-hour emergency service in a large university hospital with a 1 year prospective analysis of emergency bronchoscopy service in a tertiary care centre. METHODS: Frequencies, indications and efficiency of therapeutic interventions were evaluated after each bronchoscopy using a specially designed questionnaire. All bronchoscopies were performed as emergency procedures out of operational schedule. A total of 614 emergency bronchoscopies were performed, 88% of them in intensive care units. RESULTS: The vast majority (84.5%) of the procedures were necessary for therapeutic interventions; that is, atelectasis, airway secretion, aspiration or bronchopulmonary bleeding. According to prespecified criteria, 37.6% (n = 195) of therapeutic procedures were assessed as 'very helpful' and 3.9% (n = 20) as 'life saving'. Diagnostic bronchoscopies were performed mainly to collect airway material for microbiological evaluations in immunocompromised patients. In these cases, the diagnostic yield was approximately 50%. CONCLUSION: The availability of a 24-hour bronchoscopy service has been found to improve patient care and was occasionally considered life saving. Thus, comparable services should be made more widely available. PMID- 19443518 TI - Clinical and pharmacoeconomic profile of COPD patients with FEV1 50--60% predicted: pilot study on the impact of the extended indication of ICS/LABA. AB - BACKGROUND: The use of inhaled corticosteroids (ICS) and long-acting beta(2) adrenergics (LABA) in fixed combination (ICS/LABA) was recently extended to COPD patients with a baseline FEV(1) 50-60% predicted, thus broadening the original guideline indications (GOLD 2006) that limited their use only to stages III and IV. METHOD: The present study was carried out to assess the clinical profile of this new subset of patients, with a view to providing data for future studies on the impact of this novel extension of ICS/LABA use in COPD. RESULTS: Data from the present observational cross-sectional study suggest that COPD patients with FEV(1) 50-60% predicted depict a dichotomic condition: actually, even though resembling milder patients in terms of frequency and severity of their respiratory symptoms, they are much more similar to severer patients in terms of rate of hospital admissions and resource consumption (p50.01). In other words, this subset of patients seems to represent a peculiar condition in the evolutional phase of COPD during which therapeutic treatment should be intensified in order to slow down the disease progression effectively. Nevertheless, independently of the severity, the general therapeutic approach to COPD was found to be greatly inadequate when compared to GOLD guidelines, particularly in terms of appropriateness. CONCLUSIONS: These findings should pave the way for future studies aimed to long-term monitoring of main outcomes and to evaluate the overall impact of earlier ICS/LABA use on disease progression and lung function decline in COPD. PMID- 19443519 TI - Value of adding a polyvalent mechanical bacterial lysate to therapy of COPD patients under regular treatment with salmeterol/fluticasone. AB - BACKGROUND: This study investigated the value of adding Ismigen, a polyvalent mechanical bacterial lysate, to therapy of COPD patients (FEV(1) <60% predicted) under regular treatment with salmeterol/fluticasone (SFC). METHODS: 63 patients enrolled from September to December 2007 were randomly divided into two groups (A and B). All patients were treated with salmeterol/fluticasone (SFC) 50/500 microg BID. Thirty-three subjects also received Ismigen one capsule daily the first 10 days of three consecutive months (group B). This treatment was reaped three months after the end of the first course. We assessed at inclusion and at scheduled (every 2 months) or intercurrent visit: symptoms (amount and colour of sputum, severity of dyspnoea, frequency of cough, fever), diagnosis of exacerbation, concomitant medications (antibiotics and oral corticosteroids) and hospitalization. RESULTS: During the course of the study two patients died. At the end of the observation period (12 months), another six patients could not be visited because they had withdrawn. Compared with SFC, adding on Ismigen reduced the total number of exacerbations (23 out of 30 patients in group A and 21 out of 33 patients in group B), the number (rate) of exacerbations per patient per year (18 out of 27 patients [0.67] in group A and 15 out of 28 patients [0.54] in group B), the number of exacerbations that needed treatment with oral corticosteroids (12 out of 23 [52%] in group A and 9 out of 21 [43%] in group B) and the total number (rate) of hospitalizations (4/30 [0.13] in group A and 3/33 [0.09] in group B). There were no significant differences between treatments with respect to their effect on the symptoms of exacerbations. A decrease in the need for antibiotics was also observed in group B. CONCLUSION: Our data suggest that COPD patients benefit from the addition of Ismigen on top of the routine maintenance treatment with SFC. PMID- 19443520 TI - Use of dry powder inhalers in acute exacerbations of asthma and COPD. AB - To investigate whether dry powder inhalers (DPIs) function in a constrained situation, a literature analysis was performed to evaluate the use of DPIs compared with established therapies in the treatment of acute asthma and COPD, irrespective of rapid-acting beta(2)-agonist used. The external databases Medline, Embase, Biosis and Current Contents and AstraZeneca's internal literature database Planet were searched up to April 2008. Only publications or congress abstracts describing clinical trials in patients treated at EDs or hospitals were considered, and then only those in which exacerbation severity (measured as FEV(1)) were included. Fifteen clinical studies met these criteria; twelve in acute asthma and three in acute COPD. For acute asthma, eight studies were double-blind, randomised studies (six in adults and two in children), two were open-label studies (one in adults and one in children), and two were investigational (methacholine challenge) studies. For the acute COPD studies, one was double-blind and randomised, one was single-blind and randomised, and one was open-label. This review found that administration of fast-acting bronchodilators via DPIs, the majority of which were Turbuhaler, is effective during an asthma or COPD worsening. Our literature review finds that DPIs function in patients with acute asthma or COPD equally well as established therapies with other inhaler devices. Patients can therefore rely upon DPIs in the same way that they rely upon other inhaler devices. PMID- 19443521 TI - Improving training in spiritual care: a qualitative study exploring patient perceptions of professional educational requirements. AB - Healthcare professionals express difficulties in delivering spiritual care, despite it being a core component of palliative care national policies. The patient perspective on professional training to address difficulties has not previously been sought. The aim of this study is to describe patient suggestions for development of training to deliver spiritual care. Qualitative semi structured in-depth 'palliative patient' interviews (n = 20) were analysed thematically. Training suggestions encompassed practical care delivery. Patients supported staff who introduced questions about spiritual needs, and they expected opportunities to engage in spiritual care discussions. The 'right' attitude for spiritual care delivery was defined as being non-judgemental, providing integrated care and showing interest in individuals. Training issues included patient perspectives of boundaries between personal and professional roles. This study provides 'palliative patient' perspectives to strengthen recommended models of spiritual care delivery. It shows that user opinions on training can be helpful not only in deciding objectives but also how to achieve them. PMID- 19443522 TI - What do patients with brain metastases from non-small cell lung cancer want from their treatment? AB - Brain metastases are a common complication of non-small cell lung cancer (NSCLC). Prognosis is poor and the effectiveness of whole brain radiotherapy (WBRT) is uncertain for patients with moderate performance status. Studies on WBRT effectiveness have thus far used outcome measures, such as survival, performance status and cognitive function. The aim of this study was to study what patients with recently diagnosed brain metastases from NSCLC want from their treatment. We carried out semistructured interviews with nine patients with brain metastases from NSCLC, for whom the benefit of WBRT is uncertain. Interpretative phenomenological analysis was used. Themes identified included quality versus quantity of life, factors contributing to quality of life (including family, mobility and normality), 'Go for it!' - the desire to try anything, the desire for a cure or 'magic wand', fear and other factors (including family in decision making, information or lack of information, relationship with professionals, experience of steroids and radiotherapy including adverse effects). Quality of life is important to patients, but many are keen to try any treatment which might prolong their life. Understanding patients' values regarding treatment and goals of treatment can help clinicians discuss these issues with patients and provide appropriate information and can aid selection of appropriate outcome measures. PMID- 19443523 TI - UK doctors' attitudes to the legalisation of assisted suicide. PMID- 19443524 TI - 'They're part of the team': participant evaluation of the ACTIVE intervention. AB - This study used participant feedback to qualitatively evaluate an intervention (Assessing Caregivers for Team Intervention through Videophone Encounters [ACTIVE]) that used videophone technology to include patients and/or their family caregivers in hospice interdisciplinary team meetings. Data were generated during individual interviews with hospice staff members and family caregivers who participated in ACTIVE intervention. Modified grounded theory procedures served as the primary analysis strategy. Results indicated that ACTIVE intervention enhanced team functioning in terms of context, structure, processes and outcomes. Participants discussed challenges and offered corresponding recommendations to make the intervention more efficient and effective. Data supported the ACTIVE intervention as a way for hospice providers to more fully realise their goal of maximum patient and family participation in care planning. PMID- 19443525 TI - Symptoms and problems in a nationally representative sample of advanced cancer patients. AB - Little is known about the need for palliative care among advanced cancer patients who are not in specialist palliative care. The purpose was to identify prevalence and predictors of symptoms and problems in a nationally representative sample of Danish advanced cancer patients. Patients with cancer stage 3 or 4 from 54 hospital departments (n = 1630) received the EORTC QLQ-C30 questionnaire. Mean scores were calculated according to the scoring manual and in addition a 'symptom/problem' and a 'severe symptom/problem' was defined and calculated. Multiple logistic regression was used to identify predictors. In total, 977 (60%) patients participated. The most frequent symptoms/problems were fatigue (57%; severe 22%) followed by reduced role function, insomnia and pain. Age, cancer stage, primary tumour, type of department, marital status and whether the patient had recently been hospitalized or not were associated with several symptoms and problems. This is probably the first nationally representative study of its kind. It shows that advanced cancer patients in Denmark have symptoms and problems that deserve attention and that some patient groups are especially at risk. PMID- 19443526 TI - 3-Nitrotyrosine inhibits fibroblast-mediated collagen gel contraction and chemotaxis. AB - Reactive nitrogen species induce tissue inflammation and nitrate tyrosine residues of various kinds of proteins. Recent studies have established that the free amino acid form of 3-nitrotyrosine induces cytotoxity and growth inhibition and alters the cellular function in cultured cells. The aim of this study was to evaluate whether 3-nitrotyrosine could affect tissue remodelling in fibroblasts. To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the fibroblast-mediated contraction of floating gels and chemotaxis towards fibronectin. In addition, the ability of fibroblasts to release fibronectin, transforming growth factor (TGF)-beta1, fibronectin and vascular endothelial growth factor (VEGF) was assessed. 3-Nitrotyrosine significantly inhibited gel contraction (p<0.01) compared with control and this inhibition was abolished by nitric oxide synthase (NOS) inhibitor. 3-Nitrotyrosine did not affect TGF-beta1 and VEGF but significantly decreased fibronectin release (p<0.01) into the media. 3-Nitrotyrosine significantly inhibited chemotaxis towards fibronectin through suppression of alpha(5)beta(1) integrin expression (p<0.01). NOS inhibitor also reversed 3-nitrotyrosine-inhibited chemotaxis (p<0.01). Finally, 3-nitrotyrosine enhanced the expression of the inducible type of NOS (p<0.01) and nitric oxide release (p<0.01) through nuclear factor-kappaB activation. These results suggest that the free amino acid form of 3-nitrotyrosine can affect the tissue repair process by modulating nitric oxide production. PMID- 19443527 TI - All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice. AB - Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM. PMID- 19443528 TI - Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. AB - Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies. PMID- 19443529 TI - Swimming pool attendance and risk of asthma and allergic symptoms in children. AB - Increased asthma risk has been associated with pool attendance in children but evidence is inconsistent and inconclusive. A survey was conducted of 3,223 9-12 yr-old children in Sabadell (Spain) to evaluate association between swimming pool attendance and prevalence of asthma and allergic conditions and symptoms. Parents completed a questionnaire on lifetime frequency of pool attendance and symptoms in the last 12 months (wheezing, asthma medication, rhinitis and allergic rhinitis), ever having asthma and eczema, and potential confounders. Indicators of indoor and outdoor swimming pool attendance early in life, cumulatively and currently were calculated. Swimming pool attendance before the age of 2 yrs was associated with slightly lower prevalence of current asthma (OR 0.79, 95% CI 0.43 1.46), rhinitis (OR 0.86, 95% CI 0.68-1.08) and allergic rhinitis symptoms (OR 0.72, 95% CI 0.54-0.96) compared to those who started attending swimming pools after 4 yrs of age. An increased prevalence of eczema was associated with duration of lifetime pool attendance (OR 1.71, 95%CI 1.38-2.12 for >5 yrs versus 0 yrs). Swimming pool attendance in Spanish children was associated with slightly less upper and lower respiratory tract symptoms and with more eczema. Longitudinal studies are required to confirm these findings and avoid potential reverse causation. PMID- 19443530 TI - Determinants of asthma phenotypes in supermarket bakery workers. AB - While baker's asthma has been well described, various asthma phenotypes in bakery workers have yet to be characterised. Our study aims to describe the asthma phenotypes in supermarket bakery workers in relation to host risk factors and self-reported exposure to flour dust. A cross-sectional study of 517 supermarket bakery workers in 31 bakeries used a questionnaire, skin prick tests, and specific immunoglobulin E to wheat, rye and fungal alpha-amylase and methacholine challenge testing. The prevalence of probable occupational asthma (OA, 13%) was higher than atopic (6%), nonatopic (6%) and work-aggravated asthma (WAA, 3%) phenotypes. Previous episodes of high exposure to dusts, fumes and vapours causing asthma symptoms were more strongly associated with WAA (OR 5.8, 95% CI 1.7-19.2) than OA (2.8, 1.4-5.5). Work-related ocular-nasal symptoms were significantly associated with WAA (4.3, 1.3-13.8) and OA (3.1, 1.8-5.5). Bakers with OA had an increased odds ratio of reporting adverse reactions to ingested grain products (6.4, 2.0-19.8). OA is the most common phenotype among supermarket bakery workers. Analysis of risk factors contributes to defining clinical phenotypes, which will guide ongoing medical surveillance and clinical management of bakery workers. PMID- 19443531 TI - Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) results in chronic right heart failure, which is associated with an increase in sympathetic tone. This may adversely affect cardiac autonomic control. We investigated the changes in cardiac autonomic nervous activity in relation to disease severity in patients with PAH. In 48 patients with PAH (median World Health Organization class III, pulmonary artery pressure 52+/-14 mmHg, pulmonary vascular resistance 1,202+/-718 dyn x s x cm(-5), cardiac index 2.0+/-0.8 L x min(-1) x m(-2)) and 41 controls, cardiac autonomic nervous activity was evaluated by measurement of heart rate variability (HRV) and baroreflex sensitivity. All patients underwent cardiopulmonary exercise testing (peak oxygen uptake 13.2+/-5.1 mL x kg(-1) x min(-1), minute ventilation/carbon dioxide production slope 47+/-16). In patients with PAH, spectral power of HRV was reduced in the high-frequency (239+/-64 versus 563+/ 167 ms2), low-frequency (245+/-58 versus 599+/-219 ms2) and very low-frequency bands (510+/-149 versus 1106+/-598 ms2; all p<0.05). Baroreflex sensitivity was also blunted (5.8+/-0.6 versus 13.9+/-1.2 ms x mmHg(-1); p<0.01). The reduction in high-frequency (r = 0.3, p = 0.04) and low-frequency (r = 0.33, p = 0.02) spectral power and baroreflex sensitivity (r = 0.46, p<0.01) was related to the reduction in peak oxygen uptake. Patients with PAH have a marked alteration in cardiac autonomic control that is related to exercise capacity and may, therefore, serve as an additional marker of disease severity. PMID- 19443532 TI - Titrated sedation with propofol or midazolam for flexible bronchoscopy: a randomised trial. AB - In this study, we questioned whether propofol provided clinical benefits compared with midazolam in terms of neuropsychometric recovery, safety profile and patient tolerance. Patients, aged >18 yrs, were randomised to receive midazolam or propofol, given by non-anaesthetist physicians to achieve moderate levels of sedation as assessed by the electroencephalographic bispectral index (BIS; between 70 and 85). The primary end-point was the time delay until recovery of the BIS above 90. Other end-points included a neuropsychometric continuous performance test (CPT), serious respiratory adverse events, patient tolerance and physician satisfaction. Neuropsychometric recovery was improved in the propofol compared to the midazolam group as evidenced by faster normalisation of BIS index (5.4+/-4.7 min versus 11.7+/-10.2 min; p = 0.001) and better results at the CPT. In the midazolam group, 15% of patients presented profound sedation precluding CPT completion and one patient required mechanical ventilatory support. Patient tolerance was significantly better in the propofol group, whereas the operator's assessment was comparable in both groups. Compared with midazolam, propofol provided a higher quality of sedation in terms of neuropsychometric recovery and patient tolerance. BIS-guided propofol administration represents a safe sedation technique that can be performed by the non-anaesthesiologist. PMID- 19443533 TI - Association between modelled traffic-related air pollution and asthma score in the ECRHS. AB - The aim of our analysis was to study the association between air pollution and asthma among adults. For this goal, a previously developed "asthma score" was used. Persons aged 25-44 yrs were randomly selected (1991-1993) and followed up (2000-2002) within the European Community Respiratory Health Survey (ECRHS I and II, respectively). The asthma score was defined from 0 to 5, based on the positive answers to the following symptoms reported for the last 12 months: wheeze/breathlessness, chest tightness, dyspnoea at rest, dyspnoea after exercise and woken by dyspnoea. Participants' home addresses were linked to outdoor modelled NO2 estimates for 2001. Negative binomial regression was used to model the asthma score. The score from ECRHS II was positively associated with NO2 (ratio of the mean asthma score (RMS) 1.23, 95% CI 1.09-1.38, for an increase of 10 microg x m(-3)). After excluding participants with asthma and symptoms at baseline, the association remained (RMS 1.25, 95% CI 1.05-1.51), and was particularly high among those reporting a high score in ECRHS II. The latter probably reflects incident cases of asthma. Our results suggest that traffic related pollution causes asthma symptoms and possibly asthma incidence in adults. The asthma score offers an alternative with which to investigate the course and aetiology of asthma in adults. PMID- 19443534 TI - Quadriceps muscle strength in scoliosis. AB - Quadriceps muscle weakness is an important component of chronic obstructive pulmonary disease (COPD). We hypothesised that quadriceps weakness would also be a feature of restrictive lung disease due to scoliosis. We studied 10 patients with severe scoliosis (median (interquartile range (IQR)) forced expiratory volume in 1 s (FEV(1))() 35.3 (11)% predicted), 10 patients with severe COPD (FEV(1) 26.5 (9.0)% pred) and 10 healthy age-matched adults. We measured quadriceps strength, exercise capacity and analysed quadriceps muscle biopsies for myosin heavy-chain (MyHC) isoform expression and the presence of oxidative stress. Both groups exhibited quadriceps weakness with median (IQR) maximal voluntary contraction force being 46.0 (17.0) kg, 21.5 (21.0) kg and 31.5 (11.0) kg, respectively (p = 0.02 and 0.04, respectively, for each patient group against controls). Oxidative stress was significantly greater in the quadriceps of both restrictive and COPD patients. The scoliosis patients exhibited a decrease in the proportion of MyHC type I compared with controls; median (IQR) 35.3 (18.5)% compared with 47.7 (9.3)%, p = 0.028. The scoliosis patients also showed an increase in MyHC IIx (26.3 (15.5)% compared with 11.3 (13.0)%, p = 0.01. Quadriceps weakness is a feature of severe scoliosis; the similarities between patients with scoliosis and patients with COPD suggest a common aetiology to quadriceps weakness in both conditions. PMID- 19443535 TI - Are metallic stents really safe? A long-term analysis in lung transplant recipients. AB - Airway complications affect 20% of all lung transplant recipients. Self expandable metallic stents (SEMS) are one treatment option but their use in benign airway disorders is controversial. We studies the long-term safety of SEMS in lung transplant recipients. Between January 1998 and February 2008, all lung transplant recipients with SEMS were analysed retrospectively at a single centre. Complications were recorded until September 2008. In 65 (9.2%) out of 706 recipients, 111 (91% noncovered) bronchial SEMS were implanted a median (range) 133 (55-903) days after lung transplantation; follow-up was 777 (7-3.655) days. Clinical improvement was noted in 80% of recipients. The forced expiratory volume in 1 s increased by (mean+/-SD) 21+/-33%. Most frequent early complications were migration (3%) and mucus plugging (11%). No procedure-related deaths were noted. Re-stenosis occurred in 34 (52%) out of 65 recipients 85 (7-629) days after insertion. In multivariate analysis, stent insertion before post-operative day 90 was independently associated with an increased risk of re-stenosis (HR 3.29, 95% CI 1.50-7.18; p = 0.003). In 40% of recipients, new bacterial airway colonisation occurred after SEMS insertion. In SEMS patients, 5-yr survival was significantly lower than in the total cohort (60% versus 76%; p = 0.02). Late complications in lung transplant recipients treated with SEMS are frequent. The major problems are re-stenosis and airway colonisation. PMID- 19443536 TI - Prevalence and clinical significance of auto-antibodies in adults with cystic fibrosis. AB - The aim of this study was to determine the prevalence of different auto antibodies in adult, French cystic fibrosis (CF) patients and to look for a correlation between autoimmunity, patient characteristics and survival. The sera of 144 patients were screened for a wide range of antibodies. Clinical, biological and bacteriological characteristics and the cystic fibrosis transmembrane conductance regulator genotype were recorded and progression of lung disease was examined. 113 (78.5%) patients displayed one or several auto antibodies, predominantly immunoglobulin (Ig)A anti-Saccharomyces cerevisiae antibodies (ASCA; 43.7%) and antineutrophil cytoplasmic antibodies (ANCA; 40%), of which 59% showed bactericidal/permeability-increasing protein (BPI) specificity. The presence of BPI-ANCA was associated with the number of antibiotic courses, low body mass index, Pseudomonas aeruginosa colonisation, the presence of resistant P. aeruginosa, low forced expiratory volume in 1 s, CF related liver disease, hypergammaglobulinaemia, male sex and inflammatory syndrome. The presence of ASCA-IgA was correlated with male sex and hypergammaglobulinaemia. 41 patients presented with chronic respiratory failure and/or requested lung transplantation or died during follow-up. These events were more frequent in patients with BPI-ANCA or ASCA-IgA. These findings confirm the high frequency of auto-antibodies in CF, particularly BPI-ANCA and ASCA-IgA, and the link between BPI-ANCA, severity of lung disease and CF prognosis. PMID- 19443537 TI - Schizophrenia genetics: new insights from new approaches. AB - INTRODUCTION: Schizophrenia is a debilitating psychiatric disorder that imposes a considerable burden on sufferers, their families and society. The prominent involvement of genes, combined with the complexity and relative inaccessibility of the brain has led many to suggest that the identification of specific risk loci offers the best chance of understanding pathogenesis. SOURCES OF DATA: Recent genome-wide association studies (GWAS) and copy number variation (CNV) publications have been included in this review along with key papers from the fields of schizophrenia, functional psychoses and complex disease mapping. AREAS OF AGREEMENT: Recent GWAS have now shown that both common alleles of small effect and rare alleles of moderate to large effect contribute to the high heritability of schizophrenia. AREAS OF CONTROVERSY: It is well known that many schizophrenic patients suffer symptoms seen in patients with bipolar disease and vice versa. There is now considerable interest in using aetiologically relevant risk factors, including genes, to explore the validity of the contemporary system of classification. GROWING POINTS: Rare CNVs have been shown to play a role in at least some cases of schizophrenia and it is highly predictable that this figure will rise with the use of technologies with higher resolution or that are better designed to assay common CNVs reliably. AREAS TIMELY FOR DEVELOPING RESEARCH: The findings with common alleles thus far point to overlap in the genetic risk for schizophrenia and bipolar disorder, while the specific CNVs implicated in schizophrenia also increase susceptibility to a range of developmental disorders, including autism, mental retardation, attention deficit-hyperactivity disorder (ADHD) and epilepsy. PMID- 19443538 TI - Mechanisms of bone metastases of breast cancer. AB - Cancer development is a multi-step process driven by genetic alterations that elicit the progressive transformation of normal human cells into highly malignant derivatives. The altered cell proliferation phenotype of cancer involves a poorly characterized sequence of molecular events, which often result in the development of distant metastasis. In the case of breast cancer, the skeleton is among the most common of metastatic sites. In spite of its clinical importance, the underlying cellular and molecular mechanisms driving bone metastasis remain elusive. Despite advances in our understanding of the phenotype of cancer cells, the increased focus on the contribution of the tumor microenvironment and the recent revival of interest in the role of tumor-propagating cells (so called cancer stem cells) that may originate or be related to normal stem cells produced in the bone marrow, many important questions remain unanswered. As such, a more complete understanding of the influences of both the microenvironment and the tumor phenotype, which impact the entire multi-step metastatic cascade, is required. In this review, the importance of tumor heterogeneity, tumor propagating cells, the microenvironment of breast cancer metastasis to bone as well as many current endocrine therapies for the prevention and treatment of metastatic breast cancer is discussed. PMID- 19443539 TI - Genome-wide scan identifies novel modifier loci of acromegalic phenotypes for isolated familial somatotropinoma. AB - Isolated familial somatotropinoma (IFS) accounts for 18% of familial isolated pituitary adenoma (FIPA) cases. Recently, germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have been found in families with pituitary adenoma predisposition, FIPA, and IFS. In this study, we investigate the AIP mutation status and perform a genome-wide scan to search for the modifier regions of acromegalic phenotypes in an IFS family of 31 aborigines from Borneo. Complete endocrine diagnosis and data could not be collected due to logistical and cultural reasons. AIP mutation screening was carried out by direct sequencing and the genome-wide scan was performed using 400 microsatellites. Non parametric linkage analysis was performed to obtain the logarithm of odds (LOD) scores. A novel AIP frameshift mutation in exon 4 (c.500delC) (p.P167HfsX3) was identified in all members with acromegalic features, as well as in 15 members without acromegalic features, revealing incomplete penetrance of AIP. The data showed that patients with the same mutation may express acromegalic features of differing severity, suggesting the existence of modifier genes. The highest LOD score of 2.2 was obtained near D19S571 (19q13.41). We also found weak linkages on chromosomes 3q28, 8q12.1, and 21q22.13, with LOD scores of 1.1, 1.8, and 1.4 respectively. Our results show the first genome-wide scan that identifies novel modifier loci for acromegalic phenotypes in an IFS family. Identification of modifier loci may provide further insight into the disease mechanism and explain the clinical variability observed in its patients. PMID- 19443540 TI - H-NS and genomic bridge building: lessons from the human pathogen Salmonella Typhi. PMID- 19443541 TI - Growth of calcium-blind mutants of Yersinia pestis at 37 degrees C in permissive Ca2+-deficient environments. AB - Cells of wild-type Yersinia pestis exhibit a low-calcium response (LCR) defined as bacteriostasis with expression of a pCD-encoded type III secretion system (T3SS) during cultivation at 37 degrees C without added Ca(2+) versus vegetative growth with downregulation of the T3SS with Ca(2+) (>or=2.5 mM). Bacteriostasis is known to reflect cumulative toxicity of Na(+), l-glutamic acid and culture pH; control of these variables enables full-scale growth ('rescue') in the absence of Ca(2+). Several T3SS regulatory proteins modulate the LCR, because their absence promotes a Ca(2+)-blind phenotype in which growth at 37 degrees C ceases and the T3SS is constitutive even with added Ca(2+). This study analysed the connection between the LCR and Ca(2+) by determining the response of selected Ca(2+)-blind mutants grown in Ca(2+)-deficient rescue media containing Na(+) plus l-glutamate (pH 5.5), where the T3SS is not expressed, l-glutamate alone (pH 6.5), where l aspartate is fully catabolized, and Na(+) alone (pH 9.0), where the electrogenic sodium pump NADH : ubiquinone oxidoreductase becomes activated. All three conditions supported essentially full-scale Ca(2+)-independent growth at 37 degrees C of wild-type Y. pestis as well as lcrG and yopN mutants (possessing a complete but dysregulated T3SS), indicating that bacteriostasis reflects a Na(+) dependent lesion in bioenergetics. In contrast, mutants lacking the negative regulator YopD or the YopD chaperone (LcrH) failed to grow in any rescue medium and are therefore truly temperature-sensitive. The Ca(2+)-blind yopD phenotype was fully suppressed in a Ca(2+)-independent background lacking the injectisome associated inner-membrane component YscV but not peripheral YscK, suggesting that the core translocon energizes YopD. PMID- 19443542 TI - OmpR positively regulates urease expression to enhance acid survival of Yersinia pseudotuberculosis. AB - Yersinia pseudotuberculosis is an enteric bacterium which must overcome the acidic stress in host organs for successful colonization, but how this bacterium survives in acidic conditions remains largely unknown. In the present study, the importance of OmpR in acid survival of Y. pseudotuberculosis YpIII was confirmed by the fact that mutation of ompR (strain DeltaompR) greatly reduced cell survival at pH 4.5 or lower. To characterize the regulatory role of OmpR in this acid survival process, proteomic analysis was carried out to compare YpIII at pH 7.0 and pH 4.5 with DeltaompR at pH 7.0, and urease components were revealed to be the main targets for OmpR regulation. Addition of urea to the culture medium also enhanced acid survival of YpIII but not DeltaompR and urease activity was significantly induced by acid in YpIII but not in DeltaompR. Each of the seven components of the YpIII urease gene cluster was fused to a lacZ reporter and their expression was dramatically decreased in a DeltaompR background; this supports the notion that OmpR positively regulates urease expression. Furthermore, gel shift analysis revealed that OmpR binds to the deduced promoter regions of three polycistronic transcriptional units (ureABC, ureEF and ureGD) in the urease cluster, suggesting that the regulation of OmpR to urease components is direct. Taken together, these data strongly suggest that OmpR activates urease expression to enhance acid survival in Y. pseudotuberculosis. PMID- 19443543 TI - Enhanced citric acid biosynthesis in Pseudomonas fluorescens ATCC 13525 by overexpression of the Escherichia coli citrate synthase gene. AB - Citric acid secretion by fluorescent pseudomonads has a distinct significance in microbial phosphate solubilization. The role of citrate synthase in citric acid biosynthesis and glucose catabolism in pseudomonads was investigated by overexpressing the Escherichia coli citrate synthase (gltA) gene in Pseudomonas fluorescens ATCC 13525. The resultant approximately 2-fold increase in citrate synthase activity in the gltA-overexpressing strain Pf(pAB7) enhanced the intracellular and extracellular citric acid yields during the stationary phase, by about 2- and 26-fold, respectively, as compared to the control, without affecting the growth rate, glucose depletion rate or biomass yield. Decreased glucose consumption was paralleled by increased gluconic acid production due to an increase in glucose dehydrogenase activity. While the extracellular acetic acid yield increased in Pf(pAB7), pyruvic acid secretion decreased, correlating with an increase in pyruvate carboxylase activity and suggesting an increased demand for the anabolic precursor oxaloacetate. Activities of two other key enzymes, glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase, remained unaltered, and the contribution of phosphoenolpyruvate carboxylase and isocitrate lyase to glucose catabolism was negligible. Strain Pf(pAB7) demonstrated an enhanced phosphate-solubilizing ability compared to the control. Co-expression of the Synechococcus elongatus PCC 6301 phosphoenolpyruvate carboxylase and E. coli gltA genes in P. fluorescens ATCC 13525, so as to supplement oxaloacetate for citrate biosynthesis, neither significantly affected citrate biosynthesis nor caused any change in the other physiological and biochemical parameters measured, despite approximately 1.3- and 5-fold increases in citrate synthase and phosphoenolpyruvate carboxylase activities, respectively. Thus, our results demonstrate that citrate synthase is rate-limiting in enhancing citrate biosynthesis in P. fluorescens ATCC 13525. Significantly low extracellular citrate levels as compared to the intracellular levels in Pf(pAB7) suggested a probable limitation of efficient citrate transport. PMID- 19443544 TI - Identification of conserved antigens for early serodiagnosis of relapsing fever Borrelia. AB - Borrelia hermsii is a blood-borne pathogen transmitted by the argasid tick Ornithodoros hermsi. Since spirochaete clearance in mice is associated with an IgM-mediated response, an immunoproteomic analysis was used to identify proteins reactive with IgM. We report that IgM from both mice and human patients infected with B. hermsii not only reacted with the previously identified variable membrane proteins but also identified candidate antigens including heat-shock proteins, an adhesin protein, ABC transporter proteins, flagellar proteins, housekeeping proteins, an immune evasion protein, and proteins with unknown function. Furthermore, IgM reactivity to recombinant glycerophosphodiester phosphodiesterase was detected during early spirochaete infection and prior to a detectable IgG response. Lastly, a conserved hypothetical protein was produced in Escherichia coli and tested with immune serum against B. hermsii and Borrelia recurrentis. These results identify a much larger set of immunoreactive proteins, and could help in the early serodiagnosis of this tick-borne infection. PMID- 19443545 TI - Comparison of Bacteroides thetaiotaomicron and Escherichia coli 16S rRNA gene expression signals. AB - There are barriers to cross-expression of genes between Bacteroides spp. and Escherichia coli. In this study, a lux-based reporter system was developed for Bacteroides and used to compare the promoter structure and function of a Bacteroides thetaiotaomicron 4001 (BT4001) 16S rRNA promoter with those of E. coli in vivo. Analysis of the BT4001 sequences upstream of the 16S rRNA gene revealed the same overall structure known for E. coli 16S rRNA promoters in that there were two promoters separated by approximately 150 bp. However, the BT4001 16S rRNA promoter contains the proposed Bacteroides -7 and -33 consensus sequences instead of the E. coli -10 and -35 consensus sequences. The biological activity of various configurations of the BT4001 16S rRNA promoter was analysed. Experiments pairing the BT4001 16S rRNA promoter with an E. coli RBS, and vice versa, confirmed that gene expression between the two species is restricted at the level of transcription. In Bacteroides, a difference in translation initiation also appears to limit expression of foreign genes. PMID- 19443546 TI - The role of FIS in the Rcd checkpoint and stable maintenance of plasmid ColE1. AB - Escherichia coli plasmid ColE1 lacks active partitioning, and copies are distributed randomly to daughter cells at division. The plasmid is maintained stably in the bacterial population as long as its copy number remains high. The accumulation of plasmid dimers and higher multimers depresses copy number, and is an important cause of multicopy plasmid instability. ColE1 dimers are restored to the monomeric state by site-specific recombination, which requires the host encoded proteins XerCD, ArgR and PepA acting at the plasmid cer site. In addition, a 70 nt RNA expressed from the cer site of plasmid dimers delays the division of dimer-containing cells. Here, we report that the global regulator FIS binds to cer in a sequence-specific manner, close to the Rcd promoter (P(cer)). FIS is not required for plasmid dimer resolution, but is essential for repression of P(cer) in plasmid monomers. Repression also requires the XerCD recombinase, but not ArgR or PepA. We propose a model for monomer-dimer control of P(cer) in which the promoter is repressed in plasmid monomers by the concerted action of FIS and XerCD. Rcd transcription is triggered in plasmid dimers by the lifting of XerCD-mediated repression in the synaptic complex. PMID- 19443547 TI - Pivotal role of the Francisella tularensis heat-shock sigma factor RpoH. AB - Francisella tularensis is a highly infectious pathogen that infects animals and humans to cause the disease tularemia. The primary targets of this bacterium are macrophages, in which it replicates in the cytoplasm after escaping the initial phagosomal compartment. The ability to replicate within macrophages relies on the tightly regulated expression of a series of genes. One of the most commonly used means of coordinating the regulation of multiple genes in bacteria consists of the association of dedicated alternative sigma factors with the core of the RNA polymerase (RNAP). In silico analysis of the F. tularensis LVS genome led us to identify, in addition to the genes encoding the RNAP core (comprising the alpha1, alpha2, beta, beta' and omega subunits), one gene (designated rpoD) encoding the major sigma factor sigma(70), and a unique gene (FTL_0851) encoding a putative alternative sigma factor homologue of the sigma(32) heat-shock family (designated rpoH). Hence, F. tularensis represents one of the minority of bacterial species that possess only one or no alternative sigma factor in addition to the main factor sigma(70). In the present work, we show that FTL_0851 encodes a genuine sigma(32) factor. Transcriptomic analyses of the F. tularensis LVS heat-stress response allowed the identification of a series of orthologues of known heat shock genes (including those for Hsp40, GroEL, GroES, DnaK, DnaJ, GrpE, ClpB and ClpP) and a number of genes implicated in Francisella virulence. A bioinformatic analysis was used to identify genes preceded by a putative sigma(32)-binding site, revealing both similarities to and differences from RpoH-mediated gene expression in Escherichia coli. Our results suggest that RpoH is an essential protein of F. tularensis, and positively regulates a subset of genes involved in the heat-shock response. PMID- 19443548 TI - A novel carotenoid 1,2-hydratase (CruF) from two species of the non photosynthetic bacterium Deinococcus. AB - A novel carotenoid 1,2-hydratase (CruF) responsible for the C-1',2' hydration of gamma-carotene was identified in the non-photosynthetic bacteria Deinococcus radiodurans R1 and Deinococcus geothermalis DSM 11300. Gene expression and disruption experiments demonstrated that dr0091 and dgeo2309 encode CruF in D. radiodurans and D. geothermalis, respectively. Their homologues were also found in the genomes of cyanobacteria, and exhibited little homology to the hydroxyneurosporene synthase (CrtC) proteins found mainly in photosynthetic bacteria. Phylogenetic analysis showed that CruF homologues form a separate family, which is evolutionarily distant from the known CrtC family. PMID- 19443549 TI - The important role of actinin-like protein (AcnA) in cytokinesis and apical dominance of hyphal cells in Aspergillus nidulans. AB - The actin cytoskeleton is involved in many processes in eukaryotic cells, including interaction with a wide variety of actin-binding proteins such as the actin-capping proteins, the actin filament nucleators and the actin cross-linking proteins. Here, we report the identification and characterization of an actinin like protein (AcnA) from the filamentous fungus Aspergillus nidulans. Not only did the depletion of AcnA by alcA(p) promoter repression or the deletion of AcnA result in explicit abnormalities in septation and conidiation, but also the acnA mutants induced a loss of apical dominance in cells with dichotomous branching, in which a new branch was formed by splitting the existing tip in two. Consequently, the colony showed flabellate edges. Moreover, we found that the localization of the GFP-AcnA fusion was quite dynamic. In the isotropic expansion phase of the germinated spore, GFP-AcnA was organized as cortical patches with cables lining the cell wall. Subsequently, GFP-AcnA was localized to the actively growing hyphal tips and to the sites of septation in the form of combined double contractile rings. Our data suggest that AcnA plays an important role in cytokinesis and apical dominance of hyphal cells, possibly via actin-dependent polarization maintenance and medial ring establishment in A. nidulans. This is the first report, to our knowledge, of the function of an actinin-like protein in filamentous fungi. PMID- 19443550 TI - Uptake of L-nicotine and of 6-hydroxy-L-nicotine by Arthrobacter nicotinovorans and by Escherichia coli is mediated by facilitated diffusion and not by passive diffusion or active transport. AB - The mechanism by which l-nicotine is taken up by bacteria that are able to grow on it is unknown. Nicotine degradation by Arthrobacter nicotinovorans, a Gram positive soil bacterium, is linked to the presence of the catabolic megaplasmid pAO1. l-[(14)C]Nicotine uptake assays with A. nicotinovorans showed transport of nicotine across the cell membrane to be energy-independent and saturable with a K(m) of 6.2+/-0.1 microM and a V(max) of 0.70+/-0.08 micromol min(-1) (mg protein)(-1). This is in accord with a mechanism of facilitated diffusion, driven by the nicotine concentration gradient. Nicotine uptake was coupled to its intracellular degradation, and an A. nicotinovorans strain unable to degrade nicotine (pAO1(-)) showed no nicotine import. However, when the nicotine dehydrogenase genes were expressed in this strain, import of l-[(14)C]nicotine took place. A. nicotinovorans pAO1(-) and Escherichia coli were also unable to import 6-hydroxy-l-nicotine, but expression of the 6-hydroxy-l-nicotine oxidase gene allowed both bacteria to take up this compound. l-Nicotine uptake was inhibited by d-nicotine, 6-hydroxy-l-nicotine and 2-amino-l-nicotine, which may indicate transport of these nicotine derivatives by a common permease. Attempts to correlate nicotine uptake with pAO1 genes possessing similarity to amino acid transporters failed. In contrast to the situation at the blood-brain barrier, nicotine transport across the cell membrane by these bacteria was not by passive diffusion or active transport but by facilitated diffusion. PMID- 19443552 TI - Global priorities for patient safety research. PMID- 19443557 TI - Elastic, viscous, and mass load effects on poststroke muscle recruitment and co contraction during reaching: a pilot study. AB - BACKGROUND: Resistive exercise after stroke can improve strength (force generating capacity) without increasing spasticity (velocity-dependent hypertonicity). However, the effect of resistive load type on muscle activation and co-contraction after stroke is not clear. OBJECTIVE: The purpose of this study was to determine the effect of load type (elastic, viscous, or mass) on muscle activation and co-contraction during resisted forward reaching in the paretic and nonparetic arms after stroke. DESIGN: This investigation was a single session, mixed repeated-measures pilot study. METHODS: Twenty participants (10 with hemiplegia and 10 without neurologic involvement) reached forward with each arm against equivalent elastic, viscous, and mass loads. Normalized shoulder and elbow electromyography impulses were analyzed to determine agonist muscle recruitment and agonist-antagonist muscle co-contraction. RESULTS: Muscle activation and co-contraction levels were significantly higher on virtually all outcome measures for the paretic and nonparetic arms of the participants with stroke than for the matched control participants. Only the nonparetic shoulder responded to load type with similar activation levels but variable co-contraction responses relative to those of the control shoulder. Elastic and viscous loads were associated with strong activation; mass and viscous loads were associated with minimal co-contraction. LIMITATIONS: A reasonable, but limited, range of loads was available. CONCLUSIONS: Motor control deficits were evident in both the paretic and the nonparetic arms after stroke when forward reaching was resisted with viscous, elastic, or mass loads. The paretic arm responded with higher muscle activation and co-contraction levels across all load conditions than the matched control arm. Smaller increases in muscle activation and co-contraction levels that varied with load type were observed in the nonparetic arm. On the basis of the response of the nonparetic arm, this study provides preliminary evidence suggesting that viscous loads elicited strong muscle activation with minimal co-contraction. Further intervention studies are needed to determine whether viscous loads are preferable for poststroke resistive exercise programs. PMID- 19443559 TI - High-resolution SPECT imaging of bony pathology in early arthritis of finger joints. PMID- 19443558 TI - Assessment of physical functioning: a conceptual model encompassing environmental factors and individual compensation strategies. AB - Commonly studied physical functions include activities such as walking and climbing stairs. Despite the acknowledged role of environmental factors and behavioral strategies to compensate for reduced performance capacity or environmental barriers in characterizing physical functioning, most assessments do not take these factors into account. This article presents a new conceptual model for assessment of relevant physical functioning while accounting for habitual environmental factors and compensation strategies. PMID- 19443560 TI - Protein quantification by mass spectrometry: is it ready for prime time? PMID- 19443561 TI - Detecting minimal residual disease in neuroblastoma: still a ways to go. PMID- 19443562 TI - Quality assurance in Her-2 testing--redefining the gold standard. PMID- 19443563 TI - Assay imprecision and 99th-percentile reference value of a high-sensitivity cardiac troponin I assay. PMID- 19443564 TI - APOC3 mutation, serum triglyceride concentrations, and coronary heart disease. PMID- 19443565 TI - Hyperbilirubinemia and transcutaneous bilirubinometry. AB - BACKGROUND: Neonatal jaundice or hyperbilirubinemia is a common occurrence in newborns. Although most cases of neonatal jaundice have a benign course, severe hyperbilirubinemia can lead to kernicterus, which is preventable if the hyperbilirubinemia is identified early and treated appropriately. CONTENT: This review discusses neonatal jaundice and the use of transcutaneous bilirubin (TcB) measurements for identification of neonates at risk of severe hyperbilirubinemia. Such a practice requires appropriate serial testing and result interpretation according to risk level from a nomogram that provides bilirubin concentrations specific for the age of the neonate in hours. In this context, we have evaluated the potential impact on clinical outcome and limitations of TcB methods in current use. SUMMARY: TcB measurement is a viable option in screening neonates to determine if they are at risk for clinically significant hyperbilirubinemia. Total serum bilirubin should be measured by a clinical laboratory if a newborn is shown to be at higher risk for clinically significant hyperbilirubinemia. In addition, external quality assessment to identify biases and operator training issues should be part of any TcB monitoring program. PMID- 19443566 TI - Cell lines as candidate reference materials for quality control of ERBB2 amplification and expression assays in breast cancer. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an important biomarker whose status plays a pivotal role in therapeutic decision-making for breast cancer patients and in determining their clinical outcomes. Ensuring the accuracy and reproducibility of HER2 assays by immunohistochemistry (IHC) and by fluorescence in situ hybridization (FISH) requires a reliable standard for monitoring assay sensitivity and specificity, and for assessing methodologic variation. A prior NIST workshop addressed this need by reaching a consensus to create cell lines as reference materials for HER2 testing. METHODS: Breast carcinoma cell lines SK-BR-3 and MCF-7 were characterized quantitatively by IHC with chicken anti-HER2 IgY antibody and by FISH with biotinylated bacterial artificial chromosome DNA probes; both assays used quantum dots as detectors. Formalin-fixed and paraffin-embedded (FFPE) cell blocks were prepared and tested for suitability as candidate reference materials by IHC and FISH with commercially available reagents. IHC and FISH results were also compared with those obtained by laser-scanning cytometry and real-time PCR, respectively. RESULTS: MCF-7 cells had typical numbers of gene copies and very low production of HER2 protein, whereas SK-BR-3 cells contained approximately 10-fold more copies of the gene and exhibited approximately 15-fold higher amounts of HER2 protein than MCF-7 cells. FFPE SK-BR-3 cells showed results similar to those for fresh SK-BR-3 cells. CONCLUSIONS: SK-BR-3 and MCF-7 are suitable as candidate reference materials in QC of HER2 testing. Coupled with the associated assay platforms, they provide valuable controls for quantitative measurement of HER2 amplification and production in breast cancer samples, irrespective of the antibody/probe or detector used. PMID- 19443567 TI - Three novel CFTR polymorphic repeats improve segregation analysis for cystic fibrosis. AB - BACKGROUND: Molecular diagnosis for cystic fibrosis (CF) is based on the direct identification of mutations in the CFTR gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] (detection rate about 90% with scanning procedures) and on segregation analysis of intragenic polymorphisms for carrier and prenatal diagnosis in about 20% of CF families in which 1 or both causal mutations are unknown. METHODS: We identified 3 novel intragenic polymorphic repeats (IVS3polyA, IVS4polyA, and IVS10CA repeats) in the CFTR gene and developed and validated a procedure based on the PCR followed by capillary electrophoresis for large-scale analysis of these polymorphisms and the 4 previously identified microsatellites (IVS1CA, IVS8CA, IVS17bTA, and IVS17bCA repeats) in a single run. We validated the procedure for both single- and 2-cell samples (for a possible use in preimplantation diagnosis), and on a large number of CF patients bearing different genotypes and non-CF controls. RESULTS: The allelic distribution and heterozygosity results suggest that the 3 novel polymorphisms strongly contribute to carrier and prenatal diagnosis of CF in families in which 1 or both causal mutations have not been identified. At least 1 of the 4 previously identified microsatellites was informative in 78 of 100 unrelated CF families; at least 1 of all 7 polymorphisms was informative in 98 of the families. Finally, the analysis of haplotypes for the 7 polymorphisms revealed that most CF mutations are associated with different haplotypes, suggesting multiple slippage events but a single origin for most CFTR mutations. CONCLUSIONS: The analysis of the 7 polymorphisms is a rapid and efficient tool for routine carrier, prenatal, and preimplantation diagnosis of CF. PMID- 19443568 TI - Validation of a phosphoprotein array assay for characterization of human tyrosine kinase receptor downstream signaling in breast cancer. AB - BACKGROUND: Human epidermal growth factor receptor (HER) downstream signaling kinases have important effects on tumor response to anti-HER monoclonal antibodies and tyrosine kinase inhibitors. We validated an assay that uses phosphoprotein arrays for measurement of HER downstream signaling functionality in breast carcinomas. METHODS: Using the Bio-Plex(R) phosphoprotein array (BPA), we performed multiplex immunoanalysis to investigate the expression of phosphorylated epidermal growth factor receptor and phosphorylated HER downstream signaling proteins (phosphorylated protein kinase B, phosphorylated glycogen synthase kinase -3beta, phosphorylated P70 ribosomal protein S6 kinase, and phosphorylated extracellular signal regulated kinase 42/44) in 49 frozen specimens of ductal infiltrating breast carcinoma taken at diagnosis. BPA was cross-validated with Western blot analysis. Sample size, homogenicity, tumor content, protein extraction, and monoclonal antibody detection were in accordance with optimized standard operating procedures. RESULTS: Linear regression showed significant quantitative correlations between BPA and Western blot, with regression coefficient values of 0.71-0.87 (P < 0.001). BPA intra- and interassay CVs were <17% and 15%, respectively. Compared to limits of detection established by using the mean + 3SD of 10 blanks, large variations of phosphoprotein expression, up to several hundred-fold, were observed among the 49 tumor specimens. CONCLUSIONS: Our results validate the use of the multiplex phosphoprotein array assay in human clinical tumor specimens. Further prospective evaluation is warranted to investigate the use of HER downstream signaling phosphoproteins as predictive and/or surrogate markers for clinical response to anti-HER targeted therapy. PMID- 19443570 TI - Differential signaling activation by insulin and insulin-like growth factors I and II upon binding to insulin receptor isoform A. AB - A variety of human malignancies overexpresses isoform A of the insulin receptor (IR-A) and produces IGFs (IGF-I and/or IGF-II). IR-A binds IGF-II with high affinity (although 4-fold lower than that for insulin), whereas it binds IGF-I with low affinity (approximately 30-fold lower than that for insulin). However, in engineered cells expressing only the IR-A, but not IGF-I receptor (R(-)/IR-A cells), IGF-II is a more potent mitogen than insulin. Herein, we investigated downstream signaling of IGF-II, IGF-I, and insulin in R(-)/IR-A cells to better understand their role in cell growth. We found that despite inducing a lower IR-A autophosphorylation than insulin, IGF-II was more potent than insulin for activating p70S6 kinase (p70S6K) and approximately equally potent in activating the early peaks of ERK1/2 and Akt. However, ERK1/2 activation persisted longer after IGF-II, whereas Akt activation persisted longer after insulin. Therefore, cells stimulated with IGF-II had a higher p70S6K/Akt activation ratio than cells stimulated with insulin. Remarkably, IGF-I also elicited a similar signaling pattern as IGF-II, despite inducing minimal IR-A autophosphorylation. ERK1/2 and protein kinase C seem to be involved in the preferential stimulation of p70S6K by IGFs. In conclusion, our study has identified a novel complex role of IR-A, which not only elicits a unique signaling pattern after IGF-II binding but also induces substantial downstream signaling upon binding to the low-affinity ligand IGF-I. These results underline the role of IR-A in physiology and disease. PMID- 19443569 TI - Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge. AB - The preovulatory GnRH/LH surge depends on the presence of estradiol (E(2)) and is gated by a circadian oscillator in the suprachiasmatic nucleus (SCN) that causes the surge to occur within a specific temporal window. Although the mechanisms by which the clock times the LH surge are unclear, evidence suggests that the SCN is linked to GnRH neurons through a multisynaptic pathway that includes neurons in the anteroventral periventricular nucleus (AVPV). Recently, Kiss1 neurons in the AVPV have been implicated in the surge mechanism, suggesting that they may integrate circadian and E(2) signals to generate the LH surge. We tested whether Kiss1 neurons display circadian patterns of regulation in synchrony with the temporal pattern of LH secretion. Mice housed in 14 h light, 10 h dark were ovariectomized, given E(2) capsules (or nothing), and transferred into constant darkness. Two days later, the mice were killed at various times of day and their LH and Kiss1 levels assessed. In E(2)-treated females, LH levels were low except during late subjective day (indicative of an LH surge). Similarly, AVPV Kiss1 expression and c-fos coexpression in Kiss1 neurons showed circadian patterns that peaked coincident with LH. These temporal changes in Kiss1 neurons occurred under steady-state E(2) and constant environmental conditions, suggesting that Kiss1 neurons are regulated by circadian signals. In the absence of E(2), animals displayed no circadian pattern in LH secretion or Kiss1 expression. Collectively, these findings suggest that the LH surge is controlled by AVPV Kiss1 neurons whose activity is gated by SCN signals in an E(2)-dependent manner. PMID- 19443571 TI - Targeted gene knockdown in zebrafish reveals distinct intraembryonic functions for insulin-like growth factor II signaling. AB - IGF-II is the predominant IGF ligand regulating prenatal growth in all vertebrates, including humans, but its central role in placental development has confounded efforts to fully elucidate its functions within the embryo. Here we use a nonplacental model vertebrate (zebrafish) to interrogate the intraembryonic functions of IGF-II signaling. The zebrafish genome contains two coorthologs of mammalian IGF2 (igf2a, igf2b), which exhibit distinct patterns of expression during embryogenesis. Expression of igf2a mRNA is restricted to the notochord, primarily during segmentation/neurulation. By contrast, igf2b mRNA is expressed in midline tissues adjacent to the notochord, with additional sites of expression in the ventral forebrain, and the pronephros. To identify their intraembryonic functions, we suppressed the expression of each gene with morpholino oligonucleotides. Knockdown of igf2a led to defects in dorsal midline development, characterized by delayed segmentation, notochord undulations, and ventral curvature. Similarly, suppression of igf2b led to defects in dorsal midline development but also induced ectopic fusion of the nephron primordia, and defects in ventral forebrain development. Subsequent onset of severe body edema in igf2b, but not igf2a morphants, further suggested a distinct role for igf2b in development of the embryonic kidney. Simultaneous knockdown of both genes increased the severity of dorsal midline defects, confirming a conserved role for both genes in dorsal midline development. Collectively, these data provide evidence that the zebrafish orthologs of IGF2 function in dorsal midline development during segmentation/neurulation, whereas one paralog, igf2b, has evolved additional, distinct functions during subsequent organogenesis. PMID- 19443572 TI - Inhibition of forkhead box O1 protects pancreatic beta-cells against dexamethasone-induced dysfunction. AB - Forkhead Box O1 (FoxO1) is a key transcription regulator of insulin/IGF-I signaling pathway, and its activity can be increased by dexamethasone (DEX) in several cell types. However, the role of FoxO1 in DEX-induced pancreatic beta cell dysfunction has not been fully understood. Therefore, in this study, we investigated whether FoxO1 could mediate DEX-induced beta-cell dysfunction and the possible underlying mechanisms in pancreatic beta-cell line RINm5F cells and primary rat islet. We found that DEX markedly increased FoxO1 mRNA and protein expression and decreased FoxO1 phosphorylation through the Akt pathway, which resulted in an increase in active FoxO1 in RINm5F cells and isolated rat islets. Activated FoxO1 subsequently inhibited pancreatic duodenal homeobox-1 expression and induced nuclear exclusion of pancreatic duodenal homeobox-1. Knockdown of FoxO1 by RNA interference restored the expression of pancreatic duodenal homeobox 1 and prevented DEX-induced dysfunction of glucose-stimulated insulin secretion in rat islets. Together, the results of present study demonstrate that FoxO1 is integrally involved in DEX-induced inhibition of pancreatic duodenal homeobox-1 and glucose-stimulated insulin secretion dysfunction in pancreatic islet beta cells. Inhibition of FoxO1 can effectively protect beta-cells against DEX-induced dysfunction. PMID- 19443573 TI - A rat model of epilepsy in women: a tool to study physiological interactions between endocrine systems and seizures. AB - Epilepsy in women is influenced by endocrine status and antiepileptic drugs, but without an animal model, the effects of endocrine variables and antiepileptic drugs cannot be easily dissociated from the influence of epilepsy itself. Animal models have had limited utility because experimentally induced seizures typically result in reproductive failure. This study was conducted to develop an improved animal model. The muscarinic convulsant pilocarpine was used to elicit status epilepticus (SE) in adult female Sprague Dawley rats. The selective estrogen receptor modulator raloxifene was administered 30 min before pilocarpine. An anticonvulsant barbiturate, pentobarbital, was injected 5-10 min after the onset of SE and at least once thereafter to minimize acute convulsions. Mortality, morbidity, estrous cyclicity, and the ultimate success of the procedure (i.e. induction of recurrent, spontaneous seizures) were monitored. The combination of raloxifene and pentobarbital led to significantly improved estrous cyclicity compared with previous methods. Animals treated with raloxifene and pentobarbital became epileptic, as defined by the recurrence of spontaneous convulsions in the weeks after SE. The results of this study provide an improved animal model to examine the interactions between seizures and ovarian hormone secretion. The results also suggest that treatment of SE with raloxifene may benefit women with SE. PMID- 19443574 TI - A unique human chorionic gonadotropin antagonist suppresses ovarian hyperstimulation syndrome in rats. AB - Ovarian hyperstimulation syndrome (OHSS) is a complication of in vitro fertilization associated with physiological changes after hCG administration to induce final oocyte maturation. It presents as widespread increases in vascular permeability and, in rare cases, results in cycle cancellation, multi-organ dysfunction, and pregnancy termination. These physiological changes are due primarily to activation of the vascular endothelial growth factor (VEGF) system in response to exogenous human chorionic gonadotropin (hCG). An hCG antagonist (hCG-Ant) could attenuate these effects by competitively binding to the LH/CG receptor, thereby blocking LH activity in vivo. We expressed a form of hCG that lacks three of its four N-linked glycosylation sites and tested its efficacy as an antagonist. The hCG-Ant binds the LH receptor with an affinity similar to native hCG and inhibits cAMP response in vitro. In a rat model for ovarian stimulation, hCG-Ant dramatically reduces ovulation and steroid hormone production. In a well-established rat OHSS model, vascular permeability and vascular endothelial growth factor (VEGF) expression are dramatically reduced after hCG-Ant treatment. Finally, hCG-Ant does not appear to alter blastocyst development when given after hCG in mice. These studies demonstrate that removing specific glycosylation sites on native hCG can produce an hCG-Ant that is capable of binding without activating the LH receptor and blocking the actions of hCG. Thus hCG-Ant will be investigated as a potential therapy for OHSS. PMID- 19443575 TI - A signaling network in phenylephrine-induced benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology characterized by prostatic enlargement and coinciding with distinctive alterations in tissue histomorphology. To identify the molecular mechanisms underlying the development of BPH, we conducted a DNA microarray study using a previously described animal model in which chronic alpha(1)-adrenergic stimulation by repeated administration of phenylephrine evokes histomorphological changes in the rat prostate that resemble human BPH. Bioinformatic tools were applied to microarray data obtained from prostate tissue to construct a network model of potentially relevant signal transduction pathways. Significant involvement of inflammatory pathways was demonstrable, including evidence for activation of a TGF-beta signaling cascade. The heterodimeric protein clusterin (apolipoprotein J) was also identified as a prominent node in the network. Responsiveness of TGF-beta signaling and clusterin gene and protein expression were confirmed independently of the microarray data, verifying some components of the model. This is the first attempt to develop a comprehensive molecular network for histological BPH induced by adrenergic activation. The study also implicated clusterin as a novel biochemical target for therapy. PMID- 19443576 TI - Role of the T-type calcium channel CaV3.2 in the chronotropic action of corticosteroids in isolated rat ventricular myocytes. AB - The mineralocorticoid receptor is involved in the development of several cardiac dysfunctions, including lethal ventricular arrhythmias associated with heart failure or hyperaldosteronism, but the molecular mechanisms responsible for these effects remain to be clarified. Reexpression of low voltage-activated T-type calcium channels in ventricular myocytes together with other fetal genes during cardiac pathologies could confer automaticity to these cells and would represent a pro-arrhythmogenic condition if occurring in vivo. In the present study, we demonstrated that in isolated neonatal rat ventricular myocytes, corticosteroids selectively induced the expression of a particular isoform of T channel, Ca(V)3.2/alpha1H. This response was accompanied by an increase of the Ca(V)3.2 T type current, identified with the patch clamp technique by its sensitivity to nickel, and a concomitant acceleration of the myocyte spontaneous contractions. Silencing Ca(V)3.2 expression markedly reduced the chronotropic response to steroids. Moreover, modulation of the frequency of cell contractions by different redox agents was independent of channel expression but involved a direct regulation of channel activity. Although oxidants increased both Ca(V)3.2 current amplitude and beating frequency, they decreased L-type channel activity. Reducing agents had the opposite effect on these parameters. In conclusion, the acceleration of ventricular myocyte spontaneous contractions induced by corticosteroids in vitro appears dependent on the expression of the Ca(V)3.2 T channel isoform and modulated by the redox potential of the cells. These results provide a molecular model that could explain the high incidence of arrhythmias observed in patients upon combination of inappropriate activation of the mineralocorticoid receptor and oxidative stress. PMID- 19443578 TI - Activator protein-2 impairs the invasion of a human extravillous trophoblast cell line. AB - The reduced migration/invasion of extravillous trophoblasts (EVTs) is a key feature of the genesis of preeclampsia. We and others previously reported that transcriptional factors activator protein-2 (AP-2) alpha and AP-2gamma act as suppressors of tumor invasion. The present study examined the expressions of AP 2alpha and AP-2gamma in preeclamptic placenta vs. control placenta and investigated their effect on the function of EVTs. The expressions of AP-2alpha and AP-2gamma were elevated in the preeclamptic placentas in comparison with the gestational age-matched control placentas. Their expressions also increased in EVTs of the preeclamptic placentas. Thereafter, we transfected AP-2alpha or AP 2gamma into human EVT cell line, HTR-8/SVneo. The overexpression of AP-2alpha or AP-2gamma decreased the migratory and invasive abilities in HTR-8/SVneo cells. This was followed by the reduction of protease activated receptor-1 and matrix metalloproteinases and a significant induction of plasminogen activator inhibitor 1 and the tissue inhibitor of metalloproteinase-1. AP-2alpha and AP-2gamma were weakly expressed in the cultured EVTs and HTR-8/SVneo cells, whereas they were induced by TNF-alpha, which increases in preeclamptic placenta and impairs trophoblast invasion. In the presence of TNF-alpha, the invasion of the HTR 8/SVneo cells was partially restored by a blocking of AP-2 induction using small interfering RNA of AP-2. The present data suggest that AP-2 may suppress trophoblast migration and invasion, thus leading to a shallow placentation in preeclampsia. PMID- 19443577 TI - Endotoxin-induced growth hormone resistance in skeletal muscle. AB - Inflammation-induced skeletal muscle wasting is a serious clinical problem and arises in part because of resistance to GH-stimulated IGF-I expression. Although it is established that in the liver, resistance develops because of impaired signaling through the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) transduction pathway, together with a more distal defect in STAT5 DNA-binding activity, the situation in skeletal muscle is unclear. Accordingly, we set out to characterize the mechanisms behind the skeletal muscle resistance to GH in rats with acute inflammation induced by endotoxin. Endotoxin caused significant declines in GH-stimulated STAT5a/b phosphorylation and IGF-I gene expression, and this occurred despite a lack of change in signaling protein levels or phosphorylation of JAK2. In whole muscle, GH-stimulated phospho STAT5a/b levels were reduced by half, and in the nucleus, phospho-STAT5b levels were similarly reduced. Furthermore, the binding of phosphorylated STAT5b to DNA was reduced and to a similar extent to the reduction in nuclear phosphorylated STAT5b. Interestingly, GH-induced androgen receptor gene expression was also suppressed. Thus, it appears that skeletal muscle resistance to GH-stimulated IGF I expression in acute endotoxemia arises from a defect in STAT5b signaling, with a proportionate reduction in STAT5b DNA binding. Finally, it appears that resistance to GH-induced androgen receptor expression also develops and, together with the attenuated GH-induced IGF-I expression, likely plays an important role in the muscle wasting that arises in endotoxin-induced inflammation. PMID- 19443579 TI - Value of SPECT/CT for detection and anatomic localization of sentinel lymph nodes before laparoscopic sentinel node lymphadenectomy in prostate carcinoma. AB - Laparoscopic evaluation of sentinel nodes is useful for staging prostate cancer, but preoperative localization of deep abdominal sentinel nodes with planar lymphoscintigraphy is difficult. We evaluated the value of SPECT/CT for detecting and localizing sentinel nodes in prostate cancer. METHODS: (99m)Tc-nanocolloid was injected peri- and intratumorally, guided by transrectal ultrasonography, in 46 patients with prostate cancer of intermediate prognosis. Patients underwent planar imaging after 15 min and 2 h, SPECT/CT after 2 h, and laparoscopic sentinel node lymphadenectomy on the same day. SPECT was fused with CT and analyzed using 2-dimensional orthogonal slicing and 3-dimensional volume rendering. We evaluated the number of extra sentinel nodes found by SPECT/CT, the number of sentinel nodes found by SPECT/CT outside the area of the extended pelvic lymphadenectomy, and the anatomic information provided by SPECT/CT. Furthermore, we classified the value of the additional SPECT/CT images into 3 categories (no advantage, presumable advantage, and definite advantage) according to the extra anatomic information given and whether additional sentinel nodes were found by SPECT/CT. RESULTS: The patients had a mean age of 64 y (range, 53 74 y) and received a mean injected dose of 218 MBq (range, 147-286 MBq). The sentinel node visualization rate was 91% (42 patients) for planar imaging and 98% (45 patients) for SPECT/CT. In 29 of the 46 patients (63%), SPECT/CT revealed additional sentinel nodes (especially lymph nodes near the injection area) not seen on planar imaging. In 7 patients, those additional sentinel nodes were positive for metastasis (being the exclusive metastatic sentinel node in 4 patients). Overall, 15 patients (33%) had positive sentinel nodes. Sentinel nodes outside the area of extended pelvic lymphadenectomy were found in 16 patients (35%), whereas in 56% of these patients those nodes were not seen on planar imaging. Performing SPECT/CT had no advantage in 13% of the patients, a presumable advantage in 24%, and a definite advantage in 63%. Urologic surgeons used the SPECT/CT images to guide their trocar insertion sites and sentinel node finding with the probe. CONCLUSION: More sentinel nodes can be detected with SPECT/CT than with planar imaging alone. In comparison with planar imaging, SPECT/CT especially reveals extra sentinel nodes near the prostate and outside the area of the extended pelvic lymphadenectomy. Furthermore, the modality provides useful additional information about the anatomic location of sentinel nodes within and outside the pelvic area, leading to improved intraoperative sentinel node identification. PMID- 19443580 TI - Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues. AB - The successful peptide receptor imaging of tumors, as exemplified for somatostatin receptors, is based on the overexpression of peptide receptors in selected tumors and the high-affinity binding to these tumors of agonist radioligands that are subsequently internalized into the tumor cells in which they accumulate. Although in vitro studies have shown ample evidence that the ligand-receptor complex is internalized, in vivo evidence of agonist-induced internalization of peptide receptors, such as somatostatin receptors, is missing. METHODS: Rats subcutaneously transplanted with the somatostatin receptor subtype 2 (sst(2))-expressing AR42J tumor cells were treated with intravenous injections of various doses of the sst(2) agonist [Tyr(3), Thr(8)]-octreotide (TATE) or of the sst(2) antagonist 1,4,7,10-tetraazacyclododecane-N,N',N'',N''',-tetraacetic acid (DOTA)-Bass and were sacrificed at various times ranging from 2.5 min to 24 h after injection. The tumors and pancreas were then removed from each animal. All tissue samples were processed for sst(2) immunohistochemistry using sst(2) specific antibodies. RESULTS: Compared with the sst(2) receptors in untreated animals, which localized at the plasma membrane in pancreatic and AR42J tumor cells, the sst(2) receptors in treated animals are detected intracellularly after an intravenous injection of the agonist TATE. Internalization is fast, as the receptors are already internalizing 2.5 min after TATE injection. The process is extremely efficient, as most of the cell surface receptors internalize into the cell and are found in endosomelike structures after TATE injection. The internalization is most likely reversible, because 24 h after injection the receptors are again found at the cell surface. The process is also agonist dependent, because internalization is seen with high-affinity sst(2) agonists but not with high-affinity sst(2) antagonists. The same internalization properties are seen in pancreatic and AR42J tumor cells. They can further be confirmed in vitro in human embryonic kidney-sst(2) cells, with an immunofluorescence microscopy-based sst(2) internalization assay. CONCLUSION: These animal data strongly indicate that the process of in vivo sst(2) internalization after agonist stimulation is fast, extremely efficient, and fully functional under in vivo conditions in neoplastic and physiologic sst(2) target tissues. This molecular process is, therefore, likely to be responsible for the high and long lasting uptake of sst(2) radioligands seen in vivo in sst(2)-expressing tumors. PMID- 19443581 TI - Clinical cardiovascular molecular imaging. AB - Molecular imaging holds the promise of becoming a key diagnostic modality in cardiovascular medicine by allowing visualization of specific targets and pathways that precede or underlie changes in morphology, physiology, and function. As such, molecular imaging aims at detecting precursors or early stages of cardiovascular disease and at monitoring and guiding novel, increasingly specific and versatile cardiovascular therapies. Imaging of myocardial metabolism and autonomic innervation are already used in current practice, and a wide variety of other targets and probes is on the horizon. This focused review provides an overview of the opportunities and challenges that molecular imaging faces to fulfill its promises in clinical cardiovascular medicine. PMID- 19443582 TI - Quantification of inflammation within rabbit atherosclerotic plaques using the macrophage-specific CT contrast agent N1177: a comparison with 18F-FDG PET/CT and histology. AB - Macrophages play a key role in atherosclerotic plaque rupture. The iodine-based contrast agent N1177 accumulates in macrophages, allowing for their detection with CT. In this study, we tested whether the intensity of enhancement detected with CT in the aortic wall of rabbits injected with N1177 correlated with inflammatory activity evaluated with (18)F-FDG PET/CT and macrophage density on histology. METHODS: Atherosclerotic plaques were induced in the aorta of New Zealand White rabbits (n = 7) by a repeated balloon injury (4 wk apart) and 4 mo of hyperlipemic diet. Noninjured rabbits, fed a chow diet, were used as controls (n = 3). A CT scan of the aorta (n = 10) was acquired in each rabbit before, during, and at 2 h after intravenous injection of N1177 (250 mg of iodine/kg). One week later, the same rabbits underwent PET/CT 3 h after injection of (18)F FDG (37 MBq/kg [1 mCi/kg]). CT enhancement was calculated as the difference in aortic wall densities between images obtained before and images obtained at 2 h after injection of N1177. Mean standardized uptake values were measured on PET axial slices of the aorta in regions of interest encompassing the vessel wall. Macrophage density was measured by immunohistology (anti-RAM-11 antibody) on corresponding aortic cross-sections. RESULTS: N1177-enhanced CT measured stronger enhancement in the aortic wall of atherosclerotic rabbits than in control rabbits (10.0 +/- 5.2 vs. 2.0 +/- 2.1 Hounsfield units, respectively; P < 0.05). After the injection of (18)F-FDG, PET detected higher standardized uptake values in the aortic wall of atherosclerotic rabbits than in control rabbits (0.61 +/- 0.12 vs. 0.21 +/- 0.02; P < 0.05). The intensity of enhancement in the aortic wall measured with CT after injection of N1177 correlated with (18)F-FDG uptake on PET/CT (r = 0.61, P < 0.001) and macrophage density on immunohistology (r = 0.63, P < 0.001). CONCLUSION: The intensity of enhancement detected with CT in the aortic wall of rabbits injected with N1177 correlates with intense uptake of (18)F-FDG measured with PET and with macrophage density on histology, suggesting a role for N1177 in noninvasive identification of high-risk atherosclerotic plaques with CT. PMID- 19443583 TI - Molecular imaging without radiopharmaceuticals? AB - The limitations on the sensitivity for detecting small changes in MRI, CT, and ultrasound pulse-echo images are used to estimate the practical requirements for molecular imaging and targeted contrast enhancement for these modalities. These types of imaging are highly unlikely to approach the sensitivity for detecting molecular processes of radionuclear methods, and the prospects for achieving sufficient concentrations of appropriate agents in vivo are poor for several types of applications such as small-molecule targeting of specific receptors. However, using relatively large carrier systems such as particles and liposomes, sufficient concentrations of paramagnetic agents may be delivered to achieve MR signal changes adequate for detection. The use of higher-resolution MR images will aid the prospects for molecular imaging in small animals. Theoretic considerations also predict that a similar approach, using rather large particles or carriers of materials with a high atomic number, may also be successful for CT, especially with additional developments such as the use of monochromatic x rays. The prospects of molecular imaging by x-ray imaging may not be as bleak as has been predicted. For ultrasound detection, gas-filled bubbles can provide a sufficient backscattered sound intensity to be detectable at concentrations and sizes not much different from agents designed for these other modalities. PMID- 19443584 TI - Tumor metabolic phenotypes on 18F FDG PET. PMID- 19443585 TI - Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. AB - The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical (89)Zr-trastuzumab was compared with the SPECT tracer (111)In trastuzumab, which we have tested in the clinic already. METHODS: Trastuzumab was labeled with (89)Zr and (for comparison) with (111)In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft-bearing mice. RESULTS: Trastuzumab was efficiently radiolabeled with (89)Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 microg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of (89)Zr-trastuzumab in HER2/neu positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 +/- 7.6 [mean +/- SEM] vs. 7.1 +/- 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between (89)Zr-trastuzumab and (111)In-trastuzumab uptake in tumors (R(2) = 0.972). CONCLUSION: Clinical-grade (89)Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution. PMID- 19443586 TI - Comparison of imaging protocols for 18F-FDG PET/CT in overweight patients: optimizing scan duration versus administered dose. AB - The quality of (18)F-FDG PET/CT images of overweight patients is often degraded. We evaluated the effect of optimizing injected dose or acquisition time on the quality of images of overweight patients using lutetium oxyorthosilicate PET/CT with high-performance detector electronics. METHODS: We initially retrospectively measured radioactivity concentrations and signal-to-noise ratios (SNRs) in the liver relative to body weight for 80 patients who had undergone (18)F-FDG PET/CT according to our standard protocol (injected dose, 3.7 MBq/kg; acquisition time, 2 min/bed position). The patients were grouped (n = 20 per group) according to baseline body weight as G1 (or=85 kg). We compared the SNRs of G1 with those of G2, G3, and G4 and calculated the ratio squared as a factor to correct the acquisition parameters for overweight patients. We then prospectively enrolled 120 patients according to the same body weight criteria. We multiplied the correction factors to optimize injected doses or acquisition times and defined dose-adjusted groups (n = 20 per group) and time-adjusted groups (n = 20 per group). G2 dose was defined as 5.59 +/- 0.19 MBq/kg, G3 dose as 7.29 +/- 0.33 MBq/kg, and G4 dose as 8.88 +/- 0.43 MBq/kg. G2 time was defined as 3 min/bed position, G3 time as 4 min/bed position, and G4 time as 5 min/bed position. RESULTS: Although liver activities did not significantly differ among G1 through G4 irrespective of patient weight, SNR progressively decreased as patient weight increased. The liver activities of G2 dose, G3 dose, and G4 dose were, respectively, 1.4-, 1.9-, and 2.5-fold higher than those of the baseline counterparts. Nevertheless, the increased liver activities of G2 dose, G3 dose, and G4 dose did not significantly affect SNR, compared with the baseline groups. In contrast, the SNR of G4 time was significantly higher than that of G4. CONCLUSION: Our findings suggest that the quality of images acquired from heavier patients can be maintained only by scanning for longer periods. Increasing the dose per kilogram of body weight did not improve the quality of lutetium oxyorthosilicate PET/CT images. PMID- 19443587 TI - Vascular inflammation imaging with 18F-FDG PET/CT: when to image? AB - We prospectively investigated the ideal imaging time to measure vascular uptake after injection of (18)F-FDG. METHODS: A total of 17 patients with atherosclerotic abdominal aortic aneurysm underwent dynamic abdominal PET/CT using 2-min frames between 45 and 53, 57 and 65, 115 and 123, and 175 and 183 min after injection of (18)F-FDG. For each period of dynamic imaging, vessel wall and lumen uptake were measured using the maximum standardized uptake value (SUV(max)) and target-to-background ratio (TBR). RESULTS: No significant difference in TBR across all time points (repeated measures ANOVA, P = 0.206) was observed, despite a significant difference in aortic wall and lumen uptake with time (repeated measures ANOVA, P = 0.02 and P < 0.001, respectively). There was no significant difference between aortic wall uptake at 60 min (SUV(max), 2.15 +/- 0.11 SE) and 180 min (SUV(max), 1.99 +/- 0.18 SE) (paired t test, P = 0.367). There was a significant difference in lumen uptake at 60 min (SUV(max), 2.4 +/- 0.11 SE) and 180 min (SUV(max), 1.7 +/- 0.1 SE) (paired t test, P = 0.001). There was no significant difference in TBR between 60 min (0.91 +/- 0.03) and 180 min (1.01 +/ 0.06 SE) (paired t test, P = 0.131). With increasing delayed imaging, there was increasing variability (SE) in the SUV(max) for the aortic wall and TBRs. CONCLUSION: There was no significant advantage in imaging at 3 h over 1 h after (18)F-FDG injection. PMID- 19443589 TI - Cerebral histamine H1 receptor binding potential measured with PET under a test dose of olopatadine, an antihistamine, is reduced after repeated administration of olopatadine. AB - Some antihistamine drugs that are used for rhinitis and pollinosis have a sedative effect as they enter the brain and block the H(1) receptor, potentially causing serious accidents. Receptor occupancy has been measured with PET under single-dose administration in humans to classify antihistamines as more sedating or as less sedating (or nonsedating). In this study, the effect of repeated administration of olopatadine, an antihistamine, on the cerebral H(1) receptor was measured with PET. METHODS: A total of 17 young men with rhinitis underwent dynamic brain PET with (11)C-doxepin at baseline, under an initial single dose of 5 mg of olopatadine (acute scan), and under another 5-mg dose after repeated administration of olopatadine at 10 mg/d for 4 wk (chronic scan). The H(1) receptor binding potential was estimated using Logan graphical analysis with cerebellum as reference region input. RESULTS: The acute scan showed a slight decrease in H(1) receptor binding potential across the cerebral cortex (by 15% in the frontal cortex), but the chronic scan showed a marked decrease (by 45% from the acute scan in the frontal cortex). Behavioral data before and after the PET scans did not reveal any sedative effect. CONCLUSION: The results may be interpreted as either intracerebral accumulation of olopatadine or H(1) receptor downregulation due to repeated administration. The study shows feasibility and potential value for PET in evaluating the pharmacologic effect of a drug not only after a single dose but also after repeated administration. PMID- 19443590 TI - Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors. AB - The treatment of metastatic neuroendocrine tumors depends on the aggressiveness of the disease. We wanted to know whether (18)F-FDG PET and somatostatin receptor scintigraphy (SRS) can predict early disease progression and patient survival. METHODS: We undertook a prospective study of patients with metastatic neuroendocrine tumor diagnosed between September 2003 and January 2006. After obtaining signed informed consent from the patients, we performed CT, SRS, and (18)F-FDG PET and reviewed histologic data. CT was repeated every 3 mo to assess the risk of early progressive disease (first 6 mo), progression-free survival, and overall survival. RESULTS: Thirty-eight patients (mean age, 60 +/- 15 y) were included. Histologically, 4 patients had a high-grade and 34 a low-grade tumor. The results of (18)F-FDG PET and SRS were positive in 15 and 27 patients. The 2-y overall survival and progression-free survival were 73% and 45%; 16 patients had early progressive disease. Most (18)F-FDG PET-positive patients had early progressive disease (14/15, vs. 2/23 (18)F-FDG PET-negative patients), and most SRS-negative patients had early progressive disease (9/11, vs. 7/27 SRS-positive patients); (18)F-FDG PET gave excellent negative and positive predictive values of 91% and 93%; (18)F-FDG PET results correlated with progression-free survival (P < 0.001) and overall survival (P < 0.001) even when only low-grade tumors were considered. SRS was associated with progression-free survival (P < 0.001) and overall survival (P < 0.03). At multivariate analysis, only (18)F-FDG PET was predictive of progression-free survival. CONCLUSION: (18)F-FDG PET exhibits excellent predictive values for early tumor progression. (18)F-FDG PET and SRS results correlate with progression-free survival and overall survival even for histologically low-grade tumors. These explorations could be included in the initial work-up for metastatic neuroendocrine tumor. PMID- 19443591 TI - Noninvasive 64Cu-ATSM and PET/CT assessment of hypoxia in rat skeletal muscles and tendons during muscle contractions. AB - The purpose of the present study was to investigate exercise-related changes in oxygenation in rat skeletal muscles and tendons noninvasively with PET/CT and the hypoxia-selective tracer (64)Cu-diacetyl bis(N(4)-methylthiosemicarbazone) (ATSM) and to quantitatively study concomitant changes in gene expression of 2 hypoxia related genes, hypoxia-inducible factor 1alpha (HIF1alpha) and carbonic anhydrase III (CAIII). METHODS: Two groups of Wistar rats performed 1-leg contractions of the calf muscle by electrostimulation of the sciatic nerve. After 10 min of muscle contractions, (64)Cu-ATSM was injected and contractions were continued for 20 min. PET/CT of both hind limbs was performed immediately and 1 h after the contractions. The exercise group (n = 8) performed only muscle contractions as described, whereas the other group, exercise plus cuff (n = 8), in addition underwent cuff-induced hypoxia during the first PET/CT scan. Standardized uptake values (SUVs) were calculated for the Achilles tendons and triceps surae muscles and were correlated to gene expression of HIF1alpha and CAIII using real-time polymerase chain reaction. RESULTS: Immediately after the contractions, uptake of (64)Cu-ATSM was significantly increased, by approximately 1.5-fold in muscles and 1.3-fold in tendons, compared with resting conditions. The significant increase was maintained in late PET scans in stimulated muscles and tendons independently of cuff application. In muscles, SUV correlated significantly with gene expression of HIF1alpha and CAIII, whereas this coherence was not found in tendons. CONCLUSION: We found enhanced uptake of (64)Cu-ATSM in both early and late PET scans, thereby supporting the possibility that (64)Cu-ATSM registers exercise-induced transient hypoxia in both skeletal muscles and force transmitting tendons. The fact that skeletal muscles but not tendons showed upregulation of HIF1alpha and CAIII could indicate that healthy tendons are less responsive than skeletal muscles to low levels of oxygen. PMID- 19443592 TI - Uptake of 18F-labeled 6-fluoro-6-deoxy-D-glucose by skeletal muscle is responsive to insulin stimulation. AB - We are developing a methodology for the noninvasive imaging of glucose transport in vivo with PET and (18)F-labeled 6-fluoro-6-deoxy-d-glucose ((18)F-6FDG), a tracer that is transported but not phosphorylated. To validate the method, we evaluated the biodistribution of (18)F-6FDG to test whether it is consistent with the known properties of glucose transport, particularly with regard to insulin stimulation of glucose transport. METHODS: Under glucose clamp conditions, rats were imaged at the baseline and under conditions of hyperinsulinemia. RESULTS: The images showed that the radioactivity concentration in skeletal muscle was higher in the presence of insulin than at the baseline. We also found evidence that the metabolism of (18)F-6FDG was negligible in several tissues. CONCLUSION: (18)F-6FDG is a valid tracer that can be used in in vivo transport studies. PET studies performed under glucose clamp conditions demonstrated that the uptake of nonphosphorylated glucose transport tracer (18)F-6FDG is sensitive to insulin stimulation. PMID- 19443594 TI - A novel method of 18F radiolabeling for PET. AB - Small biomolecules are typically radiolabeled with (18)F by binding it to a carbon atom, a process that usually is designed uniquely for each new molecule and requires several steps and hours to produce. We report a facile method wherein (18)F is first attached to aluminum as Al(18)F, which is then bound to a chelate attached to a peptide, forming a stable Al(18)F-chelate-peptide complex in an efficient 1-pot process. METHODS: For proof of principle, this method was applied to a peptide suitable for use in a bispecific antibody pretargeting method. A solution of AlCl(3).6H(2)O in a pH 4.0 sodium-acetate buffer was mixed with an aqueous solution of (18)F to form the Al(18)F complex. This was added to a solution of IMP 449 (NOTA-p-Bn-CS-d-Ala-d-Lys(HSG)-d-Tyr-d-Lys(HSG)-NH(2)) (NOTA-p-Bn-CS is made from S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane 1,4,7-triacetic acid; HSG is histamine-succinyl-glycine) and heated to 100 degrees C for 15 min. In vitro and in vivo stability and targeting ability of the Al(18)F-IMP 449 were examined in nude mice bearing LS174T human colonic tumors pretargeted with an anti-CEACAM5 bispecific antibody (TF2). RESULTS: The radiolabeled peptide was produced in 5%-20% yield with an estimated specific activity of 18,500-48,100 GBq (500-1,300 Ci)/mmol. The Al(18)F-IMP 449 was stable for 4 h in serum in vitro, and in animals, activity isolated in the urine 30 min after injection was bound to the peptide. Nonchelated Al(18)F had higher tissue uptake, particularly in the bones, than the chelated Al(18)F-IMP 449, which cleared rapidly from the body by urinary excretion. Tumor uptake was 30-fold higher with TF2-pretargeted Al(18)F-IMP 449 than with the peptide alone. Dynamic PET showed tumor localization within 30 min and rapid and thorough clearance from the body. CONCLUSION: The ability to bind highly stable Al(18)F to metal-binding ligands is a promising new labeling method that should be applicable to a diverse array of molecules for PET. PMID- 19443595 TI - Quantification of cerebral glucose metabolic rate in mice using 18F-FDG and small animal PET. AB - The aim of this study was to evaluate various methods for estimating the metabolic rate of glucose utilization in the mouse brain (cMR(glc)) using small animal PET and reliable blood curves derived by a microfluidic blood sampler. Typical values of (18)F-FDG rate constants of normal mouse cerebral cortex were estimated and used for cMR(glc) calculations. The feasibility of using the image derived liver time-activity curve as a surrogate input function in various quantification methods was also evaluated. METHODS: Thirteen normoglycemic C57BL/6 mice were studied. Eighteen blood samples were taken from the femoral artery by the microfluidic blood sampler. Tissue time-activity curves were derived from PET images. cMR(glc) values were calculated using 2 different input functions (one derived from the blood samples [IF(blood)] and the other from the liver time-activity curve [IF(liver)]) in various quantification methods, which included the 3-compartment (18)F-FDG model (from which the (18)F-FDG rate constants were derived), the Patlak analysis, and operational equations. The estimated cMR(glc) value based on IF(blood) and the 3-compartment model served as a standard for comparisons with the cMR(glc) values calculated by the other methods. RESULTS: The values of K(1), k(2), k(3), k(4), and K(FDG) estimated by IF(blood) and the 3-compartment model were 0.22 +/- 0.05 mL/min/g, 0.48 +/- 0.09 min(-1), 0.06 +/- 0.02 min(-1), 0.025 +/- 0.010 min(-1), and 0.024 +/- 0.007 mL/min/g, respectively. The standard cMR(glc) value was, therefore, 40.6 +/- 13.3 micromol/100 g/min (lumped constant = 0.6). No significant difference between the standard cMR(glc) and the cMR(glc) estimated by the operational equation that includes k(4) was observed. The standard cMR(glc) was also found to have strong correlations (r > 0.8) with the cMR(glc) value estimated by the use of IF(liver) in the 3-compartment model and with those estimated by the Patlak analysis (using either IF(blood) or IF(liver)). CONCLUSION: The (18)F-FDG rate constants of normal mouse cerebral cortex were determined. These values can be used in the k(4)-included operational equation to calculate cMR(glc). IF(liver) can be used to estimate cMR(glc) in most methods included in this study, with proper linear corrections applied. The validity of using the Patlak analysis for estimating cMR(glc) in mouse PET studies was also confirmed. PMID- 19443596 TI - Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis. AB - Assessment of the activity of rheumatoid arthritis (RA) is important for the prediction of future articular destruction. (18)F-FDG PET is known to represent the metabolic activity of inflammatory disease, which correlates with the pannus volume measured by MRI or ultrasonography. To evaluate the correlation between (18)F-FDG accumulation and RA pathology, we assessed (18)F-FDG accumulation in vivo using collagen-induced arthritis (CIA) animal models and (3)H-FDG uptake in vitro using various cells involved in arthritis. METHODS: (18)F-FDG PET images of rats with CIA were acquired on days 10, 14, and 17 after arthritis induction. The specimens were subsequently subjected to macroautoradiography, and the (18)F-FDG accumulation was compared with the histologic findings. (3)H-FDG uptake in vitro in inflammatory cells (neutrophils, macrophages, T cells, and fibroblasts) was measured to evaluate the contributions of these cells to (18)F-FDG accumulation. In addition, the influence on (3)H-FDG uptake of inflammatory factors, such as cytokines (tumor necrosis factor alpha [TNFalpha], interleukin 1 [IL-1], and IL 6), and hypoxia was examined. RESULTS: (18)F-FDG PET depicted swollen joints, and (18)F-FDG accumulation increased with the progression of arthritis. Histologically, a higher level of (18)F-FDG accumulation correlated with the pannus rather than the infiltration of inflammatory cells around the joints. In the in vitro (3)H-FDG uptake assay, fibroblasts showed the highest (3)H-FDG uptake, followed by neutrophils. Although only a small amount of (3)H-FDG was incorporated by resting macrophages, a dramatic increase in (3)H-FDG uptake in both fibroblasts and macrophages was observed when these cells were exposed to inflammatory cytokines, such as TNFalpha and IL-1, and hypoxia. Although neutrophils showed relatively high (3)H-FDG uptake without activation, no increase in (3)H-FDG uptake was observed in response to inflammatory cytokines. (3)H-FDG uptake by T cells was much lower than that by other cells. Thus, fibroblasts and activated macrophages contribute to a high level of (18)F-FDG accumulation in the pannus, and hypoxia as well as cytokine stimulation significantly increases (18)F-FDG uptake by these cells. CONCLUSION: (18)F-FDG accumulation in RA reflects proliferating pannus and inflammatory activity enhanced by inflammatory cytokines and hypoxia. (18)F-FDG PET should be effective for quantifying the inflammatory activity of RA. PMID- 19443597 TI - Comparison of 18F-FDG and PiB PET in cognitive impairment. AB - The purpose of this study was to compare the diagnostic accuracy of glucose metabolism and amyloid deposition as demonstrated by (18)F-FDG and Pittsburg Compound B (PiB) PET to evaluate subjects with cognitive impairment. METHODS: Subjects were selected from existing participants in the Mayo Alzheimer's Disease Research Center or Alzheimer's Disease Patient Registry programs. A total of 20 healthy controls and 17 amnestic mild cognitive impairment (aMCI), 6 nonamnestic mild cognitive impairment (naMCI), and 13 Alzheimer disease (AD) subjects were imaged with both PiB and (18)F-FDG PET between March 2006 and August 2007. Global measures for PiB and (18)F-FDG PET uptake, normalized to cerebellum for PiB and pons for (18)F-FDG, were compared. Partial-volume correction, standardized uptake value (SUV), and cortical ratio methods of image analysis were also evaluated in an attempt to optimize the analysis for each test. RESULTS: Significant discrimination (P < 0.05) between controls and AD, naMCI and aMCI, naMCI and AD, and aMCI and AD by PiB PET measurements was observed. The paired groupwise comparisons of the global measures demonstrated that PiB PET versus (18)F-FDG PET showed similar significant group separation, with only PiB showing significant separation of naMCI and aMCI subjects. CONCLUSION: PiB PET and (18)F-FDG PET have similar diagnostic accuracy in early cognitive impairment. However, significantly better group discrimination in naMCI and aMCI subjects by PiB, compared with (18)F-FDG, was seen and may suggest early amyloid deposition before cerebral metabolic disruption in this group. PMID- 19443598 TI - Imaging of HIF-1-active tumor hypoxia using a protein effectively delivered to and specifically stabilized in HIF-1-active tumor cells. AB - Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumor progression and in the development of resistance to radiotherapy. We designed a novel fusion protein (PTD-ODD-SAV [POS]) consisting of a protein transduction domain (PTD), streptavidin (SAV), and a portion of the oxygen-dependent degradation domain (ODD) of HIF-1alpha that confers the same oxygen-dependent regulation as HIF-1alpha on POS. (3-(123/125)I-iodobenzoyl)norbiotinamide ((123/125)I-IBB) was conjugated to the SAV moiety of POS to synthesize (123/125)I IBB-labeled POS ((123/125)I-IPOS). The purpose of this study was to evaluate the feasibility of (123)I-IPOS as an imaging probe for HIF-1-active tumor hypoxia. METHODS: After a 24-h incubation of (125)I-IPOS with various tumor cell lines under either normoxic (20% O(2)) or hypoxic (0.1% O(2)) conditions, the intracellular radioactivity was investigated. Then, the biodistribution of (123/125)I-IPOS was examined with tumor-implanted mice, and an in vivo imaging study was performed. The tumoral accumulation of (125)I-IPOS was compared with HIF-1 activity using the mice carrying tumors with the HIF-1-dependent luciferase reporter gene. Furthermore, the intratumoral localization of (125)I-IPOS was examined by the autoradiographic study, and then the same slide was subjected to immunostaining for pimonidazole, which is the hypoxic marker. RESULTS: The ratios of radioactivity in hypoxic cells to that in normoxic cells were more than 2. These results indicate incorporation of (125)I-IPOS into these cells and degradation of (125)I-IPOS by normoxic tumor cells. In the biodistribution study, (125)I-IPOS accumulated in the tumor (1.4 +/- 0.3 percentage injected dose per gram) 24 h after administration. At that time, (125)I-IPOS showed high tumor-to blood and tumor-to-muscle ratios (5.1 +/- 0.3 and 14.0 +/- 3.9, respectively). The tumors were clearly visualized by in vivo imaging 24 h after (123)I-IPOS injection (tumor-to-muscle ratio was 9.6). The tumoral accumulation of (125)I IPOS correlated with HIF-1 activity (R = 0.71, P < 0.05), and its intratumoral distribution coincided with the hypoxic regions. CONCLUSION: (123)I-IPOS is a potential probe for the imaging of HIF-1 activity in tumors. Given the role of HIF-1 in tumor biology, its detection may be considered an indicator of aggressive cancer phenotypes. PMID- 19443599 TI - Transarterial injection of (131)I-lipiodol, compared with chemoembolization, in the treatment of unresectable hepatocellular cancer. AB - Transarterial chemoembolization (TACE) improves survival in patients with hepatocellular carcinoma (HCC) in whom curative therapies are not suitable. The aim of this study was to assess survival differences in patients with hepatic cirrhosis and unresectable HCC treated by (131)I-lipiodol versus TACE or transarterial embolization (TAE). METHODS: A retrospective study was performed on a cohort of 124 patients undergoing treatment for unresectable HCC between 1997 and 2006. A total of 50 patients (44 men; mean age, 59 y) received (131)I lipiodol (mean sessions per patient, 1.7), and 74 patients (63 men; mean age, 61 y) received TACE/TAE (mean sessions per patient, 1.8). Although no significant difference between the 2 treatment groups with respect to HCC size and clinical staging was observed, a higher proportion of patients with portal vein thrombosis (PVT) was treated with (131)I-lipiodol than with TACE/TAE (28% vs. 8%, P = 0.003). RESULTS: Actuarial survival was not significantly different between patients treated with (131)I-lipiodol and patients treated with TACE/TAE. Survival at 6 mo, 1 y, 2 y, and 3 y was 86%, 69%, 54%, and 45%, respectively, after (131)I-lipiodol, compared with 77%, 62%, 47%, and 43%, respectively, after TACE/TAE. However, patients with PVT survived a mean of 454 d after (131)I lipiodol, compared with a mean of 171 d after TACE/TAE (P = 0.025). In addition, patients with more advanced disease (Barcelona Clinic Liver Cancer stage D) lived on average 363 d after (131)I-lipiodol, compared with 36 d after TACE/TAE (P = 0.014). CONCLUSION: In patients with unresectable HCC, there was no difference in survival between (131)I-lipiodol therapy and TACE/TAE treatment. However, in the patients with advanced clinical staging or PVT, there was a significant survival advantage for those treated with (131)I-lipiodol. PMID- 19443600 TI - PET of glial metabolism using 2-18F-fluoroacetate. AB - Imaging of the glial activation that occurs in response to central nervous system trauma and inflammation could become a powerful technique for the assessment of several neuropathologies. The selective uptake and metabolism of 2-(18)F fluoroacetate ((18)F-FAC) in glia may represent an attractive strategy for imaging glial metabolism. METHODS: We have evaluated the use of (18)F-FAC as a specific PET tracer of glial cell metabolism in rodent models of glioblastoma, stroke, and ischemia-hypoxia. RESULTS: Enhanced uptake of (18)F-FAC was observed (6.98 +/- 0.43 percentage injected dose per gram [%ID/g]; tumor-to-normal ratio, 1.40) in orthotopic U87 xenografts, compared with healthy brain tissue. The lesion extent determined by (18)F-FAC PET correlated with that determined by MRI (R(2) = 0.934, P = 0.007). After transient middle cerebral artery occlusion in the rat brain, elevated uptake of (18)F-FAC (1.00 +/- 0.03 %ID/g; lesion-to normal ratio, 1.90) depicted the ischemic territory and correlated with infarct volumes as determined by 2,3,5-triphenyltetrazolium chloride staining (R(2) = 0.692, P = 0.010) and with the presence of activated astrocytes detected by anti glial fibrillary acidic protein. Ischemia-hypoxia, induced by permanent ligation of the common carotid artery with transient hypoxia, resulted in persistent elevation of (18)F-FAC uptake within 30 min of the induction of hypoxia. CONCLUSION: Our data support the further evaluation of (18)F-FAC PET for the assessment of glial cell metabolism associated with neuroinflammation. PMID- 19443601 TI - Simple ratio analysis of 18F-fluorodopa uptake in striatal subregions separates patients with early Parkinson disease from healthy controls. AB - 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) is widely used to investigate dopaminergic hypofunction, for instance, in Parkinson disease (PD). Conventionally, a 90-min scan with either a graphical or a metabolite-purified plasma input approach has been used for quantification. In the clinical setting, to increase compliance, especially in patients with more advanced disease, and to increase the efficacy of tracer and scanner time use, a shorter acquisition and a simple quantitative analysis are desirable. Taking into account the asymmetry of clinical symptoms and the uneven distribution of striatal dopaminergic hypofunction may also improve the use of (18)F-FDOPA PET in early disease detection. Therefore, we compared subregional striatal (18)F-FDOPA PET data from a large group of nonmedicated patients with early PD and a set of healthy elderly volunteers to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. METHODS: A total of 89 nonmedicated patients with early PD and 21 healthy volunteers were studied with (18)F-FDOPA PET, and both a region-to reference (striatal-to-occipital) ratio (SOR) calculated from 75 to 90 min after injection and a graphical analysis of data calculated from 15 to 90 min after (18)F-FDOPA injection (yielding the influx constant [K(i)(ref)]) were used. RESULTS: Both SOR and K(i)(ref) values in the PD patients were lowest, relative to those in the healthy controls, in the posterior putamen contralateral to the side with predominant clinical symptoms. The contralateral posterior putamen showed the largest areas under the receiver operating characteristic (ROC) curve 0.994 for SOR and 0.998 for K(i)(ref)-indicating excellent separation of the PD and control groups. The caudate nucleus and the ventral striatum were less impressive in this respect. CONCLUSION: A single 15-min scan 75 min after tracer injection seems to be sufficient for separating patients with PD from healthy controls in a clinical research environment. This method represents a powerful and economical alternative for research on the disease mechanism and differential diagnosis. PMID- 19443603 TI - 2-18F-fluoroacetate: a useful tool for assessing gliosis in the central nervous system? PMID- 19443605 TI - SPECT/CT. PMID- 19443604 TI - Physiologic thymic uptake of 18F-FDG in children and young adults: a PET/CT evaluation of incidence, patterns, and relationship to treatment. AB - (18)F-FDG uptake in the thymus, mainly related to hyperplasia after chemotherapy, has been described. Thymic uptake can challenge the accurate assessment of cancer patients by (18)F-FDG imaging. The present study defines the incidence, patterns, and intensity of thymic (18)F-FDG uptake in relationship to age and time after treatment in a large cohort of patients. METHODS: A total of 559 consecutive (18)F-FDG PET/CT studies in 160 patients (86 men, 74 women; age, 3-40 y) performed at baseline, during treatment, at the end of treatment, and during follow-up were retrospectively reviewed. PET/CT studies were assessed for the presence or absence (T+ or T-, respectively), pattern, and intensity (SUVmax) of increased (18)F-FDG uptake in the anterior mediastinum, localized by the CT component to the thymus. The overall incidence of (18)F-FDG avidity in the thymus in relationship to the patient's age and time after treatment administration were statistically evaluated. RESULTS: There were 137 of 559 T+ studies (25%), with equal sex distribution. T+ studies were found in significantly younger patients (20.6 +/- 9.3 y vs. 27.4 +/- 8.4 y, P < 0.001). Most T+ patients (60%) showed an inverted V pattern of thymic uptake, with additional unilateral mediastinal extension in 24% and focal midline uptake in 16% of studies. T+ studies were encountered in 80% of patients younger than 10 y, compared with 8% of patients in the 31- to 40-y age group. There were 17% T+ studies at baseline, 6% during treatment, 8% at the end of treatment, and 27%-40% during follow-up. The average SUVmax of thymic (18)F-FDG uptake was 3.73 +/- 1.22. CONCLUSION: Thymic (18)F-FDG uptake was found in 28% of the present study population, more frequently after treatment. T+ patients were significantly younger. Thymic uptake was found in 73% of untreated patients up to the age of 13 y and in 8% of patients in the fourth decade of life. Knowledge of this age- and treatment-related incidence of physiologic thymic (18)F-FDG avidity can reduce the number of potential pitfalls in reporting PET/CT studies in cancer patients. PMID- 19443606 TI - The signal pathway of gonadotrophins-induced mammalian oocyte meiotic resumption. AB - Fully grown mammalian oocytes are arrested at the first meiotic prophase until a surge of gonadotrophin at the mid-cycle. The actions of gonadotrophins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), on oocyte meiotic resumption are believed to be mediated in large part through increasing the production of cyclic adenosine 3',5'-monophosphate and subsequent activation of mitogen-activated protein kinase (MAPK) in its surrounding cumulus granulosa cells. Recent findings indicate that gonadotrophins-induced epidermal growth factor-like growth factors, meiosis activating sterol and gonadal steroid hormones, possibly via protein kinase A II and protein kinase C pathways, are involved in the activation of MAPK. Another second messenger cyclic guanosine 3',5'-monophosphate induced by nitric oxide or natriuretic peptides system mediates the function of gonadotrophins during oocyte meiotic resumption. FSH and LH induced pathways may either directly overlap or each hormone may utilize redundant pathways in oocyte maturation. A detailed appreciation of different FSH and LH-activated signaling pathways in mammalian oocytes will be needed in understanding their actions in follicular development and oocyte maturation. PMID- 19443607 TI - Signaling pathways implicated in the stimulation of beta-cell proliferation by extracellular matrix. AB - Laminin-5-rich extracellular matrix derived from 804G cells (804G-ECM) induces spreading, improves glucose-stimulated insulin secretion, and increases survival and proliferation of rat pancreatic beta-cells. The aim of the study was to determine growth signaling pathways activated by ECM with a particular focus on Ca(2+)-dependent transcription factors. 804G-ECM increased rat beta-cell proliferation, and this stimulation was glucose and Ca(2+) dependent. NF-kappaB nuclear translocation as well as IkappaBalpha gene expression were also Ca(2+) dependent. Inhibition of NF-kappaB almost completely blocked 804G-ECM-stimulated beta-cell proliferation as did the soluble IL-1 receptor antagonist IL-1Ra. 804G ECM-induced proliferation was also blocked by cyclosporin A and the VIVIT peptide, suggesting involvement of nuclear factor of activated T cells (NFAT)/calcineurin. Use of selective inhibitors further implicated other pathways in this process. Inhibition of phosphatidylinositol 3-kinase and protein kinase A both prevented beta-cell replication stimulated by 804G-ECM. Conversely, inhibition of MAPK, c-Jun N-terminal kinase, p38, and glycogen synthase kinase 3beta increased beta-cell proliferation on 804G-ECM. Our results suggest that Ca(2+) entry, which is necessary for increased beta-cell proliferation on 804G ECM, is also involved in 804G-ECM-induced NF-kappaB activity. It is proposed that increased cytosolic Ca(2+) leads to activation of the transcription factors NFAT and NF-kappaB that in turn increase beta-cell proliferation. Activation of phosphatidylinositol 3-kinase by 804G-ECM also increases proliferation possibly by synergistic coactivation of NFAT via inhibition of glycogen synthase kinase 3beta, whereas IL-1beta may amplify the process by feed-forward activation of NF kappaB. Conversely, inhibition of the MAPK pathway increased beta-cell proliferation, indicating a counterregulatory restraining role for this signaling pathway. PMID- 19443608 TI - Kinetic and thermodynamic characterization of dihydrotestosterone-induced conformational perturbations in androgen receptor ligand-binding domain. AB - Ligand-induced conformational perturbations in androgen receptor (AR) are important in coactivator recruitment and transactivation. However, molecular rearrangements in AR ligand-binding domain (AR-LBD) associated with agonist binding and their kinetic and thermodynamic parameters are poorly understood. We used steady-state second-derivative absorption and emission spectroscopy, pressure and temperature perturbations, and 4,4'-bis-anilinonaphthalene 8 sulfonate (bis-ANS) partitioning to determine the kinetics and thermodynamics of the conformational changes in AR-LBD after dihydrotestosterone (DHT) binding. In presence of DHT, the second-derivative absorption spectrum showed a red shift and a change in peak-to-peak distance. Emission intensity increased upon DHT binding, and center of spectral mass was blue shifted, denoting conformational changes resulting in more hydrophobic environment for tyrosines and tryptophans within a more compact DHT-bound receptor. In pressure perturbation calorimetry, DHT induced energetic stabilization increased the Gibbs free energy of unfolding to 8.4 +/- 1.3 kcal/mol from 3.5 +/- 1.6 kcal/mol. Bis-ANS partitioning studies revealed that upon DHT binding, AR-LBD underwent biphasic rearrangement with a high activation energy (13.4 kcal/mol). An initial, molten globule-like burst phase (k approximately 30 sec(-1)) with greater solvent accessibility was followed by rearrangement (k approximately 0.01 sec(-1)), leading to a more compact conformation than apo-AR-LBD. Molecular simulations demonstrated unique sensitivity of tyrosine and tryptophan residues during pressure unfolding with rearrangement of residues in the coactivator recruitment surfaces distant from the ligand-binding pocket. In conclusion, DHT binding leads to energetic stabilization of AR-LBD domain and substantial rearrangement of residues distant from the ligand-binding pocket. DHT binding to AR-LBD involves biphasic receptor rearrangement including population of a molten globule-like intermediate state. PMID- 19443609 TI - Direct effect of glucocorticoids on lipolysis in adipocytes. AB - Hypercortisolemia and glucocorticoid treatment cause elevated level of circulating free fatty acids (FFAs). The basis of this phenomenon has long been linked to the effect of glucocorticoids permitting and enhancing the adipose lipolysis response to various hormones. In this study, we demonstrate that glucocorticoids directly stimulate lipolysis in rat primary adipocytes in a dose- and time-responsive manner; this lipolytic action was attenuated by treatment with the glucocorticoid antagonist RU486. Dexamethasone down-regulates mRNA and protein levels of cyclic-nucleotide phosphodiesterase 3B, thereby elevating cellular cAMP production and activating protein kinase A (PKA). On inhibition of PKA but not other kinases, the lipolysis response ceases. Furthermore, dexamethasone induces phosphorylation and down-regulation of perilipin, a lipid droplet-associating protein that modulates lipolysis; this effect is restored by RU486 or PKA inhibitor H89. Dexamethasone up-regulates mRNA and protein levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase; these effects, parallel to increased lipolysis, are attenuated by RU486 or actinomycin D. Phosphorylation at Ser-563 and Ser-660 residues of HSL and activity of cellular lipases are elevated on dexamethasone stimulation but abrogated by the coaddition of H89. However, dexamethasone does not induce HSL translocation to the lipid droplet surface in differentiated adipocytes. We show that elevated FFA concentration in plasma is associated with increased lipase activity and lipolysis in vivo in adipose tissues of dexamethasone-treated rats. Therefore, the lipolytic action of glucocorticoids liberates FFA efflux from adipocytes to the bloodstream, which could be a cellular basis of systemic FFA elevation in response to glucocorticoid challenge. PMID- 19443611 TI - The role of MTOR in mouse uterus during embryo implantation. AB - Mammalian target of rapamycin (MTOR) is a protein kinase that plays a central role in cell growth and proliferation. It is a part of the signaling network transmitting growth factor signaling to translational control. Previous studies have shown that MTOR is involved in embryo implantation, but its expression in the uterus and its role in implantation are unclear. Here, we have investigated the expression and role of MTOR in mouse uterus during early pregnancy. RT-FQ PCR showed that the mRNA levels of Mtor in endometria of pregnant mice were higher than those of nonpregnant mice. The mRNA levels in the pregnant mice gradually increased from D3 of pregnancy, reached maximum on D5, and then declined afterward. In situ hybridization and immunohistochemical analysis showed that the mRNA and protein of MTOR were mainly located in stromal cells. The levels of the expressed MTOR protein correlate with those of mRNA. The number of implantation sites was greatly decreased by the intrauterine injection with rapamycin in the early morning of D4 of the pregnancy. These findings suggest that MTOR may play an important role in embryo implantation in mice. PMID- 19443612 TI - Increasing intakes of the long-chain omega-3 docosahexaenoic acid: effects on platelet functions and redox status in healthy men. AB - Docosahexaenoic acid (DHA) can prevent cardiovascular events. However, few studies have addressed the effects of DHA on both platelet reactivity and redox status in healthy subjects, and dose-related studies are scarce. The main objectives of the present study were to determine the effects of increasing doses of DHA on platelets and redox status in humans. Twelve healthy male volunteers (aged 53-65 yr) were assigned to consume an intake of successively 200, 400, 800, and 1600 mg/d DHA, as the only omega-3 fatty acid, for 2 wk each dose. Blood and urine samples were collected before and after each dose of DHA and at 8 wk after arrest of supplementation. DHA was incorporated in a dose-response fashion in platelet phospholipids. After supplementation with 400 and 800 mg/d DHA, platelet reactivity was significantly decreased. Platelet vitamin E concentration increased only after 200 mg/d DHA, while p38 MAP kinase phosphorylation decreased. Urinary isoprostane was also significantly lowered after 200 mg/d DHA but was increased after 1600 mg/d. Therefore, supplementation with only 200 mg/d DHA for 2 wk induced an antioxidant effect. It is concluded that low consumption of DHA could be an effective and nonpharmacological way to protect healthy men from platelet-related cardiovascular events. PMID- 19443613 TI - Leaf gas exchange, carbon isotope discrimination, and grain yield in contrasting rice genotypes subjected to water deficits during the reproductive stage. AB - Genotypic variations in leaf gas exchange and yield were analysed in five upland adapted and three lowland rice cultivars subjected to a differential soil moisture gradient, varying from well-watered to severely water-stressed conditions. A reduction in the amount of water applied resulted in a significant decrease in leaf gas exchange and, subsequently, in above-ground dry mass and grain yield, that varied among genotypes and distance from the line source. The comparison between the variable J and the Delta values in recently synthesized sugars methods, yielded congruent estimations of mesophyll conductance (g(m)), confirming the reliability of these two techniques. Our data demonstrate that g(m) is a major determinant of photosynthesis (A), because rice genotypes with inherently higher g(m) were capable of keeping higher A in stressed conditions. Furthermore, A, g(s), and g(m) of water-stressed genotypes rapidly recovered to the well-watered values upon the relief of water stress, indicating that drought did not cause any lasting metabolic limitation to photosynthesis. The comparisons between the A/C(i) and corresponding A/C(c) curves, measured in the genotypes that showed intrinsically higher and lower instantaneous A, confirmed this finding. Moreover, the effect of drought stress on grain yield was correlated with the effects on both A and total diffusional limitations to photosynthesis. Overall, these data indicate that genotypes which showed higher photosynthesis and conductances were also generally more productive across the entire soil moisture gradient. The analysis of Delta revealed a substantial variation of water use efficiency among the genotypes, both on the long-term (leaf pellet analysis) and short-term scale (leaf soluble sugars analysis). PMID- 19443614 TI - Altered expression of cytosolic/nuclear HSC70-1 molecular chaperone affects development and abiotic stress tolerance in Arabidopsis thaliana. AB - Molecular chaperones of the heat shock cognate 70 kDa (HSC70) family are highly conserved in all living organisms and assist nascent protein folding in normal physiological conditions as well as in biotic and abiotic stress conditions. In the absence of specific inhibitors or viable knockout mutants, cytosolic/nuclear HSC70-1 overexpression (OE) and mutants in the HSC70 co-chaperone SGT1 (suppressor of G(2)/M allele of skp1) were used as genetic tools to identify HSC70/SGT1 functions in Arabidopsis development and abiotic stress responses. HSC70-1 OE caused a reduction in root and shoot meristem activities, thus explaining the dwarfism of those plants. In addition, HSC70-1 OE did not impair auxin-dependent phenotypes, suggesting that SGT1 functions previously identified in auxin signalling are HSC70 independent. While responses to abiotic stimuli such as UV-C exposure, phosphate starvation, or seedling de-etiolation were not perturbed by HSC70-1 OE, it specifically conferred gamma-ray hypersensitivity and tolerance to salt, cadmium (Cd), and arsenic (As). Cd and As perception was not perturbed, but plants overexpressing HSC70-1 accumulated less Cd, thus providing a possible molecular explanation for their tolerance phenotype. In summary, genetic evidence is provided for HSC70-1 involvement in a limited set of physiological processes, illustrating the essential and yet specific functions of this chaperone in development and abiotic stress responses in Arabidopsis. PMID- 19443615 TI - Evolution of petal identity. AB - Petals appear in many angiosperm taxa, yet when and how these attractive organs originated remains unclear. Phylogenetic reconstructions based on morphological data suggest that petals have evolved multiple times during the radiation of the angiosperms. Based on the diversity of petal morphologies, it is likely that the developmental programmes specifying petal identity are distinct in different lineages. On the other hand, molecular genetic analyses have suggested that the specification of petal identity in different lineages utilizes similar genetic pathways. Together, these observations indicate that the evolution of petals has relied on the repeated recruitment of a suite of interacting developmental control genes, albeit in different ways in different lineages. These observations suggest that this gene regulatory network represents a 'deep homology' in plant evolution. A major challenge is to understand how this ancestral developmental pathway has been redeployed in different angiosperm lineages, and how changes in the workings of this pathway have led to the myriad shapes, colours, and sizes of petals. PMID- 19443616 TI - Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. AB - OBJECTIVES: Neurocognitive dysfunction is milder in bipolar disorders than in schizophrenia spectrum disorders, supporting a dimensional approach to severe mental disorders. The aim of this study was to investigate the role of lifetime history of psychosis for neurocognitive functioning across these disorders. We asked whether neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends more on history of psychosis than diagnostic category or subtype. METHODS: A sample of individuals with schizophrenia (n=102), schizoaffective disorder (n=27), and bipolar disorder (I or II) with history of psychosis (n=75) and without history of psychosis (n=61) and healthy controls (n=280), from a large ongoing study on severe mental disorder, were included. Neurocognitive function was measured with a comprehensive neuropsychological test battery. RESULTS: Compared with controls, all 3 groups with a history of psychosis performed poorer across neurocognitive measures, while the bipolar group without a history of psychosis was only impaired on a measure of processing speed. The groups with a history of psychosis did not differ from each other but performed poorer than the group without a history of psychosis on a number of neurocognitive measures. These neurocognitive group differences were of a magnitude expected to have clinical significance. In the bipolar sample, history of psychosis explained more of the neurocognitive variance than bipolar diagnostic subtype. CONCLUSIONS: Our findings suggest that neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders is determined more by history of psychosis than by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnostic category or subtype, supporting a more dimensional approach in future diagnostic systems. PMID- 19443617 TI - Food production: reducing water consumption by manipulating long-distance chemical signalling in plants. PMID- 19443620 TI - Functional and chemical comparison of apoplastic barriers to radial oxygen loss in roots of rice (Oryza sativa L.) grown in aerated or deoxygenated solution. AB - Radial oxygen loss (ROL) and root porosity of rice (Oryza sativa L.) plants grown in either aerated or deoxygenated (stagnant) conditions were combined for the first time with extensive histochemical and biochemical studies of the apoplastic barriers in the roots' peripheral cell layers. Growth in stagnant solution significantly affected structural and, consequently, the physiological features of rice roots. It increased adventitious root porosity by about 20% and decreased the ROL towards the base to zero at a distance of 40 mm from the apex. By contrast, roots of plants grown in aerated solutions revealed the highest rates of ROL at 30 mm from the apex. Differences in the ROL pattern along the root were related to histochemical studies, which showed an early development of Casparian bands and suberin lamellae in the exodermis, and lignified sclerenchyma cells in roots of plants grown in deoxygenated solution. In agreement with anatomical studies, absolute contents of suberin and lignin in the outer part of the roots (OPR) were higher in plants grown in deoxygenated solution. Regardless of growth conditions, the levels of suberin and lignin increased along the roots towards the base. It is concluded that radial oxygen loss can be effectively restricted by the formation of a suberized exodermis and/or lignified sclerenchyma in the OPR. However, the relative contribution of suberin and lignin in the formation of a tight barrier is unclear. Knowing the permeability coefficient across OPR for roots of plants grown in both conditions will allow a more precise understanding of the mechanisms controlling ROL. PMID- 19443619 TI - Stilbene synthase gene transfer caused alterations in the phenylpropanoid metabolism of transgenic strawberry (Fragaria x ananassa). AB - The gene encoding stilbene synthase is frequently used to modify plant secondary metabolism with the aim of producing the self-defence phytoalexin resveratrol. In this study, strawberry (Fragaria x ananassa) was transformed with the NS-Vitis3 gene encoding stilbene synthase from frost grape (Vitis riparia) under the control of the cauliflower mosaic virus 35S and the floral filament-specific fil1 promoters. Changes in leaf metabolites were investigated with UPLC-qTOF-MS (ultra performance liquid chromatography-quadrupole time of flight mass spectrometry) profiling, and increased accumulation of cinnamate, coumarate, and ferulate derivatives concomitantly with a decrease in the levels of flavonols was observed, while the anticipated resveratrol or its derivatives were not detected. The changed metabolite profile suggested that chalcone synthase was down regulated by the genetic modification; this was verified by decreased chalcone synthase transcript levels. Changes in the levels of phenolic compounds led to increased susceptibility of the transgenic strawberry to grey mould fungus. PMID- 19443622 TI - The truth about lying: inhibition of the anterior prefrontal cortex improves deceptive behavior. AB - Recent neuroimaging studies have indicated a predominant role of the anterior prefrontal cortex (aPFC) in deception and moral cognition, yet the functional contribution of the aPFC to deceptive behavior remains unknown. We hypothesized that modulating the excitability of the aPFC by transcranial direct current stimulation (tDCS) could reveal its functional contribution in generating deceitful responses. Forty-four healthy volunteers participated in a thief role play in which they were supposed to steal money and then to attend an interrogation with the Guilty Knowledge Test. During the interrogation, participants received cathodal, anodal, or sham tDCS. Remarkably, inhibition of the aPFC by cathodal tDCS did not lead to an impairment of deceptive behavior but rather to a significant improvement. This effect manifested in faster reaction times in telling lies, but not in telling the truth, a decrease in sympathetic skin-conductance response and feelings of guilt while deceiving the interrogator and a significantly higher lying quotient reflecting skillful lying. Increasing the excitability of the aPFC by anodal tDCS did not affect deceptive behavior, confirming the specificity of the stimulation polarity. These findings give causal support to recent correlative data obtained by functional magnetic resonance imaging studies indicating a pivotal role of the aPFC in deception. PMID- 19443621 TI - Cortical connections to area TE in monkey: hybrid modular and distributed organization. AB - To investigate the fine anatomical organization of cortical inputs to visual association area TE, 2-3 small injections of retrograde tracers were made in macaque monkeys. Injections were made as a terminal procedure, after optical imaging and electrophysiological recording, and targeted to patches physiologically identified as object-selective. Retrogradely labeled neurons occurred in several unimodal visual areas, the superior temporal sulcus, intraparietal sulcus (IPS), and prefrontal cortex (PFC), consistent with previous studies. Despite the small injection size (<0.5 mm wide), the projection foci in visual areas, but not in IPS or PFC, were spatially widespread (4-6 mm in extent), and predominantly consisted of neurons labeled by only one of the injections. This can be seen as a quasi-modular organization. In addition, within each projection focus, there were scattered neurons projecting to one of the other injections, together with some double-labeled (DL) neurons, in a more distributed pattern. Finally, projection foci included smaller "hotspots," consisting of intermixed neurons, single-labeled by the different injections, and DL neurons. DL neurons are likely the result of axons having extended, spatially separated terminal arbors, as demonstrated by anterograde experiments. These results suggest a complex, hybrid connectivity architecture, with both modular and distributed components. PMID- 19443623 TI - Population-based corticospinal interactions in macaques are correlated with visuomotor processing. AB - Visuomotor transformation is a fundamental process in executing voluntary actions. The final steps of this transformation are presumed to take place in the corticospinal (CS) system, yet the way in which the motor cortex (MC) interacts with spinal circuitry during this process is unclear. We studied neural correlates of visuomotor transformation in the MC and cervical spinal cord while monkeys performed an isometric wrist task. We recorded 2 measures of population activity: local field potential (LFP), reflecting local synaptic inputs and multi unit activity (MUA), reflecting spiking activity emitted by nearby neurons. We found robust cortical and spinal responses locked to visual and motor events. In motor cortex, LFP responses were predominantly visually related; MUA responses were mostly motor related. Spinal LFP responses were generally weak, yet spinal MUAs showed visual and motor responses with distinctive patterns. For both structures, amplitudes of visual responses were positively correlated with amplitudes of motor responses and negatively correlated with reaction times. The temporal relations of cortical and spinal responses shifted from weak coactivation before movement to increased coupling following torque onset, with cortical leading spinal activity. Thus, ongoing CS interactions may exist at early stages of movement preparation. These interactions are dynamic and may shape the executed motor action. PMID- 19443624 TI - Searching for genes that matter in acute kidney injury: a systematic review. AB - BACKGROUND AND OBJECTIVES: Identifying patients who may develop acute kidney injury (AKI) remains challenging, as clinical determinants explain only a portion of individual risk. Another factor that likely affects risk is intrinsic genetic variability. Therefore, a systematic review of studies was performed that related the development or prognosis of AKI to genetic variation. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: MEDLINE, EMBASE, HuGEnet, SCOPUS, and Web of Science were searched for articles from 1950 to Dec 2007. Two independent researchers screened articles using predetermined criteria. Studies were assessed for methodological quality via an aggregate scoring system. RESULTS: The 16 included studies were of cohort or case-cohort design and investigated 35 polymorphisms in 21 genes in association with AKI. Fifteen gene-gene interactions were also investigated in four separate studies. Study populations were primarily premature infants or adults who were critically ill or postcardiac bypass patients. Among the studies, five different definitions of AKI were used. Only one polymorphism, APO E e2/e3/e4, had greater than one study showing a significant impact (P < 0.05) on AKI incidence. The mean quality score of 5.8/10 (range four to nine), heterogeneity in the studies, and the dearth of studies precluded additional meta-analysis of the results. CONCLUSIONS: Current association studies are unable to provide definitive evidence linking genetic variation to AKI. Future success will require a narrow consensus definition of AKI, rigorous epidemiologic techniques, and a shift from a priori hypothesis driven to genome-wide association studies. PMID- 19443625 TI - Long-term renal function and cardiovascular disease risk in obese kidney donors. AB - BACKGROUND AND OBJECTIVES: Increasing demand for live-donor kidneys has encouraged the use of obese donors despite the absence of long-term outcome data and evidence that obesity can adversely affect renal function. We wished to determine whether obesity increased the risk for renal dysfunction and other medical comorbidities in donors several years after donation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Ninety-eight patients who donated a kidney 5 to 40 years previously were stratified according to body mass index (BMI) at donation and evaluated for renal dysfunction and risk factors for cardiovascular disease. Patients who were from the 2005 through 2006 National Health and Nutrition Examination Survey database; did not have renal disease; and were matched for age, gender, race, and BMI served as two-kidney control subjects. RESULTS: Renal function in obese (BMI > or =30) and nonobese (BMI <30) donors was similar, and both donor groups had reduced renal function compared with BMI-matched two-kidney control subjects. Obesity was associated with more hypertension and dyslipidemias in both donors and two-kidney control subjects; however, there were no significant differences between the two groups within each BMI category. CONCLUSIONS: These results indicate that obese donors are not at higher risk for long-term reduced renal function compared with nonobese donors and that the increased incidence of hypertension and other cardiovascular disease risk factors in obese donors is due to their obesity and is not further exacerbated by nephrectomy. These findings support the current practice of using otherwise healthy overweight and obese donors but emphasize the need for more intensive preoperative education and postoperative health care maintenance in this donor group. PMID- 19443626 TI - Renal biopsy in the very elderly. AB - BACKGROUND AND OBJECTIVES: Data regarding renal biopsy in the very elderly (>or=age 80 yr) are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in very elderly patients who underwent native renal biopsy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All native renal biopsies (n = 235 including 106 men, 129 women) performed in patients aged >or=80 yr over a 3.67-yr period were retrospectively identified. Results were compared with a control group of 264 patients aged 60 to 61 who were biopsied over the same period. RESULTS: The indications for biopsy were acute kidney injury (AKI) in 46.4%, chronic-progressive kidney injury in 23.8%, nephrotic syndrome (NS) in 13.2%, NS with AKI in 9.4%, and isolated proteinuria in 5.5%. Pauci-immune GN was the most frequent diagnosis (19%), followed by focal segmental glomerulosclerosis secondary to hypertension (7.6%), hypertensive nephrosclerosis (7.1%), IgA nephropathy (7.1%) and membranous nephropathy (7.1%). Comparison with the control group showed pauci-immune GN to be more frequent (P < 0.001) and diabetic glomerulosclerosis (P < 0.001) and membranous nephropathy (P < 0.05) less frequent in the very elderly. Diagnostic information had the potential to modify treatment in 67% of biopsies from the very elderly, particularly in those with AKI or NS. CONCLUSIONS: Renal biopsy in very elderly patients is a valuable diagnostic tool that should be offered in clinical settings with maximal potential benefit. Advanced age per se should no longer be considered a contraindication to renal biopsy. PMID- 19443627 TI - A case for water in the treatment of polycystic kidney disease. AB - Autosomal dominant polycystic disease (ADPKD) is an inherited disorder characterized by the development within renal tubules of innumerable cysts that progressively expand to cause renal insufficiency. Tubule cell proliferation and transepithelial fluid secretion combine to enlarge renal cysts, and 3'-5'-cyclic adenosine monophosphate (cAMP) stimulates that growth. The antidiuretic hormone, arginine vasopressin (AVP), operates continuously in ADPKD patients to stimulate the formation of cAMP, thereby contributing to cyst and kidney enlargement and renal dysfunction. Studies in animal models of ADPKD provide convincing evidence that blocking the action of AVP dramatically ameliorates the disease process. In the current analysis, the authors reason that increasing the amount of solute free water drunk evenly throughout the day in patients with ADPKD and normal renal function will decrease plasma AVP concentrations and mitigate the action of cAMP on the renal cysts. Potential pitfalls of increasing fluid intake in ADPKD patients are considered, and suggestions for how physicians may prudently implement this therapy are offered. PMID- 19443629 TI - Morphing voxels: the hype around structural imaging of headache patients. AB - Neuroimaging analysis using structural data has begun to provide insights into the pathophysiology of headache syndromes. Several independent studies have suggested a decrease in grey matter in pain-transmitting areas in migraine patients. Most of these data are discussed as damage or loss of brain grey matter, reinforcing the idea of migraine as a progressive disease. However, given what we know about the nature of morphometric changes detectable by the methods we have to date, this interpretation is highly speculative and not supported by the data. It is likely that these changes are the consequence and not the cause of the respective headache syndromes, as they are probably not irreversible and only mirror the proportion or duration of pain suffered. Moreover, structural changes are not headache specific and have to be seen in the light of a wealth of pain studies using these methods. The studies in cluster headache patients prompted the use of stereotactic stimulation of the hypothalamic target point identified by functional and structural neuroimaging. Due to the nature of the methods used and due to a high anatomical variance it is more than questionable to use this point as a definite answer to the source of the headache in clusters and even more so when it is uncritically used in individuals. We need a way to study each patient individually using the functional imaging method with the highest spatial and temporal resolution available to enable us to target the seed point for deep brain stimulation on this individual basis. One of the major future challenges is to understand the behavioural consequences and cellular mechanisms underlying neuroanatomic changes in pain and headache. PMID- 19443628 TI - Vitamin D affects survival independently of vascular calcification in chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Cardiovascular disease is the main cause of mortality in chronic kidney disease (CKD) patients. Vitamin D might have beneficial effects on vascular health. The aim of this study was to determine the prevalence of vitamin D deficiency (25-hydroxyvitamin D [25D] 16.7 ng/ml (mean follow up, 605 +/- 217 d; range, 10 to 889; P = 0.05). Multivariate adjustments (included age, gender, diabetes, arterial pressure, CKD stage, phosphate, albumin, hemoglobin, aortic calcification score and PWV) confirmed 25D level as an independent predictor of all-cause mortality. CONCLUSIONS: Vitamin D deficiency and insufficiency were highly prevalent in this CKD cohort. Low 25D levels affected mortality independently of vascular calcification and stiffness, suggesting that 25D may influence survival in CKD patients via additional pathways that need to be further explored. PMID- 19443630 TI - Encoding of human action in Broca's area. AB - Broca's area has been considered, for over a century, as the brain centre responsible for speech production. Modern neuroimaging and neuropsychological evidence have suggested a wider functional role is played by this area. In addition to the evidence that it is involved in syntactical analysis, mathematical calculation and music processing, it has recently been shown that Broca's area may play some role in language comprehension and, more generally, in understanding actions of other individuals. As shown by functional magnetic resonance imaging, Broca's area is one of the cortical areas activated by hand/mouth action observation and it has been proposed that it may form a crucial node of a human mirror-neuron system. If, on the one hand, neuroimaging studies use a correlational approach which cannot offer a final proof for such claims, available neuropsychological data fail to offer a conclusive demonstration for two main reasons: (i) they use tasks taxing both language and action systems; and (ii) they rarely consider the possibility that Broca's aphasics may also be affected by some form of apraxia. We administered a novel action comprehension test--with almost no linguistic requirements--on selected frontal aphasic patients lacking apraxic symptoms. Patients, as well as matched controls, were shown short movies of human actions or of physical events. Their task consisted of ordering, in a temporal sequence, four pictures taken from each movie and randomly presented on the computer screen. Patient's performance showed a specific dissociation in their ability to re-order pictures of human actions (impaired) with respect to physical events (spared). Our study provides a demonstration that frontal aphasics, not affected by apraxia, are specifically impaired in their capability to correctly encode observed human actions. PMID- 19443631 TI - Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective brain connectivity. AB - The neural cell adhesion molecule (NCAM) and its post-translational modification polysialic acid (polySia) are broadly implicated in neural development. Mice lacking the polysialyltransferases ST8SiaII and ST8SiaIV are devoid of polySia, and show severe malformation of major brain axon tracts. Here, we demonstrate how allelic variation of three interacting gene products (NCAM, ST8SiaII and ST8SiaIV) translates into various degrees of anterior commissure, corpus callosum and internal capsule hypoplasia. Loss of ST8SiaII alone caused mild, but distinct defects and the severity of the pathological phenotype found in mice lacking both polysialyltransferases could be stepwise attenuated by reducing NCAM expression. Analysis of mice with overall nine selected combinations of mutant NCAM and polysialyltransferase alleles revealed that the extent of the fibre tract deficiencies was not linked to the total amount of polySia or NCAM, but correlated strictly with the level of NCAM erroneously devoid of polySia during brain development. The defects implemented by the gain of polySia-free NCAM were reminiscent to abnormalities found in patients with schizophrenia. Since variations in NCAM1 and ST8SIA2 have been implicated in schizophrenia, these findings provide a mechanism how genetic interference with the complex coordination of NCAM polysialylation may lead to a neurodevelopmental predisposition to schizophrenia. PMID- 19443632 TI - Why is the mortality of dialysis patients in the United States much higher than the rest of the world? PMID- 19443633 TI - Family history of renal disease severity predicts the mutated gene in ADPKD. AB - Mutations of PKD1 and PKD2 account for 85 and 15% of cases of autosomal dominant polycystic kidney disease (ADPKD), respectively. Clinically, PKD1 is more severe than PKD2, with a median age at ESRD of 53.4 versus 72.7 yr. In this study, we explored whether a family history of renal disease severity predicts the mutated gene in ADPKD. We examined the renal function (estimated GFR and age at ESRD) of 484 affected members from 90 families who had ADPKD and whose underlying genotype was known. We found that the presence of at least one affected family member who developed ESRD at age < or =55 was highly predictive of a PKD1 mutation (positive predictive value 100%; sensitivity 72%). In contrast, the presence of at least one affected family member who continued to have sufficient renal function or developed ESRD at age >70 was highly predictive of a PKD2 mutation (positive predictive value 100%; sensitivity 74%). These data suggest that close attention to the family history of renal disease severity in ADPKD may provide a simple means of predicting the mutated gene, which has prognostic implications. PMID- 19443634 TI - Nck proteins maintain the adult glomerular filtration barrier. AB - Within the glomerulus, the scaffolding protein nephrin bridges the actin-rich foot processes that extend from adjacent podocytes to form the slit diaphragm. Mutations affecting a number of slit diaphragm proteins, including nephrin, cause glomerular disease through rearrangement of the actin cytoskeleton and disruption of the filtration barrier. We recently established that the Nck family of Src homology 2 (SH2)/SH3 cytoskeletal adaptor proteins can mediate nephrin-dependent actin reorganization. Formation of foot processes requires expression of Nck in developing podocytes, but it is unknown whether Nck maintains podocyte structure and function throughout life. Here, we used an inducible transgenic strategy to delete Nck expression in adult mouse podocytes and found that loss of Nck expression rapidly led to proteinuria, glomerulosclerosis, and altered morphology of foot processes. We also found that podocyte injury reduced phosphorylation of nephrin in adult kidneys. These data suggest that Nck is required to maintain adult podocytes and that phosphotyrosine-based interactions with nephrin may occur in foot processes of resting, mature podocytes. PMID- 19443635 TI - Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. AB - There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes. PMID- 19443636 TI - A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13. AB - Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans. PMID- 19443637 TI - 25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. AB - Vitamin D deficiency associates with increased risk for cardiovascular events and mortality, but the mechanism driving this association is unknown. Here, we tested whether circulating 25-hydroxyvitamin D concentration associates with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in the Multi Ethnic Study of Atherosclerosis. We included 1370 participants: 394 with and 976 without chronic kidney disease (estimated GFR <60 ml/min per 1.73 m(2)). At baseline, CAC was prevalent among 723 (53%) participants. Among participants free of CAC at baseline, 135 (21%) developed incident CAC during 3 yr of follow-up. Lower 25-hydroxyvitamin D concentration did not associate with prevalent CAC but did associate with increased risk for developing incident CAC, adjusting for age, gender, race/ethnicity, site, season, physical activity, smoking, body mass index, and kidney function. Further adjustment for BP, diabetes, C-reactive protein, and lipids did not alter this finding. The association of 25 hydroxyvitamin D with incident CAC seemed to be stronger among participants with lower estimated GFR. Circulating 1,25-dihydroxyvitamin D concentrations among participants with chronic kidney disease did not significantly associate with prevalent or incident CAC in adjusted models. In conclusion, lower 25 hydroxyvitamin D concentrations associate with increased risk for incident CAC. Accelerated development of atherosclerosis may underlie, in part, the increased cardiovascular risk associated with vitamin D deficiency. PMID- 19443638 TI - Expression of complement components differs between kidney allografts from living and deceased donors. AB - A disparity remains between graft survival of renal allografts from deceased donors and from living donors. A better understanding of the molecular mechanisms that underlie this disparity may allow the development of targeted therapies to enhance graft survival. Here, we used microarrays to examine whole genome expression profiles using tissue from 53 human renal allograft protocol biopsies obtained both at implantation and after transplantation. The gene expression profiles of living-donor kidneys and pristine deceased-donor kidneys (normal histology, young age) were significantly different before reperfusion at implantation. Deceased-donor kidneys exhibited a significant increase in renal expression of complement genes; posttransplantation biopsies from well functioning, nonrejecting kidneys, regardless of donor source, also demonstrated a significant increase in complement expression. Peritransplantation phenomena, such as donor death and possibly cold ischemia time, contributed to differences in complement pathway gene expression. In addition, complement gene expression at the time of implantation was associated with both early and late graft function. These data suggest that complement-modulating therapy may improve graft outcomes in renal transplantation. PMID- 19443639 TI - The E-selectin ligand basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion. AB - E-selectin and its ligands are essential for extravasation of leukocytes in inflammation. Here, we report that basigin (Bsg)/CD147 is a ligand for E-selectin that promotes renal inflammation in ischemia/reperfusion. Compared with wild-type mice, Bsg-deficient (Bsg(-/-)) mice demonstrated striking suppression of neutrophil infiltration in the kidney after renal ischemia/reperfusion. Although E-selectin expression increased similarly between the two genotypes, Bsg(-/-) mice exhibited less renal damage, suggesting that Bsg on neutrophils contribute to renal injury in this model. Neutrophils expressed Bsg with N-linked polylactosamine chains and Bsg(-)(/)(-) neutrophils showed reduced binding to E selectin. Bsg isolated from HL-60 cells bound to E-selectin, and tunicamycin treatment to abolish N-linked glycans from Bsg abrogated this binding. Furthermore, Bsg(-)(/)(-) neutrophils exhibited reduced E-selectin-dependent adherence to human umbilical vein endothelial cells in vitro. Injection of labeled neutrophils into mice showed that Bsg(-)(/)(-) neutrophils were less readily recruited to the kidney after renal ischemia/reperfusion than Bsg(+/+) neutrophils, regardless of the recipient's genotype. Taken together, these results indicate that Bsg is a physiologic ligand for E-selectin that plays a critical role in the renal damage induced by ischemia/reperfusion. PMID- 19443640 TI - Connexin 40 mediates the tubuloglomerular feedback contribution to renal blood flow autoregulation. AB - Connexins are important in vascular development and function. Connexin 40 (Cx40), which plays a predominant role in the formation of gap junctions in the vasculature, participates in the autoregulation of renal blood flow (RBF), but the underlying mechanisms are unknown. Here, Cx40-deficient mice (Cx40-ko) had impaired steady-state autoregulation to a sudden step increase in renal perfusion pressure. Analysis of the mechanisms underlying this derangement suggested that a marked reduction in tubuloglomerular feedback (TGF) in Cx40-ko mice was responsible. In transgenic mice with Cx40 replaced by Cx45, steady-state autoregulation and TGF were weaker than those in wild-type mice but stronger than those in Cx40-ko mice. N omega-Nitro-L-arginine-methyl-ester (L-NAME) augmented the myogenic response similarly in all genotypes, leaving autoregulation impaired in transgenic animals. The responses of renovascular resistance and arterial pressure to norepinephrine and acetylcholine were similar in all groups before or after L-NAME inhibition. Systemic and renal vasoconstrictor responses to L-NAME were also similar in all genotypes. We conclude that Cx40 contributes to RBF autoregulation by transducing TGF-mediated signals to the afferent arteriole, a function that is independent of nitric oxide (NO). However, Cx40 is not required for the modulation of the renal myogenic response by NO, norepinephrine-induced renal vasoconstriction, and acetylcholine- or NO-induced vasodilation. PMID- 19443641 TI - IRF-1 promotes inflammation early after ischemic acute kidney injury. AB - Acute renal ischemia elicits an inflammatory response that may exacerbate acute kidney injury, but the regulation of the initial signals that recruit leukocytes is not well understood. Here, we found that IFN regulatory factor 1 (IRF-1) was a critical, early proinflammatory signal released during ischemic injury in vitro and in vivo. Within 15 min of reperfusion, proximal tubular cells of the S3 segment produced IRF-1, which is a transcription factor that activates proinflammatory genes. Transgenic knockout of IRF-1 ameliorated the impairment of renal function, morphologic injury, and inflammation after acute ischemia. Bone marrow chimera experiments determined that maximal ischemic injury required IRF-1 expression by both leukocytes and radioresistant renal cells, the latter identified as S3 proximal tubule cells in the outer medulla by in situ hybridization and immunohistochemistry. In vitro, reactive oxygen species, generated during ischemia/reperfusion injury, stimulated expression of IRF-1 in an S3 proximal tubular cell line. Taken together, these data suggest that IRF-1 gene activation by reactive oxygen species is an early signal that promotes inflammation after ischemic renal injury. PMID- 19443642 TI - Amino acid transporter LAT3 is required for podocyte development and function. AB - LAT3 is a Na+-independent neutral l-amino acid transporter recently isolated from a human hepatocellular carcinoma cell line. Although liver, skeletal muscle, and pancreas are known to express LAT3, the tissue distribution and physiologic function of this transporter are not completely understood. Here, we observed that glomeruli express LAT3. Immunofluorescence, confocal microscopy, and immunoelectron microscopy revealed that LAT3 localizes to the apical plasma membrane of podocyte foot processes. In mice, starvation upregulated glomerular LAT3, phosphorylated AKT1, reconstituted the actin network, and elongated foot processes. In the fetal kidney, we observed intense LAT3 expression at the capillary loops stage of renal development. Finally, zebrafish morphants lacking lat3 function showed collapsed glomeruli with thickened glomerular basement membranes. Permeability studies of the glomerular filtration barrier in these zebrafish morphants demonstrated a disruption of selective glomerular permeability. Our data suggest that LAT3 may play a crucial role in the development and maintenance of podocyte structure and function by regulating protein synthesis and the actin cytoskeleton. PMID- 19443643 TI - High protein intake associates with cardiovascular events but not with loss of renal function. AB - The long-term effects of higher dietary protein intake on cardiovascular and renal outcomes in the general population are not clear. We analyzed data from 8461 individuals who did not have renal disease and participated in two or three subsequent screenings (6.4-yr follow-up) in a prospective, community-based cohort study (Prevention of Renal and Vascular ENd-stage Disease [PREVEND]). We calculated daily protein intake from 24-h urinary urea excretion (Maroni formula) and used Cox proportional hazard models to analyze the associations between protein intake, cardiovascular events, and mortality. We used mixed-effects models to investigate the association between protein intake and change in renal function over time. The mean +/- SD daily protein intake was 1.20 +/- 0.27 g/kg. Protein intake was significantly associated with cardiovascular events during follow-up. The associations seemed U-shaped; compared with intermediate protein intake, individuals with either higher or lower protein intake had higher event rates. All-cause mortality and noncardiovascular mortality also were significantly associated with protein intake; individuals with low protein intake had the highest event rates. We found no association between baseline protein intake and rate of renal function decline during follow-up. In summary, in the general population, high protein intake does not promote accelerated decline of renal function but does associate with an increased risk for cardiovascular events. PMID- 19443645 TI - Automated processing - a complement to source separation of recyclables? PMID- 19443644 TI - The CXCL12 (SDF-1)/CXCR4 axis is essential for the development of renal vasculature. AB - CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1) is a unique homeostatic chemokine that signals through its cognate receptor, CXCR4. CXCL12/CXCR4 signaling is essential for the formation of blood vessels in the gastrointestinal tract during development, but its contribution to renal development remains unclear. Here, we found that CXCL12-secreting stromal cells surround CXCR4-positive epithelial components of early nephrons and blood vessels in the embryonic kidney. In glomeruli, we observed CXCL12-secreting podocytes in close proximity to CXCR4-positive endothelial cells. Both CXCL12- and CXCR4 deficient kidneys exhibited identical phenotypes; there were no apparent abnormalities in early nephrogenesis or in differentiation of podocytes and tubules, but there was defective formation of blood vessels, including ballooning of the developing glomerular tuft and disorganized patterning of the renal vasculature. To clarify the relative importance of different cellular defects resulting from ablation of CXCL12 and CXCR4, we established endothelial cell specific CXCR4-deficient mice, which recapitulated the renal phenotypes of conventional CXCR4-deficient mice. We conclude that CXCL12 secreted from stromal cells or podocytes acts on endothelial cells to regulate vascular development in the kidney. These findings suggest new potential therapeutic targets for remodeling the injured kidney. PMID- 19443646 TI - Recycling of coal combustion wastes. AB - The separation of unburned carbon from coal-fired power plant bottom ashes was conducted in order to increase the possibility of the recycling of coal combustion wastes. A two-stage flotation technique was used for this study. In the rougher flotation experiments the amounts of collector, dispersant and frother, pulp density, pH, particle size distribution, flotation time and flotation temperature were tested as variables. After rougher flotation experiments, at optimum conditions, the carbon content of the concentrate increased from 13.85 to 51.54% at a carbon recovery of 54.54%. Under the same conditions, the carbon content was reduced to 4.54% at a weight yield of over 80% in the tailings fraction. This fraction meets the industrial specifications and can be utilized as a cement additive. After the cleaner flotation experiment the carbon content of the product was enhanced to 64.81% with a 52.16% carbon recovery. This fraction can be blended back into the coal feed to the power plant boilers. PMID- 19443647 TI - A study on the structural behavior of reduced pyrite ash pellets by XRD and XRF analysis. AB - In Turkey, pyrite ash is created as waste from the roasting of pyrite ores in the production of sulfuric acid. These processes generate great amounts of pyrite ash waste that creates serious environmental pollution due to the release of acids and toxic substances. Pyrite ash waste can be used in the iron production industry as a raw material because of its high Fe(2)O(3) concentration. The aim of this study was to investigate the reduction behaviour of pyrite ash pellets. The pyrite ashes were reduced to obtain the iron contained in pellets. Pyrite ashes samples were pelletized dried at 105 degrees C for 24 h and sintered at 1200 degrees C for 30 min. then reduced in a pressure of 4 atm. under argon gas. The mineralogical transformations that occurred during reduction were analysed by X-ray diffraction and X-ray fluorescence. The X-ray diffraction and X-ray fluorescence measurements of these samples showed that Fe(3)O(4) was successfully reduced to a metallic iron phase in a laboratory-scale electric arc furnace. PMID- 19443648 TI - Prescription of antihypertensive agents to haemodialysis patients: time trends and associations with patient characteristics, country and survival in the DOPPS. AB - BACKGROUND: Haemodialysis patients were studied in 12 countries to identify practice patterns of prescription of antihypertensive agents (AHA) associated with survival. METHODS: The sample included 28 513 patients enrolled in DOPPS I and II. The classes of AHA studied were beta blocker (BB), angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), peripheral blocker, central antagonist, vasodilator, long-acting dihydropyridine calcium channel blocker (CCB), short-acting dihydropyridine CCB and non-dihydropyridine CCB. To reduce bias due to unmeasured confounders, the associations with mortality were assessed by separate Cox models based on patient-level prescription and facility prescription practice. RESULTS: An increase in prescription of ARBs (9.5%) and BBs (9.1%) was observed from DOPPS I to II. Prescription of AHA classes varied significantly by country, ranging for BBs from 9.7% in Japan to 52.7% in Sweden and for ARBs from 5.5% in Italy to 21.3% in Japan in DOPPS II. Facilities that treated 10% more patients with ARBs had, on average, 7% lower all-cause mortality, independent of patient characteristics and the prescription patterns of other antihypertensive medications (P = 0.05). Significant and independent associations with reduction in cardiovascular mortality were observed for ARBs (RR = 0.79; P = 0.005) and BBs (RR = 0.87, P = 0.004) in analyses of patient level prescriptions. These associations in the facility-level model followed the same direction. CONCLUSIONS: DOPPS data show large variations across countries in AHA prescription for haemodialysis patients. The data suggest an association between ARB use and reduction in all-cause mortality, as well as with the use of BBs and reduction in cardiovascular mortality among haemodialysis patients. PMID- 19443649 TI - Recovery of renal function in end-stage renal failure--comparison between peritoneal dialysis and haemodialysis. AB - BACKGROUND: Recovery of dialysis-independent renal function in long-term dialysis patients has not been studied extensively. The aim of this study was to investigate the effect of dialysis modality on the likelihood, timing and durability of recovery of dialysis-independent renal function. METHODS: The study reviewed all patients in Australia and New Zealand who commenced dialysis for treatment of end-stage renal disease (ESRD) between 1963 and 2006. Dialysis modality was assigned at 90 days. A supplementary analysis was also conducted using a contemporary cohort that included data on comorbidities, smoking and eGFR at dialysis onset. RESULTS: During the study period, 15 912 individuals received peritoneal dialysis (PD) and 23 658 received haemodialysis (HD). Renal recovery occurred in 176 (1.1%) PD and 244 (1.0%) HD patients. Using multivariate Cox proportional hazards regression analyses, dialysis modality was not independently predictive of time to renal recovery (HR 0.92, 95% CI 0.76-1.13, P = 0.4). Recovery was significantly more likely in patients with higher baseline eGFR, with no hypertension or peripheral vascular disease, and with certain causes of kidney failure (autoimmune renal disease, haemolytic uraemic syndrome, interstitial nephritis, obstructive uropathy, paraproteinaemia and renovascular nephrosclerosis). Recovery was less likely in Maori/Pacific Islanders and polycystic kidney disease. Among patients who recovered, 328 (78%) subsequently experienced renal death, mostly within the first year. The duration of renal recovery was not associated with initial dialysis modality (OR 0.82, 95% CI 0.50- 1.32). CONCLUSIONS: Dialysis modality is not associated with the likelihood, timing or durability of spontaneous recovery of dialysis-independent renal function in patients thought to have ESRD. PMID- 19443650 TI - Phosphate levels--time for a rethink? PMID- 19443651 TI - Conformational transition associated with E1-E2 interaction in small ubiquitin like modifications. AB - Ubiquitin-like modifications regulate nearly every aspect of cellular functions. A key step in these modifications is the recognition of the carrier enzyme (E2) by the activating enzyme (E1). In this study, we have found that a critical E2 binding surface on the E1 of the small ubiquitin-like modifier has unusually high populations in both ordered and disordered states. Upon binding the E2, the disordered state is converted to the ordered state, which resembles the structure of the bound conformation, providing a mechanism to resolve the "Levinthal Paradox" search problem in a folding-upon-binding process. The significance of the folding-unfolding equilibrium is shown by the loss of functions of the mutations that shift the equilibrium to the folded state. This study highlights the importance of conformational flexibility in the molecular recognition event. PMID- 19443652 TI - NFAT-3 is a transcriptional repressor of the growth-associated protein 43 during neuronal maturation. AB - Transcription is essential for neurite and axon outgrowth during development. Recent work points to the involvement of nuclear factor of activated T cells (NFAT) in the regulation of genes important for axon growth and guidance. However, NFAT has not been reported to directly control the transcription of axon outgrowth-related genes. To identify transcriptional targets, we performed an in silico promoter analysis and found a putative NFAT site within the GAP-43 promoter. Using in vitro and in vivo experiments, we demonstrated that NFAT-3 regulates GAP-43, but unexpectedly, does not promote but represses the expression of GAP-43 in neurons and in the developing brain. Specifically, in neuron-like PC 12 cells and in cultured cortical neurons, the overexpression of NFAT-3 represses GAP-43 activation mediated by neurotrophin signaling. Using chromatin immunoprecipitation assays, we also show that prior to neurotrophin activation, endogenous NFAT-3 occupies the GAP-43 promoter in PC-12 cells, in cultured neurons, and in the mouse brain. Finally, we observe that NFAT-3 is required to repress the physiological expression of GAP-43 and other pro-axon outgrowth genes in specific developmental windows in the mouse brain. Taken together, our data reveal an unexpected role for NFAT-3 as a direct transcriptional repressor of GAP 43 expression and suggest a more general role for NFAT-3 in the control of the neuronal outgrowth program. PMID- 19443653 TI - Role of 20-kDa amelogenin (P148) phosphorylation in calcium phosphate formation in vitro. AB - The potential role of amelogenin phosphorylation in enamel formation is elucidated through in vitro mineralization studies. Studies focused on the native 20-kDa porcine amelogenin proteolytic cleavage product P148 that is prominent in developing enamel. Experimental conditions supported spontaneous calcium phosphate precipitation with the initial formation of amorphous calcium phosphate (ACP). In the absence of protein, ACP was found to undergo relatively rapid transformation to randomly oriented plate-like apatitic crystals. In the presence of non-phosphorylated recombinant full-length amelogenin, rP172, a longer induction period was observed during which relatively small ACP nanoparticles were transiently stabilized. In the presence of rP172, these nanoparticles were found to align to form linear needle-like particles that subsequently transformed and organized into parallel arrays of apatitic needle-like crystals. In sharp contrast to these findings, P148, with a single phosphate group on serine 16, was found to inhibit calcium phosphate precipitation and stabilize ACP formation for more than 1 day. Additional studies using non-phosphorylated recombinant (rP147) and partially dephosphorylated forms of P148 (dephoso-P148) showed that the single phosphate group in P148 was responsible for the profound effect on mineral formation in vitro. The present study has provided, for the first time, evidence suggesting that the native proteolytic cleavage product P148 may have an important functional role in regulating mineralization during enamel formation by preventing unwanted mineral formation within the enamel matrix during the secretory stage of amelogenesis. Results obtained have also provided new insights into the functional role of the highly conserved hydrophilic C terminus found in full-length amelogenin. PMID- 19443654 TI - MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated epithelial mesenchymal transdifferentiation. AB - T cell factor 4 (TCF4) interacts with beta-catenin in the WNT signaling pathway and transactivates downstream target genes involved in cancer progression. To identify proteins that regulate TCF4-mediated biological responses, we performed a yeast two-hybrid screen to search for a TCF4-binding protein(s) and found that MAD2B interacts with TCF4. We confirmed that MAD2B is a TCF4-binding protein by co-immunoprecipitation. Using the TOPFLASH reporter assay, we found that MAD2B blocks TCF4-mediated transactivation. The MAD2B binding regions of TCF4 were identified by TCF4 deletion mapping and electrophoretic mobility shift assay analysis. TCF4 and MAD2B interactions abolished the DNA binding ability of TCF4. Knockdown of MAD2B in SW480 colorectal cancer cells led to the conversion of epithelial cells to a mesenchymal fibroblastoid phenotype (epithelial-mesenchymal transdifferentiation). An E-cadherin promoter reporter analysis showed that MAD2B modulates TCF4-mediated E-cadherin expression. MAD2B knockdown blocked E-cadherin expression and significantly induced mesenchymal markers, such as N-cadherin and vimentin. Mesenchymal induction was accompanied by F-actin redistribution and the appearance of a fibroblastoid phenotype. MAD2B knockdown also increased both mRNA and protein levels of Slug, a known TCF4-induced E-cadherin transcriptional repressor. A chromatin immunoprecipitation assay showed that MAD2B silencing enhances the ability of TCF4 to bind the Slug promoter. Thus, MAD2B is a novel TCF4-interacting protein. This study provides the first evidence for the involvement of MAD2B in TCF4-mediated epithelial-mesenchymal transdifferentiation. PMID- 19443655 TI - Plasmodial aspartyl-tRNA synthetases and peculiarities in Plasmodium falciparum. AB - Distinctive features of aspartyl-transfer RNA (tRNA) synthetases (AspRS) from the protozoan Plasmodium genus are described. These apicomplexan AspRSs contain 29-31 amino acid insertions in their anticodon binding domains, a remarkably long N terminal appendix that varies in size from 110 to 165 amino acids and two potential initiation codons. This article focuses on the atypical functional and structural properties of Plasmodium falciparum cytosolic AspRS, the causative parasite of human malaria. This species encodes a 626 or 577 amino acids AspRS depending on whether initiation starts on the first or second in-frame initiation codon. The longer protein has poor solubility and a propensity to aggregate. Production of the short version was favored as shown by the comparison of the recombinant protein with endogenous AspRS. Comparison of the tRNA aminoacylation activity of wild-type and mutant parasite AspRSs with those of yeast and human AspRSs revealed unique properties. The N-terminal extension contains a motif that provides unexpectedly strong RNA binding to plasmodial AspRS. Furthermore, experiments demonstrated the requirement of the plasmodial insertion for AspRS dimerization and, therefore, tRNA aminoacylation and other putative functions. Implications for the parasite biology are proposed. These data provide a robust background for unraveling the precise functional properties of the parasite AspRS and for developing novel lead compounds against malaria, targeting its idiosyncratic domains. PMID- 19443656 TI - Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. AB - The naive phenotype of cord blood (CB) T cells may reduce graft-versus-host disease after umbilical cord blood transplantation, but this naivety and their low absolute numbers also delays immune reconstitution, producing higher infection-related mortality that is predominantly related to CMV, adenovirus (Adv), and EBV. Adoptive immunotherapy with peripheral blood-derived virus specific cytotoxic T lymphocytes (CTLs) can effectively prevent viral disease after conventional stem cell transplantation, and we now describe the generation of single cultures of CTLs from CB that are specific for multiple viruses. Using EBV-infected B cells transduced with a clinical-grade Ad5f35CMVpp65 adenoviral vector as sources of EBV, Adv, and CMV antigens, we expanded virus-specific T cells even from CB T cells with a naive phenotype. After expansion, each CTL culture contained both CD8(+) and CD4(+) T-cell subsets, predominantly of effector memory phenotype. Each CTL culture also had HLA-restricted virus specific cytotoxic effector function against EBV, CMV, and Adv targets. The CB CTLs recognized multiple viral epitopes, including CD4-restricted Adv-hexon epitopes and immunosubdominant CD4- and CD8-restricted CMVpp65 epitopes. Notwithstanding their naive phenotype, it is therefore possible to generate trivirus-specific CTLs in a single culture of CB, which may be of value to prevent or treat viral disease in CB transplant recipients. This study is registered at www.clinicaltrials.gov as NCT00078533. PMID- 19443658 TI - Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias. AB - Chromosomal translocations generating fusion proteins are frequently found in human leukemias. The fusion proteins play an important role in leukemogenesis by subverting the function of one or both partner proteins. The leukemogenic CALM AF10 fusion protein is capable of interacting with the histone H3 lysine 79 (H3K79)-specific methyltransferase hDOT1L through the fused AF10 moiety. This interaction leads to local H3K79 hypermethylation on Hoxa5 loci, which up regulates the expression of Hoxa5 and contributes to leukemogenesis. However, the long latency of leukemogenesis of CALM-AF10 transgenic mice suggests that the direct effects of fusion oncogene are not sufficient for the induction of leukemia. In this study, we show that the CALM-AF10 fusion protein can also greatly reduce global H3K79 methylation in both human and murine leukemic cells by disrupting the AF10-mediated association of hDOT1L with chromatin. Cells with reduced H3K79 methylation are more sensitive to gamma-irradiation and display increased chromosomal instability. Consistently, leukemia patients harboring CALM AF10 fusion have more secondary chromosomal aberrations. These findings suggest that chromosomal instability associated with global epigenetic alteration contributes to malignant transformation in certain leukemias, and that leukemias with this type of epigenetic alteration might benefit from treatment regimens containing DNA-damaging agents. This study is registered with www.clinicaltrials.gov as NCT00266136. PMID- 19443657 TI - F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. AB - F18-fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful tool to investigate the role of tumor metabolic activity and its suppression by therapy for cancer survival. As part of Total Therapy 3 for newly diagnosed multiple myeloma, metastatic bone survey, magnetic resonance imaging, and FDG-PET scanning were evaluated in 239 untreated patients. All 3 imaging techniques showed correlations with prognostically relevant baseline parameters: the number of focal lesions (FLs), especially when FDG-avid by PET-computed tomography, was positively linked to high levels of beta-2-microglobulin, C-reactive protein, and lactate dehydrogenase; among gene expression profiling parameters, high-risk and proliferation-related parameters were positively and low-bone-disease molecular subtype inversely correlated with FL. The presence of more than 3 FDG-avid FLs, related to fundamental features of myeloma biology and genomics, was the leading independent parameter associated with inferior overall and event-free survival. Complete FDG suppression in FL before first transplantation conferred significantly better outcomes and was only opposed by gene expression profiling defined high-risk status, which together accounted for approximately 50% of survival variability (R(2) test). Our results provide a rationale for testing the hypothesis that myeloma survival can be improved by altering treatment in patients in whom FDG suppression cannot be achieved after induction therapy. PMID- 19443660 TI - Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation. AB - Non-Hodgkin lymphoma (NHL) incidence is greatly increased after kidney transplantation. NHL risk was investigated in a nationwide cohort of 8164 kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry. NHL diagnoses were ascertained using linkage with national cancer registry records. Multivariate Poisson regression was used to compute incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing risk by transplant function, and risk factors for early (< 2 years) and late (>/= 2 years) NHL during the first transplantation. NHL occurred in 133 patients. Incidence was strikingly lower after transplant failure and cessation of immunosuppression than during transplant function (IRR, 0.25; 95% CI, 0.08-0.80; P = .019). Early NHL (n = 27) was associated with Epstein-Barr virus (EBV) seronegativity at transplantation (IRR, 4.66; 95% CI, 2.10-10.36, P < .001) and receipt of T cell-depleting antibodies (IRR, 2.39; 95% CI, 1.08-5.30; P = .031). Late NHL (n = 79) was associated with increasing year of age (IRR, 1.02; 95% CI, 1.01-1.04; P = .006), increasing time since transplantation (P < .001), and current use of calcineurin inhibitors (IRR, 3.13; 95% CI, 1.53-6.39; P = .002). These findings support 2 mechanisms of lymphomagenesis, one predominantly of primary EBV infection in the context of intense immunosuppression, and another of dysregulated lymphoid proliferation in a prolonged immunosuppressed state. PMID- 19443659 TI - Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. AB - Acute graft-versus-host disease (aGVHD) is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of patients completely respond. This randomized, 4 arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n = 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, MMF 44%, denileukin 62%, and pentostatin 57%. Efficacy and toxicity data suggest the use of MMF plus corticosteroids is the most promising regimen to compare against corticosteroids alone in a definitive phase 3 trial. This study is registered at http://www.clinicaltrials.gov as NCT00224874. PMID- 19443661 TI - RhoA and Rac1 GTPases play major and differential roles in stromal cell-derived factor-1-induced cell adhesion and chemotaxis in multiple myeloma. AB - The interaction of multiple myeloma (MM) cells with the bone marrow (BM) milieu plays a crucial role in MM pathogenesis. Stromal cell-derived factor-1 (SDF1) regulates homing of MM cells to the BM. In this study, we examined the role of RhoA and Rac1 GTPases in SDF1-induced adhesion and chemotaxis of MM. We found that both RhoA and Rac1 play key roles in SDF1-induced adhesion of MM cells to BM stromal cells, whereas RhoA was involved in chemotaxis and motility. Furthermore, both ROCK and Rac1 inhibitors reduced SDF1-induced polymerization of actin and activation of LIMK, SRC, FAK, and cofilin. Moreover, RhoA and Rac1 reduced homing of MM cells to BM niches. In conclusion, we characterized the role of RhoA and Rac1 GTPases in SDF1-induced adhesion, chemotaxis, and homing of MM cells to the BM, providing the framework for targeting RhoA and Rac1 GTPases as novel MM therapy. PMID- 19443662 TI - Enhanced development of CD4+ gammadelta T cells in the absence of Itk results in elevated IgE production. AB - The Tec kinase Itk is critical for the development of alphabeta T cells as well as differentiation of CD4(+) T cells into Th2 cells. Itk null mice have defects in the production of Th2 cytokines; however, they paradoxically have significant elevations in serum IgE. Here we show that Itk null mice have increased numbers of gammadelta T cells in the thymus and spleen. This includes elevated numbers of CD4(+) gammadelta T cell, the majority of which carry the Vgamma1.1 and Vdelta6.2/3 gammadelta T-cell receptor with a distinct phenotype. The development of these CD4(+) gammadelta T cells is T cell intrinsic, independent of either major histocompatibility complex class I or class II, and is favored during development in the absence of Itk. Itk null CD4(+) gammadelta T cells secrete significant amounts of Th2 cytokines and can induce the secretion of IgE by wild type B cells. Our data indicate that Itk plays important role in regulating gammadelta T-cell development and function. In addition, our data indicate that the elevated IgE observed in Itk-deficient mice is due in part to the enhanced development of CD4(+) gammadelta T cells in the absence of Itk. PMID- 19443663 TI - Microarray-based classifiers and prognosis models identify subgroups with distinct clinical outcomes and high risk of AML transformation of myelodysplastic syndrome. AB - The diagnosis of myelodysplastic syndrome (MDS) currently relies primarily on the morphologic assessment of the patient's bone marrow and peripheral blood cells. Moreover, prognostic scoring systems rely on observer-dependent assessments of blast percentage and dysplasia. Gene expression profiling could enhance current diagnostic and prognostic systems by providing a set of standardized, objective gene signatures. Within the Microarray Innovations in LEukemia study, a diagnostic classification model was investigated to distinguish the distinct subclasses of pediatric and adult leukemia, as well as MDS. Overall, the accuracy of the diagnostic classification model for subtyping leukemia was approximately 93%, but this was not reflected for the MDS samples giving only approximately 50% accuracy. Discordant samples of MDS were classified either into acute myeloid leukemia (AML) or "none-of-the-targets" (neither leukemia nor MDS) categories. To clarify the discordant results, all submitted 174 MDS samples were externally reviewed, although this did not improve the molecular classification results. However, a significant correlation was noted between the AML and "none-of-the targets" categories and prognosis, leading to a prognostic classification model to predict for time-dependent probability of leukemic transformation. The prognostic classification model accurately discriminated patients with a rapid transformation to AML within 18 months from those with more indolent disease. PMID- 19443664 TI - CD4+ T-cell clones recognizing human lymphoma-associated antigens: generation by in vitro stimulation with autologous Epstein-Barr virus-transformed B cells. AB - Epstein-Barr virus (EBV)-specific T-cell preparations, generated by stimulating immune donor lymphocytes with the autologous virus-transformed B-lymphoblastoid cell line (LCL) in vitro, can be used to target EBV-positive malignancies. Although these preparations are enriched for EBV antigen-specific CD8(+) T cells, most also contain a CD4(+) T-cell population whose specificity is unknown. Here, we show that, although CD4(+) T-cell clones derived from such cultures recognize HLA class II-matched LCLs but not mitogen-activated B lymphoblasts, many (1) do not map to any known EBV antigen, (2) can be raised from EBV-naive as well as EBV immune persons, and (3) can recognize a broad range of human B lymphoma-derived cell lines irrespective of EBV genome status, providing those lines to express the relevant HLA class II-restricting allele. Importantly, such CD4(+) clones not only produce IFNgamma but are also cytotoxic and can control the outgrowth of HLA matched lymphoma cells in cocultivation assays. We infer that such CD4(+) T cells recognize cellular antigens that are preferentially up-regulated in EBV transformed but not mitogen-activated B lymphoblasts and that are also expressed in a range of B-cell malignancies. Such antigens are therefore of potential value as targets for CD4(+) T cell-based immunotherapy. PMID- 19443665 TI - Effect of reducing indoor air pollution on women's respiratory symptoms and lung function: the RESPIRE Randomized Trial, Guatemala. AB - Exposure to household wood smoke from cooking is a risk factor for chronic obstructive lung disease among women in developing countries. The Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) is a randomized intervention trial evaluating the respiratory health effects of reducing indoor air pollution from open cooking fires. A total of 504 rural Mayan women in highland Guatemala aged 15-50 years, all using traditional indoor open fires, were randomized to either receive a chimney woodstove (plancha) or continue using the open fire. Assessments of chronic respiratory symptoms and lung function and individual measurements of carbon monoxide exposure were performed at baseline and every 6 months up to 18 months. Use of a plancha significantly reduced carbon monoxide exposure by 61.6%. For all respiratory symptoms, reductions in risk were observed in the plancha group during follow-up; the reduction was statistically significant for wheeze (relative risk = 0.42, 95% confidence interval: 0.25, 0.70). The number of respiratory symptoms reported by the women at each follow-up point was also significantly reduced by the plancha (odds ratio = 0.7, 95% confidence interval: 0.50, 0.97). However, no significant effects on lung function were found after 12-18 months. Reducing indoor air pollution from household biomass burning may relieve symptoms consistent with chronic respiratory tract irritation. PMID- 19443667 TI - Some like it hot: lymphoma radioimmunotherapy. PMID- 19443668 TI - Tipifarnib and etoposide for older AML patients: from bench to bedside. PMID- 19443669 TI - Nothing typical about HIT. PMID- 19443666 TI - Caregiving intensity and change in physical functioning over a 2-year period: results of the caregiver-study of osteoporotic fractures. AB - It is unknown whether caregivers who perform more caregiving tasks have a greater decline in health from higher stress or less decline because of better health, staying active, or psychological factors. This 1999-2004 US study examined caregiving intensity and 2-year change in performance-based functioning among 901 elderly women from the Caregiver-Study of Osteoporotic Fractures sample. Caregivers were categorized as high (n = 167) or low (n = 166) intensity based on how many activities of daily living they performed for the care recipient. Caregiving intensity status and physical performance score (sum of quartiles of walking pace, grip strength, and chair-stand speed; range, 0-9) were assessed at baseline and at 2 annual follow-up interviews. At baseline, high-intensity caregivers reported the most stress but had the best physical functioning; noncaregivers (n = 568) had the poorest physical functioning (adjusted scores = 5.09 vs. 4.54, P = 0.03). Low-intensity caregivers declined more than noncaregivers over 2 years, but high-intensity caregivers did not (adjusted difference = -0.33, P = 0.07 vs. 0.03, P = 0.89). Among respondents with the same caregiving status at baseline and 1-year interviews, high-intensity caregivers maintained the highest physical performance throughout follow-up. Higher levels of physical performance persisted over 2 years among high-intensity caregivers, which did not support the traditional stress hypothesis. PMID- 19443670 TI - A new role for P(k): finding the 1 in a million. PMID- 19443671 TI - Flipping the wound that doesn't heal: the upside of coagulation in cancer. PMID- 19443672 TI - Systemic dasatinib fails to prevent development of central nervous system progression in a patient with BCR-ABL unmutated Philadelphia chromosome-positive leukemia. PMID- 19443673 TI - Does the presence of anti-HIV miRNAs in monocytes explain their resistance to HIV 1 infection? PMID- 19443675 TI - Anticoagulants in portal vein thrombosis: don't be so shy! PMID- 19443676 TI - Scientific profiling. PMID- 19443679 TI - The VYtorin on Carotid intima-media thickness and overall arterial rigidity (VYCTOR) study. AB - This study assessed the effect of 3 lipid-lowering therapies on the reduction of the carotid intima-media thickness (IMT) in high-risk coronary Mexican patients. The study was a randomized, comparative, and open clinical trial. Ninety high risk coronary patients were allocated to 3 groups: pravastatin 40 mg, simvastatin 40 mg, and simvastatin 20 mg and ezetimibe 10 mg initially. If the therapeutic goals were not attained (<100 mg/dL of low-density lipoprotein cholesterol [LDL C] for type C and <70 mg for type D), patients in group 1 received pravastatin 40 mg and ezetimibe 10 mg, group 2 received simvastatin 80 mg, and group 3 received simvastatin 40 mg and ezetimibe 10 mg. The primary endpoint was the change of IMT over the course of 1 year. The secondary endpoints were changes in LDL-C and in high sensitive C-reactive protein (CRPhs). The overall baseline IMTs generated by combining measurements in the internal carotid artery were 1.33+/-0.32 mm, 1.30+/ 0.11 mm, and 1.23+/-0.28 mm for groups 1, 2, and 3, respectively. After 1 year, IMT values were 0.93+/-0.13 mm, 0.90+/-0.11 mm, and 0.92+/-0.01 mm for groups 1, 2, and 3, respectively. At the end of the study, LDL-C levels were 48+/-41, 45+/ 37, and 48+/-31 in groups 1, 2, and 3, respectively. No significant differences were observed in CRP, high-density lipoprotein cholesterol, triglycerides, blood pressure, and body mass index, among the groups. This study is one of the first providing evidence that dual therapy has a beneficial effect on a surrogate marker of atherosclerosis. PMID- 19443680 TI - Lack of pharmacokinetic drug interactions following concomitant administration of telavancin with aztreonam or piperacillin/tazobactam in healthy participants. AB - This randomized crossover study in healthy participants assessed pharmacokinetic interactions between telavancin, aztreonam, and piperacillin/tazobactam. Part 1: 11 participants received telavancin 10 mg/kg, aztreonam 2 g, or a combination of telavancin 10 mg/kg+aztreonam 2 g intravenously on 3 separate days. Part 2: 12 participants received telavancin 10 mg/kg, piperacillin/tazobactam 4.5 g, or a combination of telavancin 10 mg/kg+piperacillin/tazobactam 4.5 g intravenously on 3 separate days. Blood and urine drug concentrations were measured up to 48 hours posttreatment. Drug interactions were assessed by equivalence analysis of noncompartmental pharmacokinetic parameters, focusing on area under plasma concentration-time curves (AUC), log transformed; if the antilog of the 90% confidence intervals (CIs) for the mean log AUC difference was within equivalence bounds (0.70, 1.43), the effect of coadministration on the pharmacokinetics of the respective drug was deemed not clinically significant. Plasma concentration time curves for all treatment pairs were nearly superimposable with comparable values for pharmacokinetic parameter estimates. In equivalence analyses, 90% CI for the mean difference in log AUC in each comparison fell within the predefined clinical equivalence limits and bioequivalence limits (0.80, 1.25). Administration of aztreonam or piperacillin/tazobactam with telavancin had no clinically significant effect on the pharmacokinetic disposition of any of these drugs. PMID- 19443681 TI - The effect of etoricoxib on the pharmacokinetics of oral contraceptives in healthy participants. AB - The pharmacokinetics of oral contraceptive (OC) components, ethinyl estradiol (EE) and norethindrone (NET), were evaluated after coadministration with etoricoxib in 3 double-blind, randomized, 2-period crossover studies of healthy women. There were 16, 39, and 24 participants enrolled in studies 1 (part I, part II), and 2, respectively. Each participant received triphasic OC (EE 35 microg/NET 0.5 mgx7 days, 0.75 mgx7 days, 1.0 mgx7 days) throughout each 28-day period. OC was coadministered with 21 days of etoricoxib daily followed by placebo for 7 days; the alternate period followed the reverse regimen (placebo to etoricoxib). Study 1 (part I) examined concurrent (morning) administration of OC/etoricoxib 120 mg, study 1 (part II) examined staggered (morning/night) administration of OC/etoricoxib 120 mg, and study 2 examined concurrent (morning) administration of OC/etoricoxib 60 mg. Coadministration of OC and etoricoxib 120 mg once daily was associated with a approximately 50% to 60% increase in EE concentrations, whereas etoricoxib 60 mg once daily was associated with a approximately 37% increase in EE concentrations. Coadministration of OC and etoricoxib was generally well tolerated. A clinically important change in NET AUC0-24 h was not observed. Adverse events included dyspepsia, diarrhea, headache, nausea, fatigue, loss of appetite, and taste disturbance. PMID- 19443682 TI - Three subclasses of a Drosophila insulator show distinct and cell type-specific genomic distributions. AB - Insulators are protein-bound DNA elements that are thought to play a role in chromatin organization and the regulation of gene expression by mediating intra- and interchromosomal interactions. Suppressor of Hair-wing [Su(Hw)] and Drosophila CTCF (dCTCF) insulators are found at distinct loci throughout the Drosophila melanogaster genome and function by recruiting an additional protein, Centrosomal Protein 190 (CP190). We performed chromatin immunoprecipitation (ChIP) and microarray analysis (ChIP-chip) experiments with whole-genome tiling arrays to compare Su(Hw), dCTCF, boundary element-associated factor (BEAF), and CP190 localization on DNA in two different cell lines and found evidence that BEAF is a third subclass of CP190-containing insulators. The DNA-binding proteins Su(Hw), dCTCF, and BEAF show unique distribution patterns with respect to the location and expression level of genes, suggesting diverse roles for these three subclasses of insulators in genome organization. Notably, cell line-specific localization sites for all three DNA-binding proteins as well as CP190 indicate multiple levels at which insulators can be regulated to affect gene expression. These findings suggest a model in which insulator subclasses may have distinct functions that together organize the genome in a cell type-specific manner, resulting in differential regulation of gene expression. PMID- 19443684 TI - The elastic modulus, percolation, and disaggregation of strongly interacting, intersecting antiplane cracks. AB - We study the modulus of a medium containing a varying density of nonintersecting and intersecting antiplane cracks. The modulus of nonintersecting, strongly interacting, 2D antiplane cracks obeys a mean-field theory for which the mean field on a crack inserted in a random ensemble is the applied stress. The result of a self-consistent calculation in the nonintersecting case predicts zero modulus at finite packing, which is physically impossible. Differential self consistent theories avoid the zero modulus problem, but give results that are more compliant than those of both mean-field theory and computer simulations. For problems in which antiplane cracks are allowed to intersect and form crack clusters or larger effective cracks, percolation at finite packing is expected when the shear modulus vanishes. At low packing factor, the modulus follows the dilute, mean-field curve, but with increased packing, mutual interactions cause the modulus to be less than the mean-field result and to vanish at the percolation threshold. The "nodes-links-blobs" model predicts a power-law approach to the percolation threshold at a critical packing factor of p(c) = 4.426. We conclude that a power-law variation of modulus with packing, with exponent 1.3 drawn tangentially to the mean-field nonintersecting relation and passing through the percolation threshold, can be expected to be a good approximation. The approximation is shown to be consistent with simulations of intersecting rectangular cracks at all packing densities through to the percolation value for this geometry, p(c) = 0.4072. PMID- 19443683 TI - A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild type mice, mAb1 increases hepatic LDLR protein levels approximately 2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR( /-) mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia. PMID- 19443685 TI - LKB1 regulates polarity remodeling and adherens junction formation in the Drosophila eye. AB - The serine-threonine kinase LKB1 regulates cell polarity from Caenorhabditis elegans to man. Loss of lkb1 leads to a cancer predisposition, known as Peutz Jeghers Syndrome. Biochemical analysis indicates that LKB1 can phosphorylate and activate a family of AMPK- like kinases, however, the precise contribution of these kinases to the establishment and maintenance of cell polarity is still unclear. Recent studies propose that LKB1 acts primarily through the AMP kinase to establish and/or maintain cell polarity. To determine whether this simple model of how LKB1 regulates cell polarity has relevance to complex tissues, we examined lkb1 mutants in the Drosophila eye. We show that adherens junctions expand and apical, junctional, and basolateral domains mix in lkb1 mutants. Surprisingly, we find LKB1 does not act primarily through AMPK to regulate cell polarity in the retina. Unlike lkb1 mutants, ampk retinas do not show elongated rhabdomeres or expansion of apical and junctional markers into the basolateral domain. In addition, nutrient deprivation does not reveal a more dramatic polarity phenotype in lkb1 photoreceptors. These data suggest that AMPK is not the primary target of LKB1 during eye development. Instead, we find that a number of other AMPK-like kinase, such as SIK, NUAK, Par-1, KP78a, and KP78b show phenotypes similar to weak lkb1 loss of function in the eye. These data suggest that in complex tissues, LKB1 acts on an array of targets to regulate cell polarity. PMID- 19443686 TI - V-region mutation in vitro, in vivo, and in silico reveal the importance of the enzymatic properties of AID and the sequence environment. AB - The somatic hypermutation of Ig variable regions requires the activity of activation-induced cytidine deaminase (AID) which has previously been shown to preferentially deaminate WRC (W = A/T, R = A/G) motif hot spots in in vivo and in vitro assays. We compared mutation profiles of in vitro assays for the 3' flanking intron of VhJ558-Jh4 region to previously reported in vivo profiles for the same region in the Msh2(-/-)Ung(-/-) mice that lack base excision and mismatch repair. We found that the in vitro and in vivo mutation profiles were highly correlated for the top (nontranscribed) strand, while for the bottom (transcribed) strand the correlation is far lower. We used an in silico model of AID activity to elucidate the relative importance of motif targeting in vivo. We found that the mutation process entails substantial complexity beyond motif targeting, a large part of which is captured in vitro. To elucidate the contribution of the sequence environment to the observed differences between the top and bottom strands, we analyzed intermutational distances. The bottom strand shows an approximately exponential distribution of distances in vivo and in vitro, as expected from a null model. However, the top strand deviates strongly from this distribution in that mutations approximately 50 nucleotides apart are greatly reduced, again both in vivo and in vitro, illustrating an important strand asymmetry. While we have confirmed that AID targeting of hot and cold spots is a key part of the mutation process, our results suggest that the sequence environment plays an equally important role. PMID- 19443687 TI - Automated high-dimensional flow cytometric data analysis. AB - Flow cytometric analysis allows rapid single cell interrogation of surface and intracellular determinants by measuring fluorescence intensity of fluorophore conjugated reagents. The availability of new platforms, allowing detection of increasing numbers of cell surface markers, has challenged the traditional technique of identifying cell populations by manual gating and resulted in a growing need for the development of automated, high-dimensional analytical methods. We present a direct multivariate finite mixture modeling approach, using skew and heavy-tailed distributions, to address the complexities of flow cytometric analysis and to deal with high-dimensional cytometric data without the need for projection or transformation. We demonstrate its ability to detect rare populations, to model robustly in the presence of outliers and skew, and to perform the critical task of matching cell populations across samples that enables downstream analysis. This advance will facilitate the application of flow cytometry to new, complex biological and clinical problems. PMID- 19443688 TI - Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast. AB - Conserved chromosomal HP1 proteins capable of binding to histone H3 methylated at lysine 9 are believed to provide a dynamic platform for the recruitment and/or spreading of various regulatory proteins involved in diverse chromosomal processes. The fission yeast Schizosaccharomyces pombe HP1 family members Chp2 and Swi6 are important for heterochromatin assembly and transcriptional silencing, but their precise roles are not fully understood. Here, we show that Swi6 and Chp2 associate with histone deacetylase (HDAC) protein complexes containing class I HDAC Clr6 and class II HDAC Clr3 (a component of Snf2/HDAC repressor complex), which are critical for transcriptional silencing of centromeric repeats targeted by the heterochromatin machinery. Mapping of RNA polymerase (Pol) II distribution in single and double mutant backgrounds revealed that Swi6 and Chp2 proteins and their associated HDAC complexes have overlapping functions in limiting Pol II occupancy across pericentromeric heterochromatin domains. The purified Swi6 fraction also contains factors involved in various chromosomal processes such as chromatin remodeling and DNA replication. Also, Swi6 copurifies with Mis4 protein, a cohesin loading factor essential for sister chromatid cohesion, and with centromere-specific histone H3 variant CENP-A, which is incorporated into chromatin in a heterochromatin-dependent manner. These analyses suggest that among other functions, HP1 proteins associate with chromatin-modifying factors that in turn cooperate to assemble repressive chromatin; thus, precluding accessibility of underlying DNA sequences to transcriptional machinery. PMID- 19443689 TI - Synthesis of orthogonal transcription-translation networks. AB - Orthogonal, parallel and independent, systems are one key foundation for synthetic biology. The synthesis of orthogonal systems that are uncoupled from evolutionary constraints, and selectively abstracted from cellular regulation, is an emerging approach to making biology more amenable to engineering. Here, we combine orthogonal transcription by T7 RNA polymerase and translation by orthogonal ribosomes (O-ribosomes), creating an orthogonal gene expression pathway in Escherichia coli. We design and implement compact, orthogonal gene expression networks. In particular we focus on creating transcription-translation feed-forward loops (FFLs). The transcription-translation FFLs reported cannot be created by using the cells' gene expression machinery and introduce information processing delays on the order of hours into gene expression. We refactor the rRNA operon, uncoupling the synthesis of the orthogonal 16S rRNA for the O ribosome from the synthesis and processing of the rest of the rRNA operon, thereby defining a minimal module that can be added to the cell for O-ribosome production. The minimal O-ribosome permits the rational alteration of the delay in an orthogonal gene expression FFL. Overall this work demonstrates that system level dynamic properties are amenable to rational manipulation and design in orthogonal systems. In the future this system may be further evolved and tuned to provide a spectrum of tailored dynamics in gene expression and investigate the effects of delays in cellular decision-making processes. PMID- 19443690 TI - Neurotensin induces IL-6 secretion in mouse preadipocytes and adipose tissues during 2,4,6,-trinitrobenzensulphonic acid-induced colitis. AB - Mesenteric fat is known to undergo inflammatory changes after 2,4,6, trinitrobenzensulphonic acid (TNBS)-induced colitis. Neurotensin (NT) and neurotensin receptor 1 (NTR1) have been shown to play a major role in the pathogenesis of intestinal inflammation. This led us to explore whether NT and NTR1 are expressed in the mesenteric fat depots during TNBS-induced colitis and whether NT participates in the increased interleukin (IL)-6 secretion in this inflammatory response. TNBS-induced inflammation in the colon increases NT and NTR1 expression in mesenteric adipose tissues, including mesenteric preadipocytes. Compared with wild-type mice, NT knockout (KO) mice have reduced TNBS-induced colitis accompanied by diminished inflammatory responses in mesenteric adipose tissue. Specifically, IL-6 and p65 phosphorylation levels in mesenteric fat of NT KO mice are also reduced compared with wild-type mice. Mouse 3T3-L1 preadipocytes express NTR1 and its expression is increased after stimulation of preadipocytes with proinflammatory cytokines. NT stimulation of 3T3-L1 preadipocytes overexpressing NTR1 causes PKCdelta phosphorylation and IL-6 secretion in a time- and dose-dependent fashion. Moreover, NT-mediated IL-6 expression is nuclear factor-kappaB and PKCdelta dependent. We also found that supernatants from NT-exposed 3T3-L1-NTR1 preadipocytes and mesenteric fat obtained from wild-type mice 2 days after TNBS administration stimulate an IL-6 dependent macrophage migration measured by a macrophage migration assay, whereas this response is reduced when mesenteric fat from NT KO mice is used. These results demonstrate an important role for NT in acute colitis and adipose tissue inflammation associated with experimental colitis that involves direct NT proinflammatory responses in preadipocytes. PMID- 19443692 TI - Evaluation of speed, repeatability, and reproducibility of digital radiography with manual versus computer-assisted cephalometric analyses. AB - The aims of this study were to evaluate intra-examiner repeatability and inter examiner reproducibility of landmarks using two cephalometric analysing techniques, manual and computerized, and to compare these for speed. One hundred lateral cephalometric radiographs were randomly selected and 11 angular and six linear parameters were traced and measured by two examiners using the manual method and Dolphin Image Software 9.0 on each radiograph. A Student's t-test for paired and independent samples was used to compare the mean values of intra- and inter-examiner differences. Intraclass correlation coefficients (ICC) were calculated to determine intra- and inter-examiner correlation (r value). Both operators were generally consistent in the repeated measurements; however, for one examiner, the differences for Na is perpendicular to A (P < 0.001), Na is perpendicular Pog, and U1-NA (P < 0.01) distance measurements were found to be statistically significant. Intra-examiner repeatability of landmarks both with the manual and Dolphin techniques showed high correlation coefficients. While inter-examiner reproducibility of landmarks was unacceptable, measurement errors with the manual technique were generally comparable with the Dolphin technique. The mean tracing times of the two operators for a single tracing was 2 minutes 41 seconds for Dolphin and 6 minutes 51 seconds for manual tracings. Computer assisted cephalometric analysis does not increase intra- and inter-examiner reliability but can result in time saving. PMID- 19443691 TI - The small G-proteins Rac1 and Cdc42 are essential for myoblast fusion in the mouse. AB - Rac1 and Cdc42 are small G-proteins that regulate actin dynamics and affect plasma membrane protrusion and vesicle traffic. We used conditional mutagenesis in mice to demonstrate that Rac1 and Cdc42 are essential for myoblast fusion in vivo and in vitro. The deficit in fusion of Rac1 or Cdc42 mutant myoblasts correlates with a deficit in the recruitment of actin fibers and vinculin to myoblast contact sites. Comparison of the changes observed in mutant myogenic cells indicates that Rac1 and Cdc42 function in a nonredundant and not completely overlapping manner during the fusion process. Our genetic analysis demonstrates thus that the function of Rac in myoblast fusion is evolutionarily conserved from insects to mammals and that Cdc42, a molecule hitherto not implicated in myoblast fusion, is essential for the fusion of murine myoblasts. PMID- 19443693 TI - RecX is involved in the switch between DNA damage response and normal metabolism in D. radiodurans. AB - Apart from inhibiting RecA activity through protein-protein interactions, Deinococcus radiodurans RecX inhibits the expression of RecA and two other anti oxidant proteins. To identify the repertoire of proteins regulated by RecX, comparative proteomic studies were undertaken on a wild-type strain (R1) and recX null mutant (RecX(-)). Two-dimensional electrophoresis followed by MALDI-TOF identification revealed 35 differentially expressed proteins, including 12 up regulated and 23 down-regulated proteins in the mutant. The 12 up-regulated proteins are DNA repair proteins, stress response proteins, and metabolism related proteins. Most of these have been previously characterized as ionizing radiation-induced proteins. The 23 down-regulated proteins are mainly involved in cellular metabolism, and some of these are key enzymes in the metabolic pathway. Thus, RecX is suggested to be involved in the switch between DNA damage response and normal metabolism in D. radiodurans. PMID- 19443694 TI - Peptic ulcer and mental disorders among adults in the community: the role of nicotine and alcohol use disorders. AB - OBJECTIVE: Previous studies have documented links between peptic ulcer disease (PUD) and mood and anxiety disorders among adults in the community. Several substance use disorders (e.g., nicotine and alcohol dependence) are highly comorbid with mood/anxiety disorders and have been also linked with PUD. No previous study has examined the potentially explanatory role of substance use disorders in the link between mood and anxiety disorders and PUD. The objective of the study is to examine relationships between a range of mental disorders and PUD among adults in the United States and to examine the potentially explanatory role of substance use disorders in these links. METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample of US adults 18 years of age and over (n = 43,098). Diagnostic and Statistical Manual for Mental Disorders IV diagnoses of mood, anxiety, and substance use disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV, and PUD status was assessed via self-report. RESULTS: Findings show that mood/anxiety disorders were associated with PUD. Specifically, generalized anxiety disorder (GAD) (Odds ratio (OR) = 3.43) was most strongly associated with PUD, followed by panic disorder (OR = 3.11), dysthymia (OR = 3.59), and bipolar disorder (OR = 2.91). The relationships between most mood/anxiety disorders and PUD were substantially attenuated after adjusting for nicotine and alcohol dependence. CONCLUSIONS: Mood/anxiety disorders are associated with increased rates of PUD; nicotine and alcohol dependence seems to play a substantial role in explaining the link with PUD. PMID- 19443695 TI - Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. AB - Ezetimibe lowers plasma cholesterol levels by inhibiting the uptake of cholesterol in the intestine. Because of the extensive enterohepatic circulation of ezetimibe, relatively low doses are required to be effective. In blood and bile the majority of ezetimibe is present as a glucuronide conjugate, which is formed in the enterocyte. Presently, it is not clear which mechanisms are responsible for this efficient enterohepatic circulation. Abcc2, Abcc3, and Abcg2 are ATP-binding cassette (ABC) transporters that are expressed in both liver and intestine and are capable of transporting glucuronidated compounds. The aim of this study was to investigate the contribution of these transporters in the enterohepatic cycling of ezetimibe glucuronide (Ez-gluc). Transport studies were performed in plasma membrane vesicles from ABCC2-, ABCC3-, and ABCG2-expressing Sf21 insect cells. Furthermore, intestinal explants from wild-type and Abcc3(-/-) mice were used to study vectorial transport in a Ussing chamber setup. Finally, biliary excretion of Ez-gluc was measured in vivo after duodenal delivery of ezetimibe in wild-type, Abcc3(-/-), Abcc2(-/-), Abcg2(-/-), and Abcg2(-/-)/Abcc2( /-) mice. ABCC3-, ABCC2-, and ABCG2-mediated transport was dose dependently inhibited by Ez-gluc. In the Ussing chamber Ez-gluc recovered from the basolateral side was significantly reduced in duodenal (2.2%), in jejunal (23%), and in ileal (23%) tissue of Abcc3(-/-) mice compared with that in tissues of wild-type mice. Biliary excretion of Ez-gluc was significantly reduced in Abcc3( /-) (34%), Abcc2(-/-) (56%), and Abcg2(-/-)/Abcc2(-/-) (2.5%) compared with that in wild-type mice. These data demonstrate that the enterohepatic circulation of Ez-gluc strongly depends on the joint function of Abcc3, Abcc2, and Abcg2. PMID- 19443696 TI - It's your journal. PMID- 19443697 TI - Tai chi and meditation: A conceptual (re)synthesis? AB - The aim of this article is to review the literature on Tai Chi and meditation. A coherent construct is developed that includes a comparative analysis and conceptual synthesis of existing theories. The authors discuss a set of assumptions that justify this synthesis; they also argue that this construct would facilitate greater understanding of Tai Chi from the perspective of meditation. Such synthesis may bring "additional" benefits to Tai Chi practitioners as they could recognize that this mind-body technique holds the essence of meditation. Within the scope of this article, the evidence shows a majority of common features when concerning Tai Chi and meditation. These mutual similarities should be taken into account when performing this type of mind-body medicine by patients and/or therapists. Finally, the authors suggest that this inspiring compilation of movements and mindfulness can be used for practical purposes. PMID- 19443699 TI - A conceptual model of intentional comfort touch. AB - This article discusses the application and integration of intentional comfort touch as a holistic nursing practice. A review of the literature on touch and its related concepts is included. Although nurses use touch frequently in patient encounters, it is not always used intentionally or deliberately to enhance care. The article compares and contrasts intentional comfort touch with nonintentional or procedural touch. The use of intentional comfort touch in innovative clinical settings with diverse and at-risk populations is described. Based on clinical experiences and the current literature, a conceptual model of intentional comfort touch is proposed. The application of touch is discussed as is the meaning and importance of intentional touch for students, faculty, and patients. PMID- 19443700 TI - Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. AB - Significant host heterogeneity in susceptibility to tuberculosis exists both between and within mammalian species. Using a mouse model of infection with virulent Mycobacterium tuberculosis (Mtb), we identified the genetic locus sst1 that controls the progression of pulmonary tuberculosis in immunocompetent hosts. In this study, we demonstrate that within the complex, multigenic architecture of tuberculosis susceptibility, sst1 functions to control necrosis within tuberculosis lesions in the lungs; this lung-specific sst1 effect is independent of both the route of infection and genetic background of the host. Moreover, sst1 dependent necrosis was observed at low bacterial loads in the lungs during reactivation of the disease after termination of anti-tuberculosis drug therapy. We demonstrate that in sst1-susceptible hosts, nonlinked host resistance loci control both lung inflammation and production of inflammatory mediators by Mtb infected macrophages. Although interactions of the sst1-susceptible allele with genetic modifiers determine the type of the pulmonary disease progression, other resistance loci do not abolish lung necrosis, which is, therefore, the core sst1 dependent phenotype. Sst1-susceptible mice from tuberculosis-resistant and susceptible genetic backgrounds reproduce a clinical spectrum of pulmonary tuberculosis and may be used to more accurately predict the efficacy of anti tuberculosis interventions in genetically heterogeneous human populations. PMID- 19443701 TI - Coordinate expression of colony-stimulating factor-1 and colony-stimulating factor-1-related proteins is associated with poor prognosis in gynecological and nongynecological leiomyosarcoma. AB - Previously, we showed that the presence of high numbers of macrophages correlates with poor prognosis in nongynecological leiomyosarcoma (LMS). In gynecological LMS, a similar trend was noted but did not reach statistical significance. Colony stimulating factor-1 (CSF1) is a major chemoattractant for macrophages. Here we show that in a subset of LMS cases, CSF1 is expressed by the malignant cells. Previously, we found that CSF1 is translocated and highly expressed in tenosynovial giant cell tumors (TGCTs), and this observation allowed us to identify genes that showed a coordinate expression with CSF1. Here, we evaluated the expression of CSF1 and TGCT-associated proteins in 149 cases of LMS. The coordinate expression of CSF1 and three TGCT-associated proteins (CD163, FCGR3a, and CTSL1) identified cases with poor prognosis in both gynecological LMS (P = 0.00006) and nongynecological LMS (P = 0.03). In gynecological LMS, the coordinate expression of these four markers was the only independent prognosticator in multivariate analysis (hazard ratio, 4.2; 95% CI, 1.12 to 16; P = 0.03). Our findings indicate that CSF1 may play an important role in the clinical behavior of LMS that may open a window for new therapeutic reagents. PMID- 19443702 TI - Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury. AB - Matrix metalloproteinase 9 (MMP-9) is a critical mediator of leukocyte migration in hepatic ischemia/reperfusion (I/R) injury. To test the relevance of inducible nitric oxide synthase (iNOS) expression on the regulation of MMP-9 activity in liver I/R injury, our experiments included both iNOS-deficient mice and mice treated with ONO-1714, a specific iNOS inhibitor. The inability of iNOS-deficient mice to generate iNOS-derived nitric oxide (NO) profoundly inhibited MMP-9 activity and depressed leukocyte migration in livers after I/R injury. While macrophages expressed both iNOS and MMP-9 in damaged wild-type livers, neutrophils expressed MMP-9 and were virtually negative for iNOS; however, exposure of isolated murine neutrophils and macrophages to exogenous NO increased MMP-9 activity in both cell types, suggesting that NO may activate MMP-9 in leukocytes by either autocrine or paracrine mechanisms. Furthermore, macrophage NO production through the induction of iNOS was capable of promoting neutrophil transmigration across fibronectin in a MMP-9-dependent manner. iNOS expression in liver I/R injury was also linked to liver apoptosis, which was reduced in the absence of MMP-9. These results suggest that MMP-9 activity induced by iNOS derived NO may also lead to detachment of hepatocytes from the extracellular matrix and cell death, in addition to regulating leukocyte migration across extracellular matrix barriers. These data provide evidence for a novel mechanism by which MMP-9 can mediate iNOS-induced liver I/R injury. PMID- 19443703 TI - Capillary defects and exaggerated inflammatory response in the airways of EphA2 deficient mice. AB - Both Eph receptors and ephrin ligands have been implicated in blood vessel and neuronal development. Recent studies suggested that EphA2 inhibition reduces tumor angiogenesis, but its role in blood vessel development and inflammation is unclear. We examined these issues using either airways of pathogen-free, EphA2 deficient mice at various ages or EphA2-deficient mice whose airways were inflamed by either Mycoplasma pulmonis infection or ovalbumin sensitization and challenge. EphA2-deficient mice had fewer capillaries, a greater number of endothelial sprouts, and greater capillary diameters than age-matched, wild-type control mice. Moreover, capillaries in EphA2-deficient mice had significantly less pericyte coverage, suggesting abnormal interactions between endothelial cells and pericytes. These differences were apparent in early postnatal life but decreased during progression into adulthood. In inflamed airways, significantly more angiogenesis and lymphangiogenesis, a greater number of infiltrating leukocytes, and higher expression levels of inflammatory cytokine mRNA were present in EphA2-deficient mice after M. pulmonis infection. Additionally, in allergic airway inflammation with ovalbumin sensitization and challenge, a greater number of lymphatic sprouts and infiltrating leukocytes, higher mRNA expression levels of TH2 cytokines and chemokines related to allergic airway inflammation, and enhanced airway hyper-responsiveness were present in EphA2 deficient mice. We conclude that defective pericyte coverage causes capillary defects, abundant endothelial sprouts, and thick capillary diameters in EphA2 deficient mice, indicating that these animals have exaggerated responses to airway inflammation. PMID- 19443704 TI - Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants. AB - It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease. PMID- 19443705 TI - alpha5beta1 Integrin blockade inhibits lymphangiogenesis in airway inflammation. AB - The integrin alpha5beta1 has been previously implicated in tumor angiogenesis, but its role in the remodeling of both blood vessels and lymphatics during inflammation is at an early stage of understanding. We examined this issue using a selective, small-molecule inhibitor of alpha5beta1 integrin, 2-aroylamino-3-{4 [(pyridin-2-ylaminomethyl)heterocyclyl]phenyl}propionic acid (JSM8757), in a model of sustained airway inflammation in mice with Mycoplasma pulmonis infection, which is known to be accompanied by robust blood vessel remodeling and lymphangiogenesis. The inhibitor significantly decreased the proliferation of lymphatic endothelial cells in culture and the number of lymphatic sprouts and new lymphatics in airways of mice infected for 2 weeks but did not reduce remodeling of blood vessels in the same airways. In inflamed airways, alpha5 integrin immunoreactivity was present on lymphatic sprouts, but not on collecting lymphatics or blood vessels, and was not found on any lymphatics of normal airways. Macrophages, potential targets of the inhibitor, did not have alpha5 integrin immunoreactivity in inflamed airways. In addition, macrophage recruitment, assessed in infected airways by quantitative reverse transcription polymerase chain reaction measurements of expression of the marker protein ionized calcium-binding adapter molecule 1 (Iba1), was not reduced by JSM8757. We conclude that inhibition of the alpha5beta1 integrin reduces lymphangiogenesis in inflamed airways after M. pulmonis infection because expression of the integrin is selectively increased on lymphatic sprouts and plays an essential role in lymphatic growth. PMID- 19443706 TI - A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1. AB - Loss of function at the Pten tumor-suppressor locus is a common genetic modification found in human prostate cancer. While recent in vivo and in vitro data support an important role of aberrant ErbB-2 signaling to clinically relevant prostate target genes, such as cyclin D1, the role of Pten in ErbB-2 induced prostate epithelial proliferation is not well understood. In the Pten deficient prostate cancer cell line, LNCaP, restoration of Pten was able to inhibit ErbB-2- and heregulin-induced cell cycle progression, as well as cyclin D1 protein levels and promoter activity. Previously, we established that probasin driven ErbB-2 transgenic mice presented with high-grade prostate intraepithelial neoplasia and increased nuclear cyclin D1 levels. We show that mono-allelic loss of pten in the probasin-driven-ErbB-2 model resulted in increased nuclear cyclin D1 and proliferating cell nuclear antigen levels and decreased disease latency compared to either individual genetic model and, unlike the probasin-driven-ErbB 2 mice, progression to adenocarcinoma. Activated 3-phosphoinositide-dependent protein kinase-1 was observed during cancer initiation combined with the activation of p70S6K (phospho-T389) and inactivation of the 4E-binding protein-1 (phosphorylated on T37/46) and was primarily restricted to those cases of prostate cancer that had progressed to adenocarcinoma. Activation of mTOR was not seen. Our data demonstrates that Pten functions downstream of ErbB-2 to restrict prostate epithelial transformation by blocking full activation of the PDK1 signaling cascade. PMID- 19443707 TI - Platelet-derived hyaluronidase 2 cleaves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines. AB - Hyaluronan (HA) occurs in the body as a large, hydrating, space-filling, carbohydrate polymer in the extracellular matrix; it has both anti-angiogenic and immunosuppressive properties. Cleavage of HA results in the generation of variably sized fragments that stimulate multiple angiogenic and inflammatory responses in a size-specific manner. In this study, we report that platelets, as well as their megakaryocyte precursors, are unusual among somatic cells in that they contain only hyaluronidase 2 (HYAL2) but not HYAL1. Platelet HYAL2 is sufficient to cleave HA into fragments that are specific for inflammatory and angiogenic signaling; this process occurs in the absence of HYAL1, which is necessary in all other tissues to perform further HA degradation. Platelets can bind to HA, some of which derives from the stressed microvessel endothelial cell surface. Platelet-derived HYAL2 cleaves HA into fragments that stimulate mononuclear leukocytes in the immediate microenvironment to produce proinflammatory cytokines, including interleukin-6 and interleukin-8. Platelets, thus, are not only involved in hemostasis, the earliest step in wound healing, but are also important in the signaling of subsequent inflammatory and angiogenic steps. We hypothesize that aberrations in these sequential steps can promote chronic inflammation, as found in inflammatory bowel disease. The platelet may thus provide an interface between acute and chronic inflammation, wound healing, and their subsequent fibrotic responses. PMID- 19443708 TI - The methylation of the TSC2 promoter underlies the abnormal growth of TSC2 angiomyolipoma-derived smooth muscle cells. AB - Tuberous sclerosis complex (TSC) is an autosomal-dominant disease that is caused by mutations in either the TSC1 or TSC2 gene. Smooth muscle-like cells (ASMs) were isolated from an angiomyolipoma of a patient with TSC. These cells lacked tuberin, were labeled by both HMB45 and CD44v6 antibodies, and had constitutive S6 phosphorylation. The cells bear a germline TSC2 intron 8-exon 9 junction mutation, but DNA analysis and polymerase chain reaction amplification failed to demonstrate loss of heterozygosity. Testing for an epigenetic alteration, we detected methylation of the TSC2 promoter. Its biological relevance was confirmed by tuberin expression and a reduction in HMB45 labeling and S6 constitutive phosphorylation after exposure to the chromatin-remodeling agents, trichostatin A and 5-azacytidine. These cells were named TSC2(-/meth) ASMs. Their proliferation required epidermal growth factor in the medium as previously described for TSC2( /-) ASMs. Blockade of epidermal growth factor with monoclonal antibodies caused the death of TSC2(-/meth) ASMs. In addition, rapamycin effectively blocked the proliferation of these cells. Our data show for the first time that methylation of the TSC2 promoter might cause a complete loss of tuberin in TSC2 cells, and that the pathogenesis of angiomyolipomas might also originate from epigenetic defects in smooth muscle cells. Additionally, the effect of chromatin-remodeling agents in these cells suggests a further avenue for the treatment of TSC as well as lymphangioleiomyomatosis. PMID- 19443709 TI - Systematic review of oocyte donation: investigating attitudes, motivations and experiences. AB - BACKGROUND: The social and psychological factors determining intentions to donate gametes are important for clinics, policy-makers and recruitment campaigns. The aims of this systematic review were therefore to integrate the research findings regarding the psychosocial determinants of oocyte donation and extrapolate women's experiences of donation. METHODS: A bibliographic search of English language publications of four computerized databases was undertaken with no time restriction set for publications. RESULTS: A total of 64 studies met the inclusion criteria and were included in the review. The research syntheses revealed there were distinct differences between patient and non-patient (known, commercial, volunteer and potential) donors on demographic characteristics, motives for donation, and issues relating to disclosure and attitudes towards the resultant offspring. Further, studies have found that a significant proportion of oocyte donors and women from the general population were prepared to donate their oocytes as identifiable donors. Studies which have examined the experiences of donors report positive experiences of oocyte donation. However, a number of methodological limitations relating to the oocyte donation research literature have been identified in this systematic review. CONCLUSION: Differences between donor groups on a range of factors highlight the need for tailored psychosocial evaluation and counselling. The review has demonstrated that it is not useful to generalize across donor groups on various factors relating to oocyte donation. PMID- 19443710 TI - A test of a linear model of glaucomatous structure-function loss reveals sources of variability in retinal nerve fiber and visual field measurements. AB - PURPOSE: Retinal nerve fiber (RNFL) thickness and visual field loss data from patients with glaucoma were analyzed in the context of a model, to better understand individual variation in structure versus function. METHODS: Optical coherence tomography (OCT) RNFL thickness and standard automated perimetry (SAP) visual field loss were measured in the arcuate regions of one eye of 140 patients with glaucoma and 82 normal control subjects. An estimate of within-individual (measurement) error was obtained by repeat measures made on different days within a short period in 34 patients and 22 control subjects. A linear model, previously shown to describe the general characteristics of the structure-function data, was extended to predict the variability in the data. RESULTS: For normal control subjects, between-individual error (individual differences) accounted for 87% and 71% of the total variance in OCT and SAP measures, respectively. SAP within individual error increased and then decreased with increased SAP loss, whereas OCT error remained constant. The linear model with variability (LMV) described much of the variability in the data. However, 12.5% of the patients' points fell outside the 95% boundary. An examination of these points revealed factors that can contribute to the overall variability in the data. These factors include epiretinal membranes, edema, individual variation in field-to-disc mapping, and the location of blood vessels and degree to which they are included by the RNFL algorithm. CONCLUSIONS: The model and the partitioning of within- versus between individual variability helped elucidate the factors contributing to the considerable variability in the structure-versus-function data. PMID- 19443711 TI - Eye movement abnormalities in Joubert syndrome. AB - PURPOSE: Joubert syndrome is a genetic disorder characterized by hypoplasia of the midline cerebellum and deficiency of crossed connections between neural structures in the brain stem that control eye movements. The goal of the study was to quantify the eye movement abnormalities that occur in Joubert syndrome. METHODS: Eye movements were recorded in response to stationary stimuli and stimuli designed to elicit smooth pursuit, saccades, optokinetic nystagmus (OKN), vestibulo-ocular reflex (VOR), and vergence using video-oculography or Skalar search coils in 8 patients with Joubert syndrome. All patients underwent high resolution magnetic resonance imaging (MRI). RESULTS: All patients had the highly characteristic molar tooth sign on brain MRI. Six patients had conjugate pendular (n = 4) or see-saw nystagmus (n = 2); gaze holding was stable in four patients. Smooth-pursuit gains were 0.28 to 1.19, 0.11 to 0.68, and 0.33 to 0.73 at peak stimulus velocities of 10, 20, and 30 deg/s in six patients; smooth pursuit could not be elicited in four patients. Saccade gains in five patients ranged from 0.35 to 0.91 and velocities ranged from 60.9 to 259.5 deg/s. Targeted saccades could not be elicited in five patients. Horizontal OKN gain was uniformly reduced across gratings drifted at velocities of 15, 30, and 45 deg/s. VOR gain was 0.8 or higher and phase appropriate in three of seven subjects; VOR gain was 0.3 or less and phase was indeterminate in four subjects. CONCLUSIONS: The abnormalities in gaze-holding and eye movements are consistent with the distributed abnormalities of midline cerebellum and brain stem regions associated with Joubert syndrome. PMID- 19443713 TI - Investigation of the corneal filament in filamentary keratitis. AB - PURPOSE: To date, no studies have elucidated the composition of the corneal filament in detail. In this study, an immunohistochemical technique was used to clarify the exact composition of the corneal filament in filamentary keratitis. In addition, the mechanisms responsible for filament formation were identified. METHODS: Filaments were obtained from 13 patients with filamentary keratitis with a background of penetrating keratoplasty, aqueous tear deficiency, and severe ocular surface disorders, who were receiving treatment at an outpatient facility. From those tissues, transverse and longitudinal frozen sections were prepared and subjected to an indirect fluorescent immunohistochemical analysis with primary antibodies, including cytokeratins (CK1, -4, -6, -10, -12, and -13), mucins (MUC1, -4, -5AC, and -16), keratinization-related proteins (transglutaminase [TGase]-1 and filaggrin), cell proliferation marker Ki67, and markers of infiltration cells (HLA-DR and neutrophil-elastase). TUNEL staining was used for the detection of apoptosis. Fluorescent images of the sections were inspected with a fluorescence microscope. RESULTS: The filaments were composed of CK12 positive cells and had a roll-formed central core. They were covered with MUC5AC- and -16-positive mucins including CK4- and -13-positive cells and neutrophil elastase-positive cells. The filaments also included broken cells and DNA fiber form postlesional nuclei that were positive for TUNEL staining. However, those areas stained weakly for CK6 and HLA-DR; faintly for CK1, CK10, MUC1, and MUC4; and not at all for Ki67, TGase-1, and filaggrin. CONCLUSIONS: The results of this research have the potential to open new pathways toward understanding the mechanism that generates the filament in filamentary keratitis, as well as new treatments in the future. PMID- 19443712 TI - Enhanced HtrA2/Omi expression in oxidative injury to retinal pigment epithelial cells and murine models of neurodegeneration. AB - PURPOSE: To investigate the role of HtrA2/Omi, a nuclear-encoded mitochondrial serine protease with a proapoptosis function, under H(2)O(2)-induced oxidative stress in human RPE, in the Ccl2(-)(/)(-)Cx3cr1(-)(/)(-) double-knockout (DKO) mouse retina, and the HtrA2/Omi-deficient mice. METHODS: Oxidative stress was induced in ARPE-19 cells by 1 mM H(2)O(2) for 2 hours. HtrA2/Omi and caspase-3 expression was evaluated using RQ-PCR, immunohistochemistry, or Western blot. Cell viability was detected by MTT assay. HtrA2/Omi expression in the subcellular components and activated caspase-3 were measured. These processes were also evaluated in cells treated with UCF-101, an HtrA2/Omi inhibitor or in cells subjected to RNAi against HtrA2/Omi. Oxidative stress was assayed and compared in retinas of DKO and wild-type (WT) mice by determining serum NADPH oxidase subunits and nitrite levels. Transmission electron microscopy was used to view the retinal ultrastructure of the HtrA2/Omi-deficient mice. RESULTS: H(2)O(2) induced oxidative damage resulted in HtrA2/Omi translocation from mitochondria to cytosol, leading to RPE cell apoptosis via a caspase-mediated pathway. Treatment of RPE cells with UCF-101 reduced the cytosolic translocation of HtrA2/Omi, attenuated caspase-3 activation, and decreased apoptosis. After specific HtrA2 downregulation, increased cell viability was measured in H(2)O(2)-treated ARPE-19 cells. Retina of DKO mice exhibit increased oxidative stress and upregulation of HtrA2/Omi. Fewer and abnormal mitochondria were found in HtrA2/Omi(-)(/)(-) photoreceptors and RPE. CONCLUSIONS: These findings suggest that HtrA2/Omi is related to RPE apoptosis due to oxidative stress, which may play an important role in the integrity of mitochondria and the pathogenesis of AMD. PMID- 19443714 TI - Role of DAF in protecting against T-cell autoreactivity that leads to experimental autoimmune uveitis. AB - PURPOSE: To investigate the role of decay-accelerating factor (DAF), a cell surface complement regulator that recently has been linked to T-cell responses and autoimmunity in the pathogenesis of experimental autoimmune uveitis (EAU). METHODS: EAU was induced in wild-type (WT) and Daf1(-/-) mice, and their disease severities, IRBP specific Th1/Th17 responses, and cytokine expression profiles were compared. In a test of the efficacy of treatment with soluble mouse DAF protein, EAU was induced in disease-susceptible B10.RIII mice, and they were treated with 0.5 mg soluble DAF protein or equal volume of PBS IP every other day. Retinal histology and IRBP-specific T-cell responses were compared after 14 days. RESULTS: Both EAU incidence and histopathology scores were significantly greater in Daf1(-/-) mice. There was a >10-fold greater mononuclear cell influx into the retina together with severe vasculitic lesions, retinal folding, and photoreceptor cell layer destruction. There were 5- to 7-fold greater Th1 and 3- to 4-fold greater Th17 responses against IRBP in Daf1(-/-) mice with EAU, and they expressed significantly elevated levels of GM-CSF, IL-2, IL-3, and IFN gamma. WT B10.RIII mice that received soluble DAF protein treatments exhibited decreased IRBP-specific Th1/Th17 responses and were protected from retinal injury compared with the mice that received PBS treatments. CONCLUSIONS: DAF significantly influences IRBP-specific Th1 and Th17 responses and disease severity in EAU. Systemic upregulation of DAF levels could be used to suppress retinal antigen(s)-specific autoimmunity to treat autoimmune posterior uveitis. PMID- 19443715 TI - Effect of various platelet preparations on retinal muller cells. AB - PURPOSE: Peeling of the internal limiting membrane is the treatment of choice for macular holes. Fresh platelet suspension (PS) is used to support wound healing in persistent macular holes. The concentration of growth factors in fresh, frozen, and thrombin-activated PSs were compared, to optimize their trophic potential and examine their capacity to support proliferation, migration, and contraction of human retinal Muller cells. METHODS: The concentration of various growth factors in frozen PS, thrombin-activated PS, and plasma were evaluated by ELISA. The effect of these preparations on proliferation, migration, and contraction of human Muller cells were evaluated with an ATP-assay, a colony-dispersion assay, and a detached collagen gel contraction assay respectively. Plasma was tested as a control. RESULTS: Frozen and thrombin-activated PSs contained significantly more EGF, TGF-beta1, and PDGF than did plasma. The highest concentrations of EGF and FGF were found in frozen PS. All platelet preparations and plasma supported cell growth significantly better than the control, which was serum-free culture medium. Muller cells migrated better when incubated with thrombin-activated PS than with any other test solution. Contraction was extremely strong after incubation with fresh PS compared with plasma or thrombin-activated or frozen PSs. CONCLUSIONS: Frozen and thrombin-activated PSs may be suitable alternatives to fresh PS for persisting macular holes, due to their superior effect on Muller cell migration. PMID- 19443716 TI - Ocular responses and visual performance after high-acceleration force exposure. AB - PURPOSE: To evaluate ocular responses and visual performance after high acceleration force exposure. METHODS: Fourteen men were enrolled in the study. A human centrifuge was used to induce nine times the acceleration force in the head to-toe (z-axis) direction (+9 Gz force). Visual performance was evaluated using the ETDRS (Early Treatment of Diabetic Retinopathy Study) visual chart, and contrast sensitivity (CS) was examined before and after centrifugation. Ocular responses were assessed with biomicroscopy and topographic mapping after gravitational stress. RESULTS: Transient visual acuity reduction (0.02 +/- 0.04 logMar vs. 0.19 +/- 0.07 logMar VA; P < 0.05) and temporary ocular anterior segment reactions were observed immediately after centrifugation. These reactions included changes in corneal thickening (553.7 +/- 21.7 mum vs. 591.2 +/- 20.6 mum; P < 0.05), increasing anterior chamber depth (ACD; 3.19 +/- 0.26 mm vs. 4.53 +/- 0.34 mm; P < 0.05), and pupillary enlargement (3.54 +/- 0.73 mm vs. 5.76 +/- 0.61 mm; P < 0.05). The increase in ACD continued for 15 minutes after exposure to acceleration (3.19 +/- 0.26 mm vs. 4.39 +/- 0.27 mm; P < 0.05). Pupillary dilation was noted both 15 (3.54 +/- 0.73 mm vs. 5.56 +/- 0.67 mm; P < 0.05) and 30 (5.47 +/- 0.59 mm, P < 0.05) minutes after the gravitational stress. CS decreased significantly at low and medium spatial frequencies (1.5, 3, and 6 cyc/deg) and did not return to the baseline level by 30 minutes. CONCLUSIONS: High-acceleration force may induce transient visual acuity reduction and temporary corneal thickening. Prolonged increase in ACD and pupillary dilation were also observed. The decrease in CS persisted for 30 minutes after centrifugation. The mechanisms underlying these observations are not clear, because there are no previous reports on this topic. Further studies are needed. PMID- 19443717 TI - Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells. AB - PURPOSE: The role of miR-34a, a p53-regulated microRNA, in retinoblastoma (RB) was investigated. METHODS: The expression of miR-34 family members in RB cells was determined by semiquantitative RT-PCR and real-time qPCR. Regulation of miR 34a expression by p53-activating compounds was determined by qPCR analysis. The tumor suppressor functions of miR-34a in RB cell lines were determined by tetrazolium-based cell growth assay and by caspase-3/7 and activated caspase-3 apoptotic activity assays. Additive growth inhibitory properties of miR-34a in combination with topotecan were determined by cell growth assay. miR-34a targets in RB cells were identified by real-time qPCR expression analysis of previously reported and GenMiR++-predicted mRNAs. RESULTS: Differential miR-34a and miR-34b expression was observed in RB cell lines and tumor samples. miR-34a expression could be increased in Y79 cells, but not Weri-Rb1 cells, after p53 activation. This differential regulation was not caused by genomic alterations at the miR-34a p53 binding site or mature gene. Exogenous miR-34a inhibited Y79 and Weri-Rb1 cell growth and increased apoptotic activity in Y79 cells. Increased inhibition of Y79 and Weri-Rb1 cell growth was observed with combination miR-34a and topotecan treatment. mRNA expression changes were observed in 7 of 7 previously reported and 13 of 18 GenMiR++-predicted miR-34a targets after transfection of Y79 cells with miR-34a compared with negative control microRNA. CONCLUSIONS: miR 34a functions as a tumor suppressor in RB cells and is a potential therapeutic target. Differential expression, regulation, and activity of miR-34a in RB cells may suggest further p53 pathway inactivation in RB. PMID- 19443718 TI - Comparison of clinical and spectral domain optical coherence tomography optic disc margin anatomy. AB - PURPOSE: To investigate spectral domain optical coherence tomography (SD-OCT) detected optic disc margin anatomy in the monkey eye by colocalizing disc photographs to SD-OCT scans acquired from the same eyes. METHODS: The neural canal opening (NCO) was delineated within 40 digital radial sections generated from SD-OCT volumes acquired from 33 normal monkey eyes (15 degrees, 290 x 768 horizontal grid pattern). Each volume was colocalized to its disc photograph by matching the retinal vessels within each photograph to vessel outlines visible within en face SD-OCT images. Border tissue was delineated where it extended internally to the NCO. A clinician (masked to delineated points) marked the disc margin onto each photograph while viewing the relevant stereophotograph pair. Alignment of the clinician-ascribed disc margin to the NCO and border tissue delineation was assessed. The process was repeated in a single myopic human eye. RESULTS: In 23 eyes, the NCO aligned to the disc margin. In 10 eyes, externally oblique border tissue was detectable in the temporal disc. In these regions of the disc, the termination of border tissue was the disc margin. An exaggerated form of this phenotype was observed in the myopic human eye. In this case, temporal border tissue terminated at the anterior scleral canal opening, which was detected as the disc margin. CONCLUSIONS: The termination of Bruch's membrane, border tissue, and the anterior scleral canal opening may constitute the disc margin within the same eye, depending on the border tissue architecture; this anatomy is consistently visualized by SD-OCT. PMID- 19443719 TI - Is routine pupil dilation safe among asian patients with diabetes? AB - PURPOSE: To investigate the risk of acute angle closure (AAC), changes in intraocular pressure (IOP), and factors associated with these outcomes after routine pupil dilation in a cohort of Asian subjects with diabetes mellitus. METHODS: The study was a prospective observational case series of 1910 consecutive Asian subjects newly referred for assessment of diabetic retinopathy at a tertiary clinic. All subjects underwent routine pupil dilation unless there was a prior history of angle-closure glaucoma. Noncontact air-puff tonometry was used to assess IOP, which was measured by the same observer before and 1 hour after pupil dilation. Subjects were assessed for signs and symptoms of AAC before leaving the clinic, and their charts were also subsequently reviewed for revisits with AAC. RESULTS: Of the 1910 subjects who participated, none developed AAC. Sixty-nine subjects (3.6%, 95% CI: 2.8%-4.5%) showed an increase in IOP of >or=5 mm Hg in the either eye, 37 subjects (1.9%, 95% CI: 1.4%-2.6%) had a postdilation IOP >25 mm Hg in either eye, and only 10 subjects (0.52%, 95% CI: 0.25%-0.96%) had an increase in IOP >or=5 mm Hg and had a postdilation IOP >25 mm Hg in either eye. The level of predilation IOP and a known history of glaucoma were significant risk factors for a postdilation IOP >or=25 mm Hg. CONCLUSIONS: In this cohort of Asian persons with diabetes, the risk of AAC was insignificant after routine dilation of pupils for fundus examination. These data substantiate the safety of routine dilation of pupils in Asian patients with diabetes. PMID- 19443720 TI - Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy. AB - PURPOSE: The majority of patients with autosomal dominant optic atrophy (DOA) harbor pathogenic OPA1 mutations and certain missense mutations, mostly within the GTPase domain, have recently been shown to cause multiple mitochondrial DNA (mtDNA) deletions in skeletal muscle. This raises the possibility that the optic neuropathy could be the result of secondary mtDNA defects accumulating within retinal ganglion cells (RGCs). To explore this hypothesis, the authors looked for evidence of mitochondrial dysfunction in a mouse model of DOA and documented the visual and neurologic progression in aging mutant mice. METHODS: Visual function was assessed with a rotating optokinetic (OKN) drum at ages 13 and 18 months and neurologic phenotyping was performed using the primary SHIRPA screen at age 13 months, comparing mutant Opa1(+/)(-) mice with wild-type C57Bl/6 mice. The presence of cytochrome c oxidase (COX) deficiency and multiple mtDNA deletions was investigated in gastrocnemius muscle and eye specimens harvested from 2- and 11-month-old Opa1(+/+) and Opa1(+/)(-) mice. RESULTS: At age 13 months, Opa1(+/)( ) mice had a statistically significant reduction in OKN responses compared to C57Bl/6 controls with both 2 degrees and 8 degrees gratings (P < 0.001). At age 18 months, the difference between the two groups was significant for the 8 degrees grating (P = 0.003) but not for the 2 degrees grating (P = 0.082). Opa1(+/)(-) mice did not exhibit any significant neuromuscular deficits and no COX deficient areas or secondary mtDNA deletions were identified in skeletal muscle or the RGC layer. There was also no evidence of significant mtDNA depletion or proliferation in skeletal muscle from Opa1(+/)(-) mice. CONCLUSIONS: COX deficiency and mtDNA abnormalities do not contribute to optic nerve dysfunction in pure DOA. PMID- 19443721 TI - Plasminogen activator inhibitor-1 (PAI-1) facilitates retinal angiogenesis in a model of oxygen-induced retinopathy. AB - PURPOSE: Angiogenesis, or the formation of new retinal blood vessels, is a key feature of many proliferative retinal diseases including diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity. The aim of the present study was to investigate the role of the serine proteinase inhibitor plasminogen activator inhibitor -1 (PAI-1) in facilitating retinal angiogenesis. METHODS: The temporal expression of PAI-1 was examined by real-time PCR, Western blot analysis, and immunohistochemistry in retinal tissues from mice with oxygen induced retinopathy. The requirement for PAI-1 in facilitating the retinal angiogenic response in this model was examined by quantitating the angiogenic response with wild-type and PAI-1 null mice. The mechanism by which PAI-1 mediates angiogenesis was further investigated with isolated human retinal vascular endothelial cells. RESULTS: PAI-1 expression was upregulated in the retinas of mice with oxygen-induced retinopathy, which coincided with a significant increase in the expression of vitronectin in the retina of the experimental mice. There was significant reduction in the angiogenic response of PAI-1(-/-) mice compared with wild-type mice. PAI-1 promotes endothelial cell migration in vitro and facilitates the migration of cells on a vitronectin substrate by regulating alpha v integrin cell surface expression. CONCLUSIONS: These observations suggest a role for PAI-1 during retinal angiogenesis and point to a potential new therapeutic target in the prevention or treatment of retinal neovascularization seen in many ocular diseases. PMID- 19443722 TI - Corneal biomechanical changes in diabetes mellitus and their influence on intraocular pressure measurements. AB - PURPOSE: To investigate possible corneal biomechanical changes in patients with diabetes mellitus and understand the influence of such changes on intraocular pressure measurements. METHODS: The study group was composed of 120 eyes from 61 healthy control subjects and 81 eyes from 43 diabetic subjects. IOP was measured first with an ocular response analyzer (ORA) and subsequently with a Goldmann applanation tonometer (GAT). Central corneal thickness (CCT) was measured with an ultrasonic pachymeter attached to the ORA. Axial length (AL), anterior chamber depth (ACD), and keratometry readings were acquired with partial coherence laser interferometry during the same visit before all IOP and CCT determinations were made. RESULTS: Corneal hysteresis (CH) was found to be significantly lower in diabetic patients when compared with healthy control subjects (9.51 +/- 1.82 mm Hg vs. 10.41 +/- 1.66 mm Hg, P < 0.0001). There was no significant difference in terms of corneal resistance factor (CRF; P = 0.8). Mean CCT, GAT IOP, Goldmann correlated IOP (IOPg), and corneal-compensated IOP (IOPcc) were significantly higher in diabetic patients than in healthy control subjects (P = 0.01 for CCT, P < 0.0001 for GAT IOP, IOPg, and IOPcc). CONCLUSIONS: Diabetes affects corneal biomechanics and results in lower CH values than those in healthy control subjects, which may cause clinically relevant high IOP measurements independent of CCT. PMID- 19443724 TI - Resolvins E1 and D1 in choroid-retinal endothelial cells and leukocytes: biosynthesis and mechanisms of anti-inflammatory actions. AB - PURPOSE: To investigate the biosynthesis of resolvins E1 and D1 (RvE1 and RvD1) in choroid-retinal endothelial cells (CRECs) and leukocytes under inflammatory conditions and to define the mechanisms of anti-inflammatory actions of RvE1 and RvD1 in CRECs and leukocytes, cells crucial to posterior ocular inflammation. METHODS: RvE1, RvD1, and markers of their biosynthesis were determined by lipidomic analysis. After CRECs or cocultures of CRECs and leukocytes were treated with RvE1 or RvD1 and inflammatory stimuli, inflammatory signaling molecules were quantified by Western blot analysis, ELISA, or protein array. Transmigration of polymorphonuclear leukocytes (PMNs) across CRECs monolayers was quantified. RESULTS: Inflammatory stimulation increased the biosynthesis of RvE1 and RvD1 from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, in coculture of CRECs and leukocytes. CRECs alone did not produce RvE1 and RvD1. RvE1 or RvD1 inhibited the expressions of vascular cell adhesion molecule-1, IL-8, macrophage inflammatory protein-1beta, regulated on activation normal T cell expressed and secreted, and tumor necrosis factor-alpha from CRECs or cocultures of CRECs and leukocytes. RvD1 reduced prostaglandin E(2) generation from CRECs. However, neither resolvin affected cyclooxygenase-2 formation. Treating CRECs or PMNs with RvE1 or RvD1 inhibited PMN transmigration across CREC barriers. CONCLUSIONS: The interplay of inflammatory stimuli-activated CRECs and leukocytes biosynthesizes RvE1 and RvD1 from EPA and DHA. These resolvins inhibit inflammatory signaling from CRECs and leukocytes and inflammatory activity as PMN transmigration across CRECs barriers. Thus, these resolvins and their biosynthesis pathways are potential targets for novel treatment of inflammatory ocular diseases. PMID- 19443723 TI - FAK and p38-MAP kinase-dependent activation of apoptosis and caspase-3 in retinal endothelial cells by alpha1(IV)NC1. AB - PURPOSE: To determine the impact of the antiangiogenic factor alpha1(IV)NC1 on vascular endothelial growth factor-mediated proangiogenic activity in mouse retinal endothelial cells (MRECs). METHODS: Primary culture of MRECs was established as previously described and was used to determine the effects of alpha1(IV)NC1 on the proangiogenic activity of VEGF. Cell proliferation was evaluated using [(3)H]-thymidine incorporation and 3,(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide colorimetric assays. Cell migration was determined using modified Boyden chamber and scratch wound assays and tube formation was assessed on basement membrane matrix (BMM). Intracellular signaling events Bcl-2/Bcl-x(L) and caspase-3/poly (ADP-ribose) polymerase (PARP) activities were evaluated in cells stimulated with VEGF and plated on type IV collagen-coated dishes. Apoptosis was assessed by measuring caspase activity and by performing quantitative fluorescence analysis using fluorescence-activated cell sorting assay. Subcutaneously injected VEGF induced in vivo neovascularization was studied with the BMM plug assay. RESULTS: VEGF-induced subconfluent MREC proliferation, migration, and tube formation were significantly inhibited by alpha1(IV)NC1 at 1 muM (P < 0.001). alpha1(IV)NC1 induced MREC apoptosis is mediated by inhibition of Bcl-2 and Bcl-x(L) expression and activation of caspase-3/PARP through FAK/p38-MAPK signaling. In addition, alpha1(IV)NC1 dose dependently inhibited VEGF-mediated neovascularization in vivo. CONCLUSIONS: alpha1(IV)NC1 inhibited VEGF-mediated angiogenesis by promoting apoptosis and caspase-3/PARP activation and by negatively impacting FAK/p38-MAPK phosphorylation, Bcl-2, and Bcl-x(L) expression leading to MREC death. The endothelial-specific inhibitory actions of recombinant alpha1(IV)NC1 may be of benefit in the treatment of a variety of eye diseases with a neovascular component. PMID- 19443725 TI - Dependence of EGF-induced increases in corneal epithelial proliferation and migration on GSK-3 inactivation. AB - PURPOSE: This study was designed to determine in human corneal epithelial cells (HCEC) whether the balance between epidermal growth factor (EGF)-induced increases in proliferation and migration is dependent on the duration and magnitude of extracellular signal-regulated kinase (Erk)1/2 activation. METHODS: Western blot analysis evaluated the phosphorylation status of Erk1/2 and phosphoinositide 3-kinase (PI3-K) along with cell cycle kinases, paxillin, and mitogen kinase protein phosphatase (MKP)-1. Proliferation and migration rates were determined by [(3)H]-thymidine incorporation and scratch wound healing assay, respectively. RESULTS: EGF induced increases in paxillin Ser-126 phosphorylation and cyclin D1 expression through transient Erk1/2 phosphorylation. However, preinhibition of glycogen synthase kinase (GSK)-3 activation with 20 microM SB415286 prolonged and augmented this Erk1/2 response to EGF but decreased cyclin D1 expression, whereas p27Kip1 levels rose. In turn, the mitogenic response fell, whereas paxillin phosphorylation occurred 45 minutes sooner than without SB415286. In contrast, blocking PI3-K activation with LY294002 (50 microM) eliminated EGF-induced GSK-3 inhibition and Erk1/2 phosphorylation as well as increases in proliferation and migration. SB415286 or U0126 (10 microM) suppression of Erk1/2 phosphorylation blocked EGF-induced MKP-1 phosphorylation. Inhibition of EGF-induced increases in proliferation and migration by LY294002 was associated with sustained MKP-1 phosphorylation induced by GSK-3. Prolonging MKP-1 phosphorylation by LY294002 increased p27Kip1, whereas cyclin D1 levels fell. CONCLUSIONS: GSK-3-induced MKP-1 phosphorylation mediates negative feedback control between EGF receptor-linked PI3-K and ERK signaling pathways. Inhibition of such control prolongs Erk1/2 activation and alters the balance between EGF-induced increases in proliferation and migration. Therefore, these responses to EGF can be modulated through altering the feedback between these two pathways. PMID- 19443726 TI - Relationship of retinal vascular caliber with retinal nerve fiber layer thickness: the singapore malay eye study. AB - PURPOSE: To describe the relationship of retinal arteriolar and venular caliber with retinal nerve fiber layer (RNFL) thickness. METHODS: A population-based, cross-sectional study of Malay persons aged 40 to 80 years residing in Singapore was conducted from 2004 to 2006. Retinal arteriolar and venular calibers were measured with a computer-based technique according to a validated, standardized protocol. RNFL was assessed with retinal tomography. RESULTS: There were 2706 persons with gradable retinal photographs and HRT images of acceptable quality available for analysis. In linear regression models that adjusted for age, sex, diabetes, body mass index, intraocular pressure, and other factors, each standard deviation decrease in arteriolar and venular caliber was associated with a 5.81- and 8.37-microm decrease, respectively, in mean global RNFL thickness (both P < 0.001). These associations remained similar after persons with glaucoma were excluded. In persons with glaucoma, retinal venular caliber was independently associated with the temporal and temporal-to-inferior region of mean RNFL thickness in multivariate analysis; each SD decrease in retinal venular diameter was associated with an 8.54-microm decrease in the temporal region (P = 0.022), and a 38.32-microm decrease in the temporal-to-inferior region (P = 0.006) of mean RNFL thickness. CONCLUSIONS: Narrower retinal vessel caliber was associated with reduced RNFL thickness in this Asian population. PMID- 19443727 TI - Regulatory role of TLR ligands on the activation of autoreactive T cells by retinal astrocytes. AB - PURPOSE: To determine whether Toll-like receptor (TLR) ligands regulate the activation of retinal astrocytes (RACs) and the possible role of RACs in the polarization of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells. METHODS: TLR expression on RACs isolated from C57BL/6 mice was examined using real-time PCR and flow cytometry. The ability of RACs before or after treatment with TLR ligands to interact with T cells was assessed by measuring major histocompatibility complex class II and costimulatory molecule expression and cytokine production. The stimulatory effect of RACs, with or without TLR stimulation, on responder IRBP-specific T cells was examined by T-cell proliferation, cytokine production, and disease-inducing ability. RESULTS: Cultured mouse RACs expressed TLR2, TLR3, and TLR4. Different TLR ligands had distinct stimulatory effects on RACs. PolyI:C (a TLR3 ligand) had the greatest effect in stimulating RACs to acquire antigen-presentation function, whereas BLP (a TLR2 ligand) had the lowest effect. TLR3 ligation increased the expression of MHC and costimulatory molecules and induced the production of IL-6, IL-12, and IL 23 by RACs. IRBP-specific T cells activated by polyI:C-treated RACs expanded vigorously, produced significant amounts of IFN-gamma and IL-17, and induced experimental autoimmune uveitis when injected into naive mice. CONCLUSIONS: The stimulatory effect of RACs on autoreactive T cells is regulated by TLR ligands. TLR3 had a marked effect on the ability of RACs to promote the activation of Th1 and Th17 IRBP-specific T cells. Thus, exposure to microbial antigen(s) may alter susceptibility to autoimmune uveitis by promoting the activation of autoreactive T cells. PMID- 19443728 TI - Regulation of dynamic behavior of retinal microglia by CX3CR1 signaling. AB - PURPOSE: Microglia in the central nervous system display a marked structural dynamism in their processes in the resting state. This dynamic behavior, which may play a constitutive surveying role in the uninjured neural parenchyma, is also highly responsive to tissue injury. The role of CX3CR1, a chemokine receptor expressed in microglia, in regulating microglia morphology and dynamic behavior in the resting state and after laser-induced focal injury was examined. METHODS: Time-lapse confocal imaging of retinal explants was used to evaluate the dynamic behavior of retinal microglia labeled with green fluorescent protein (GFP). Transgenic mice in which CX3CR1 signaling was ablated (CX3CR1(GFP/GFP)/CX3CR1(-/ )) and preserved (CX3CR1(+/GFP)/CX3CR1(+/-)) were used. RESULTS: Retinal microglial density, distribution, cellular morphology, and overall retinal tissue anatomy were not altered in young CX3CR1(-/-) animals. In the absence of CX3CR1, retinal microglia continued to exhibit dynamic motility in their processes. However, rates of process movement were significantly decreased, both under resting conditions and in response to tissue injury. In addition, microglia migration occurring in response to focal laser injury was also significantly slowed in microglia lacking CX3CR1. CONCLUSIONS: CX3CR1 signaling in retinal microglia, though not absolutely required for the presence of microglial dynamism, plays a role in potentiating the rate of retinal microglial process dynamism and cellular migration. CX3CL1 signaling from retinal neurons and endothelial cells likely modulates dynamic microglia behavior so as to influence the level of microglial surveillance under basal conditions and the rate of dynamic behavior in response to tissue injury. PMID- 19443729 TI - Effect of bimatoprost, latanoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human ciliary body smooth muscle cells. AB - PURPOSE: Matrix metalloproteinase (MMP)-mediated turnover of extracellular matrix (ECM) affects outflow resistance in the uveoscleral pathway. The balance of MMPs and tissue inhibitors of metalloproteinases (TIMPs) governs the rate of ECM turnover in many tissues. The hypothesis was that a differential effect on MMPs and TIMPs in ciliary body smooth muscle (CBSM) cells would relate to the relative intraocular pressure-lowering effectiveness of the prostaglandin analogues (PGAs) bimatoprost, latanoprost, and unoprostone. METHODS: Human CBSM cells isolated from donor corneoscleral rims were incubated for 24 hours with control (0.015% ethanol in DMEM) or the free acid forms of bimatoprost (0.01 or 0.1 microg/mL), latanoprost (0.03 or 0.3 microg/mL), or unoprostone (0.145 or 1.45 microg/mL). Western blot analysis determined the relative protein concentrations of MMP-1, 2, -3. -9, and -24 as well as TIMP-1 through -4. Zymography measured the relative activity levels of MMP-1, -2, -3, and -9. RESULTS: All PGAs increased MMP-1, -3, and -9. Bimatoprost and latanoprost did not change MMP-2. Unoprostone decreased MMP-2 (21% +/- 3%). On zymography, MMP-1 and -2 did not change. Bimatoprost and latanoprost increased MMP-9 activity by 75% +/- 27% and 75% +/- 24%, respectively. MMP-3 activity was not detected on zymography. All PGAs increased TIMP-3, but only unoprostone increased TIMPs1 and -4 by 100% +/- 20% and 61% +/- 11%, respectively. TIMP-2 was unchanged by bimatoprost and latanoprost, but decreased by unoprostone (35% +/- 8%). CONCLUSIONS: Decreased MMP-2 with concurrent increases of TIMP-1 and -4 by unoprostone may explain the lower clinical efficacy of unoprostone. The MMP/TIMP balance relates to the observed intraocular pressure-lowering effectiveness in clinical studies with PGAs. PMID- 19443730 TI - Recharacterization of the RGC-5 retinal ganglion cell line. AB - PURPOSE: The transformed RGC-5 retinal ganglion cell line is used widely in glaucoma research. Increased resistance to glutamate was noted in published literature and led to the recharacterization of the RGC-5 cell line. METHODS: Characterization of the RGC-5 cell line was performed by sequencing of a region of the nuclear Thy1 gene and mitochondrial DNA sequencing of a region of the d loop and tRNA(Phe) gene. Marker expression was examined in undifferentiated cells, and cells differentiated with 50 microg/mL succinyl concanavalin A (S Con A) for 3 days. Glutamate sensitivity was examined in undifferentiated and S Con A differentiated cells by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24-hours of glutamate treatment. RESULTS: RGC-5 cells were found to be of mouse (Mus musculus), not rat (Rattus norvegicus), origin by mitochondrial and nuclear DNA analyses. RGC-5 DNA sequenced in a second laboratory was subsequently found to be of M. musculus origin. Cells stained positively for the neuronal markers beta-tubulin and PGP9.5 and for the microtubule-associated protein tau, but not for known markers of ganglion cells such as neurofilaments or Thy1.2, suggesting that they likely represented a lineage of mouse neuronal precursor cells. Differentiation with S Con A did not increase RGC-5 sensitivity to glutamate excitotoxicity or increase the expression of retinal or ganglion cell marker proteins. CONCLUSIONS: Investigators using cells designated as RGC-5 should confirm the species to be of rat origin and retinal-specific marker expression before considering their use as retinal ganglion-like cells. PMID- 19443731 TI - Histamine H1 receptor induces cytosolic calcium increase and aquaporin translocation in human salivary gland cells. AB - One of the common side effects of antihistamine medicines is xerostomia (dry mouth). The current consensus is that antihistamine-induced xerostomia comes from an antimuscarinic effect. Although the effect of antihistamines on salivary secretion is both obvious and significant, the cellular mechanism whereby this happens is still unclear because of the lack of knowledge of histamine signaling in human salivary glands. Here, we have studied histamine receptors and the effect of antihistamines on human submandibular acinar cells. In primary cultured human submandibular gland and a HSG cell line, histamine increased the intracellular Ca(2+) concentration. The histamine-induced cytosolic free Ca(2+) concentration ([Ca(2+)](i)) increase was inhibited by histamine H1 receptor specific antagonists, and the expression of the functional histamine H1 receptor was confirmed by reverse transcription-polymerase chain reaction. Interestingly, histamine pretreatment did not inhibit a subsequent carbachol-induced [Ca(2+)](i) rise without "heterologous desensitization." Chlorpheniramine inhibited a carbachol-induced [Ca(2+)](i) increase at a 100-fold greater concentration than histamine receptor antagonism, whereas astemizole and cetrizine showed more than 1000-fold difference, which in part explains the xerostomia-inducing potency among the antihistamines. Notably, histamine resulted in translocation of aquaporin-5 to the plasma membrane in human submandibular gland cells and green fluorescent protein-tagged aquaporin-5 expressing HSG cells. We found that histidine decarboxylase and the histamine H1 receptor are broadly distributed in submandibular gland cells, whereas choline acetyltransferase is localized only at the parasympathetic terminals. Our results suggest that human salivary gland cells express histamine H1 receptors and histamine-synthesizing enzymes, revealing the cellular mechanism of antihistamine-induced xerostomia. PMID- 19443733 TI - Activation of PPARgamma by rosiglitazone attenuates intestinal Cl- secretion. AB - The thiazolidinedione (TZD) drugs rosiglitazone (Ro) and pioglitazone (Po) are PPARgamma agonists in widespread clinical use as insulin-sensitizing agents in Type 2 diabetes. On the basis of recent evidence implicating PPARgamma as a positive modulator of intestinal epithelial differentiation, we hypothesized that TZD drugs might attenuate intestinal secretory function. To evaluate this possibility, we examined the effects of Ro and Po on electrogenic Cl- secretion [short-circuit current (I(sc))] in mouse intestinal segments and in cultured human intestinal epithelial cells (HT29-Cl.19A). As hypothesized, oral administration of Ro (20 mg.kg(-1).day(-1)) to mice for 8 days markedly reduced intestinal I(sc) responses to cAMP (forskolin)- and Ca2+ (carbachol)-dependent stimuli. In these Ro-treated mice, cholera toxin-induced intestinal fluid accumulation was reduced 65%. With continued Ro treatment, the I(sc) response to carbachol recovered significantly, whereas that to forskolin remained attenuated. Treatment of HT29 cells for 5 days with 10 muM Ro or Po in vitro brought about a similar hyposecretory state. In HT29 cells, the loss of cAMP-dependent Cl- secretion was attributable to a reduced expression of CFTR Cl- channel, KCNQ1 K+ channel, and Na-K-2Cl cotransporter-1 proteins. The transient loss of Ca2+ dependent Cl- secretion involved an impairment of basolateral Ca2+-stimulated K+ channel activity without a detectable loss of K(Ca)3.1 channel protein. Our results establish TZD drugs as important modulators of intestinal Cl- secretory function. PMID- 19443732 TI - Epithelial cells in fetal intestine produce chemerin to recruit macrophages. AB - Macrophages are first seen in the fetal intestine at 11-12 wk and rapidly increase in number during the 12- to 22-wk period of gestation. The development of macrophage populations in the fetal intestine precedes the appearance of lymphocytes and neutrophils and does not require the presence of dietary or microbial antigens. In this study, we investigated the role of chemerin, a recently discovered, relatively selective chemoattractant for macrophages, in the recruitment of macrophage precursors to the fetal intestine. Chemerin mRNA/protein expression was measured in jejunoileal tissue from 10- to 24-wk human fetuses, neonates operated for intestinal obstruction, and adults undergoing bariatric surgery. The expression of chemerin in intestinal epithelial cells (IECs) was confirmed by using cultured primary IECs and IEC-like cell lines in vitro. The regulatory mechanisms involved in chemerin expression were investigated by in silico and immunolocalization techniques. IECs in the fetal, but not mature, intestine express chemerin. Chemerin expression peaked in the fetal intestine at 20-24 wk and then decreased to original low levels by full term. During the 10- to 24-wk period, chemerin accounted for most of the macrophage chemotactic activity of cultured fetal IECs. The maturational changes in chemerin expression correlated with the expression of retinoic acid receptor beta in the intestine. Chemerin is an important mediator of epithelial-macrophage cross talk in the fetal/premature, but not in the mature, intestine. Understanding the regulation of the gut macrophage pool is an important step in development of novel strategies to boost mucosal immunity in premature infants and other patient populations at risk of microbial translocation. PMID- 19443734 TI - Sexual assault and rape perpetration by college men: the role of the big five personality traits. AB - A sample of 521 college men completed the Revised NEO Personality Inventory and an expanded version of the Sexual Experiences Survey to examine whether variation in the Big Five personality traits in a normal, college population provides any insight into the nature of sexual assault and rape perpetrators. Rape perpetrators reported lower levels of Agreeableness and Conscientiousness when compared to both sexual assault perpetrators and nonperpetrators, and lower levels of Extraversion when compared to nonperpetrators. Rape perpetrators also endorsed lower levels of tendermindedness, excitement-seeking, warmth, positive emotions, feelings, altruism, competence, and dutifulness, and higher levels of vulnerability. Contrary to expectation, overall personality profiles followed remarkably comparable patterns for sexual assault and nonperpetrators, suggesting that sexual assault perpetrators were more similar to nonperpetrators than to rape perpetrators. Findings suggest that individuals who perpetrate sexual offenses, particularly rape, differ from nonperpetrators on dimensions of normal personality. Clinical and research implications are discussed. PMID- 19443735 TI - A vital role for interleukin-21 in the control of a chronic viral infection. AB - Understanding the factors that regulate the induction, quality, and longevity of antiviral T cell responses is essential for devising rational strategies to prevent or combat infections. In this study, we show that interleukin-21 (IL-21), likely produced by CD4+ T cells, directly influences the generation of polyfunctional CD8+ T cells and that the number of CD4+ T cells that produce IL 21 differs markedly between acute and chronic infections. IL-21 regulates the development of CD8+ T cell exhaustion and the ability to contain chronic lymphocytic choriomeningitis virus infection. Thus, IL-21 serves as a critical helper factor that shapes the functional quality of antiviral CD8+ T cells and is required for viral control. PMID- 19443736 TI - Determining the dynamics of entanglement. AB - The estimation of the entanglement of multipartite systems undergoing decoherence is important for assessing the robustness of quantum information processes. It usually requires access to the final state and its full reconstruction through quantum tomography. General dynamical laws may simplify this task. We found that when one of the parties of an initially entangled two-qubit system is subject to a noisy channel, a single universal curve describes the dynamics of entanglement for both pure and mixed states, including those for which entanglement suddenly disappears. Our result, which is experimentally demonstrated using a linear optics setup, leads to a direct and efficient determination of entanglement through the knowledge of the initial state and single-party process tomography alone, foregoing the need to reconstruct the final state. PMID- 19443737 TI - Synapse- and stimulus-specific local translation during long-term neuronal plasticity. AB - Long-term memory and synaptic plasticity require changes in gene expression and yet can occur in a synapse-specific manner. Messenger RNA localization and regulated translation at synapses are thus critical for establishing synapse specificity. Using live-cell microscopy of photoconvertible fluorescent protein translational reporters, we directly visualized local translation at synapses during long-term facilitation of Aplysia sensory-motor synapses. Translation of the reporter required multiple applications of serotonin, was spatially restricted to stimulated synapses, was transcript- and stimulus-specific, and occurred during long-term facilitation but not during long-term depression of sensory-motor synapses. Translational regulation only occurred in the presence of a chemical synapse and required calcium signaling in the postsynaptic motor neuron. Thus, highly regulated local translation occurs at synapses during long term plasticity and requires trans-synaptic signals. PMID- 19443738 TI - Pd-Pt bimetallic nanodendrites with high activity for oxygen reduction. AB - Controlling the morphology of Pt nanostructures can provide a great opportunity to improve their catalytic properties and increase their activity on a mass basis. We synthesized Pd-Pt bimetallic nanodendrites consisting of a dense array of Pt branches on a Pd core by reducing K2PtCl4 with L-ascorbic acid in the presence of uniform Pd nanocrystal seeds in an aqueous solution. The Pt branches supported on faceted Pd nanocrystals exhibited relatively large surface areas and particularly active facets toward the oxygen reduction reaction (ORR), the rate determining step in a proton-exchange membrane fuel cell. The Pd-Pt nanodendrites were two and a half times more active on the basis of equivalent Pt mass for the ORR than the state-of-the-art Pt/C catalyst and five times more active than the first-generation supportless Pt-black catalyst. PMID- 19443739 TI - Diversity and complexity in DNA recognition by transcription factors. AB - Sequence preferences of DNA binding proteins are a primary mechanism by which cells interpret the genome. Despite the central importance of these proteins in physiology, development, and evolution, comprehensive DNA binding specificities have been determined experimentally for only a few proteins. Here, we used microarrays containing all 10-base pair sequences to examine the binding specificities of 104 distinct mouse DNA binding proteins representing 22 structural classes. Our results reveal a complex landscape of binding, with virtually every protein analyzed possessing unique preferences. Roughly half of the proteins each recognized multiple distinctly different sequence motifs, challenging our molecular understanding of how proteins interact with their DNA binding sites. This complexity in DNA recognition may be important in gene regulation and in the evolution of transcriptional regulatory networks. PMID- 19443740 TI - Forced expiratory flows and volumes in intubated and paralyzed infants and children: normative data up to 5 years of age. AB - Reference equations that express indexes obtained from forced expiratory maneuvers in relation to height and/or other independent variables are lacking for infants and children with artificial airways. The present study was performed to establish normative data of forced expiration by forced deflation in healthy intubated and paralyzed infants and children and to develop prediction equations in relation to height and to ulna length to enable pulmonary assessments in children whose height is difficult to measure. Measurements of forced and passive expiratory maneuvers after inflation to +40 cmH(2)O inspiratory pressure were prospectively obtained in 100 healthy anesthetized children from 0 to 5 yr of age. Linear regressions of log-transformed forced vital capacity (FVC) and maximum expiratory flow at 25% and 10% FVC (MEF(25) and MEF(10), respectively) obtained by forced deflation (-40 cmH(2)O airway opening pressure) and of analogous indexes obtained by passive deflation were used to develop prediction equations from height or ulna length. FVC was significantly dependent on age and height or ulna length. Prediction equations for FVC using height or ulna length were as follows: ln(FVC in ml) = -5.6 + 2.8 x ln(height in cm) and ln(FVC in ml) = 0.46 + 2.5 x ln(ulna length in cm). Younger subjects had a significantly steeper slope for FVC vs. height than the older age group. Normal reference data for forced expiratory maneuvers in intubated infants and children up to 5 yr of age will enable improved assessment of pulmonary dysfunction in acutely or chronically ventilator-dependent children. Using ulna length instead of height should facilitate respiratory assessment in ventilated children with spinal or joint deformities. PMID- 19443741 TI - Increases in corticospinal responsiveness during a sustained submaximal plantar flexion. AB - Studying the responsiveness of specific central nervous system pathways to electrical or magnetic stimulation can provide important information regarding fatigue processes in the central nervous system. We investigated the changes in corticospinal responsiveness during a sustained submaximal contraction of the triceps surae. Comparisons were made between the size of motor-evoked potentials (MEPs) elicited by motor cortical stimulation and cervicomedullary motor-evoked potentials (CMEPs) elicited by magnetic stimulation of the descending tracts to determine the site of any change in corticospinal responsiveness. Participants maintained an isometric contraction of triceps surae at 30% of maximal voluntary contraction (MVC) for as long as possible on two occasions. Stimulation was applied to the motor cortex or the cervicomedullary junction at 1-min intervals during contraction until task failure. Peripheral nerve stimulation was also applied to evoke maximal M waves (M(max)) and a superimposed twitch. Additionally, MEPs and CMEPs were evoked during brief contractions at 80%, 90%, and 100% of MVC as a nonfatigue control. During the sustained contractions, MEP amplitude increased significantly in soleus (113%) and medial gastrocnemius (108%) muscles and, at task failure, matched MEP amplitude in the prefatigue MVC ( approximately 20-25% M(max)). In contrast, CMEP amplitude increased significantly in medial gastrocnemius (51%), but not in soleus (63%) muscle and, at task failure, was significantly smaller than during prefatigue MVC (5-6% M(max) vs. 11-13% M(max)). The data indicate that cortical processes contribute substantially to the increase in corticospinal responsiveness during sustained submaximal contraction of triceps surae. PMID- 19443742 TI - The prone position results in smaller ventilation defects during bronchoconstriction in asthma. AB - The effect of body posture on regional ventilation during bronchoconstriction is unknown. In five subjects with asthma, we measured spirometry, low-frequency (0.15-Hz) lung elastance, and resistance and regional ventilation by intravenous (13)NN-saline positron emission tomography before and after nebulized methacholine. The subjects were imaged prone on 1 day and supine on another, but on both days the methacholine was delivered while prone. From the residual (13)NN after washout, ventilation defective areas were defined, and their location, volume, ventilation, and fractional gas content relative to the rest of the lung were calculated. Independent of posture, all subjects developed ventilation defective areas. Although ventilation within these areas was similarly reduced in both postures, their volume was smaller in prone than supine (25 vs. 41%, P < 0.05). The geometric center of the ventilation defective areas was gravitationally dependent relative to that of the lung in both postures. Mean lung fractional gas content was greater in the prone position before methacholine and did not increase as much as in the supine position after methacholine. In the prone position at baseline, areas that became ventilation defects had lower gas content than the rest of the lung. In both positions at baseline, there was a gradient of gas content in the vertical direction. In asthma, the size and location of ventilation defects is affected by body position and likely affected by small differences in lung expansion during bronchoconstriction. PMID- 19443743 TI - Adaptation of the NDIR technology to 13CO2 breath tests under increased inspiratory O2 concentrations. AB - Nondispersive infrared spectroscopy (NDIR) allows the continuous analysis of respiratory gases. Due to its high selectivity, simple and robust setup, and small footprint, it is also used to support (13)CO(2) breath tests to assess bacterial growth in the stomach, gut, or liver function. CO(2) NDIR signals, however, are biased by oxygen in the gas matrix. This complicates NDIR-based breath tests, if the inspired oxygen concentration has to be adjusted to the subject's requirements, or hyperoxia-induced effects were studied. To avoid the oxygen-induced bias, a "dilution" approach was developed: expired gas is mixed with N(2) to lower the oxygen content down to the usual range of 15-20%. Accuracy and precision were tested using synthetic gas mixtures with increasing (13)CO(2) to-(12)CO(2) ratios ((13)CO(2)/(12)CO(2)), either based on synthetic air with approximately 20% volume O(2) or on pure O(2). For samples with delta(13)C values smaller than 300 (or (13)CO(2)/(12)CO(2) smaller than 0.003), the dilution does not significantly increase the bias in the (13)CO(2)/(12)CO(2) determination, and the within-run imprecision is smaller than 1 delta(13)C. The practical use of this approach was validated in a pig study using a sepsis model reflecting a clinical situation that requires an increased oxygen concentration for respiration. The N(2) dilution eliminated the high bias in NDIR measurement, thus allowing the determination of the impact of oxygenation on glucose oxidation in patients ventilated with increased oxygen. PMID- 19443744 TI - Effect of short-term high-intensity interval training vs. continuous training on O2 uptake kinetics, muscle deoxygenation, and exercise performance. AB - The early time course of adaptation of pulmonary O(2) uptake (Vo(2)(p)) (reflecting muscle O(2) consumption) and muscle deoxygenation kinetics (reflecting the rate of O(2) extraction) were examined during high-intensity interval (HIT) and lower-intensity continuous endurance (END) training. Twelve male volunteers underwent eight sessions of either HIT (8-12 x 1-min intervals at 120% maximal O(2) uptake separated by 1 min of rest) or END (90-120 min at 65% maximal O(2) uptake). Subjects completed step transitions to a moderate-intensity work rate ( approximately 90% estimated lactate threshold) on five occasions throughout training, and ramp incremental and constant-load performance tests were conducted at pre-, mid-, and posttraining periods. Vo(2)(p) was measured breath-by-breath by mass spectrometry and volume turbine. Deoxygenation (change in deoxygenated hemoglobin concentration; Delta[HHb]) of the vastus lateralis muscle was monitored by near-infrared spectroscopy. The fundamental phase II time constants for Vo(2)(p) (tauVo(2)) and deoxygenation kinetics {effective time constant, tau' = (time delay + tau), Delta[HHb]} during moderate-intensity exercise were estimated using nonlinear least-squares regression techniques. The tauVo(2) was reduced by approximately 20% (P < 0.05) after only two training sessions and by approximately 40% (P < 0.05) after eight training sessions (i.e., posttraining), with no differences between HIT and END. The tau'Delta[HHb] ( approximately 20 s) did not change over the course of eight training sessions. These data suggest that faster activation of muscle O(2) utilization is an early adaptive response to both HIT and lower-intensity END training. That Delta[HHb] kinetics (a measure of fractional O(2) extraction) did not change despite faster Vo(2)(p) kinetics suggests that faster kinetics of muscle O(2) utilization were accompanied by adaptations in local muscle (microvascular) blood flow and O(2) delivery, resulting in a similar "matching" of blood flow to O(2) utilization. Thus faster kinetics of Vo(2)(p) during the transition to moderate-intensity exercise occurs after only 2 days HIT and END training and without changes to muscle deoxygenation kinetics, suggesting concurrent adaptations to microvascular perfusion. PMID- 19443745 TI - Newton's force as countermeasure for disuse atrophy. PMID- 19443746 TI - The respiratory muscles in chronic obstructive pulmonary disease. Introducing the highlighted topic series. PMID- 19443747 TI - Hindlimb unweighting induces changes in the p38MAPK contractile pathway of the rat abdominal aorta. AB - Hindlimb unweighting (HLU) of rats is a model used to mimic the cephalic fluid shift potentially involved in the orthostatic intolerance experienced by astronauts. Certain arteries in these rats exhibit a decreased contractile response to adrenergic agonists. It was shown previously that this may be caused by changes in thick filament regulation (Summers et al., Vascul Pharmacol 48: 208 214, 2008). In the present study, it was hypothesized that HLU also modifies thin filament regulation by effects on p38(MAPK) and ERK. Abdominal aorta rings from 20-day HLU rats and untreated controls were subjected to phenylephrine and phorbol 12,13-dibutyrate (PDBU) concentration response curves in the presence and absence of two inhibitors: the p38(MAPK) inhibitor SB-203580 and the MEK inhibitor U-0126. SB-203580 decreased control sensitivity to both agonists, but HLU sensitivity was not significantly affected. U-0126, which blocks enzymes immediately upstream of ERK, affected sensitivity to both agonists equally between control and HLU. Western blot analysis revealed no change in total levels of p38(MAPK) and its downstream target heat shock protein 27 but did reveal a decrease in phosphorylated levels of both after stimulation with PDBU and phenylephrine after HLU treatment. Neither total ERK nor phosphorylated levels after stimulation were affected by HLU. Total levels of caldesmon, a molecule downstream of both pathways, were decreased, but phosphorylated levels after stimulation were decreased by roughly twice as much. The results of this study demonstrate that HLU downregulates p38(MAPK), but not ERK, signaling. In turn, this may decrease actin availability for contraction. PMID- 19443748 TI - Deep inspirations protect against airway closure in nonasthmatic subjects. AB - The mechanism by which deep inspirations protect against increased airway responsiveness in nonasthmatic subjects is not known. The aim was to investigate the role of airway closure and airway narrowing in deep inspiration bronchoprotection. Twelve nonasthmatic and nine asthmatic subjects avoided deep inspirations (DI) for 20 min, then took five DI expired to functional residual capaciy (DI-FRC) or, on a separate day, no DI (no DI) before inhaling a single dose of methacholine. On another day, eight nonasthmatic subjects took five DI expired to residual volume (DI-RV). Peripheral airway function was measured by respiratory system reactance (Xrs), using the forced oscillation technique, and by forced vital capacity (FVC) as an index of airway closure. Respiratory system resistance (Rrs) and forced expiratory volume in 1 s (FEV1)/FVC were measured as indexes of airway narrowing. In nonasthmatic subjects, DI-FRC reduced the response measured by FEV1 (P=0.019), Xrs (P=0.02), and FVC (P=0.0005) but not by Rrs (P=0.15) or FEV1/FVC (P=0.52) compared with no DI. DI-RV had a less protective effect than DI-FRC on response measured by FEV1 (P=0.04) and FVC (P=0.016). There was no difference between all protocols when the response was measured by Xrs (P=0.20), Rrs (P=0.88), or FEV1/FVC (P=0.88). DI had no effect on methacholine response in asthmatic subjects. DI protect against airway responsiveness through an effect on peripheral airways involving reduced airway closure. The protective effect of DI on FEV1 and FVC was abolished by expiration to residual volume. We speculate that the reduced airway closure is due to reduced baseline ventilation heterogeneity and/or reduced airway surface tension. PMID- 19443749 TI - Retraction. PMID- 19443750 TI - Translational careers. PMID- 19443751 TI - The 2010 budget. Navigating treacherous waters. PMID- 19443752 TI - The 2010 budget. Stimulus spending looms large as Obama charts a course for science. PMID- 19443754 TI - Biomedical research. Stimulus funding elicits a tidal wave of 'challenge grants'. PMID- 19443757 TI - Particle physics. Austria's possible CERN withdrawal rattles physicists. PMID- 19443755 TI - Newsmaker interview. Texas transplant Alfred Gilman guides $3 billion cancer project. Interview by Jocelyn Kaiser. PMID- 19443758 TI - Swine flue outbreak. Flu researchers train sights on novel tricks of novel H1N1. PMID- 19443759 TI - Swine flue outbreak. Swine flu names evolving faster than swine flu itself. PMID- 19443760 TI - Science and the media. 'Vengeance' bites back at Jared Diamond. PMID- 19443761 TI - Materials science. Carbon sheets an atom thick give rise to graphene dreams. PMID- 19443762 TI - Materials science. Relativistic physics in the lab. PMID- 19443763 TI - Lunar resources. Two missions go in search of a watery lunar bonanza. PMID- 19443764 TI - Mining the data on coal. PMID- 19443765 TI - Invest in postdocs. PMID- 19443766 TI - Politics still in play. PMID- 19443767 TI - Conference covered climate from all angles. PMID- 19443768 TI - Public health. The cholera crisis in Africa. PMID- 19443769 TI - Ecology. Seasons and life cycles. PMID- 19443770 TI - Ecology. Phenology feedbacks on climate change. PMID- 19443771 TI - Ocean science. Ice sheet stability and sea level. PMID- 19443772 TI - Development. Ovulation signals. PMID- 19443773 TI - Applied physics. Photovoltaics power up. PMID- 19443774 TI - Applied physics. Two beams squeeze feature sizes in optical lithography. PMID- 19443775 TI - Neuroscience. Crossing the line. PMID- 19443776 TI - The tail of integrins, talin, and kindlins. AB - Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits. PMID- 19443777 TI - A key role for similarity in vicarious reward. AB - Humans appear to have an inherent prosocial tendency toward one another in that we often take pleasure in seeing others succeed. This fact is almost certainly exploited by game shows, yet why watching others win elicits a pleasurable vicarious rewarding feeling in the absence of personal economic gain is unclear. One explanation is that game shows use contestants who have similarities to the viewing population, thereby kindling kin-motivated responses (for example, prosocial behavior). Using a game show-inspired paradigm, we show that the interactions between the ventral striatum and anterior cingulate cortex subserve the modulation of vicarious reward by similarity, respectively. Our results support studies showing that similarity acts as a proximate neurobiological mechanism where prosocial behavior extends to unrelated strangers. PMID- 19443778 TI - Reassessment of the potential sea-level rise from a collapse of the West Antarctic Ice Sheet. AB - Theory has suggested that the West Antarctic Ice Sheet may be inherently unstable. Recent observations lend weight to this hypothesis. We reassess the potential contribution to eustatic and regional sea level from a rapid collapse of the ice sheet and find that previous assessments have substantially overestimated its likely primary contribution. We obtain a value for the global, eustatic sea-level rise contribution of about 3.3 meters, with important regional variations. The maximum increase is concentrated along the Pacific and Atlantic seaboard of the United States, where the value is about 25% greater than the global mean, even for the case of a partial collapse. PMID- 19443779 TI - Input-specific spine entry of soma-derived Vesl-1S protein conforms to synaptic tagging. AB - Late-phase synaptic plasticity depends on the synthesis of new proteins that must function only in the activated synapses. The synaptic tag hypothesis requires input-specific functioning of these proteins after undirected transport. Confirmation of this hypothesis requires specification of a biochemical tagging activity and an example protein that behaves as the hypothesis predicts. We found that in rat neurons, soma-derived Vesl-1S (Homer-1a) protein, a late-phase plasticity-related synaptic protein, prevailed in every dendrite and did not enter spines. N-methyl-d-aspartate receptor activation triggered input-specific spine entry of Vesl-1S proteins, which met many criteria for synaptic tagging. These results suggest that Vesl-1S supports the hypothesis and that the activity dependent regulation of spine entry functions as a synaptic tag. PMID- 19443780 TI - Observing the quantization of zero mass carriers in graphene. AB - Application of a magnetic field to conductors causes the charge carriers to circulate in cyclotron orbits with quantized energies called Landau levels (LLs). These are equally spaced in normal metals and two-dimensional electron gases. In graphene, however, the charge carrier velocity is independent of their energy (like massless photons). Consequently, the LL energies are not equally spaced and include a characteristic zero-energy state (the n = 0 LL). With the use of scanning tunneling spectroscopy of graphene grown on silicon carbide, we directly observed the discrete, non-equally-spaced energy-level spectrum of LLs, including the hallmark zero-energy state of graphene. We also detected characteristic magneto-oscillations in the tunneling conductance and mapped the electrostatic potential of graphene by measuring spatial variations in the energy of the n = 0 LL. PMID- 19443781 TI - Direct detection of abortive RNA transcripts in vivo. AB - During transcription initiation in vitro, prokaryotic and eukaryotic RNA polymerase (RNAP) can engage in abortive initiation-the synthesis and release of short (2 to 15 nucleotides) RNA transcripts-before productive initiation. It has not been known whether abortive initiation occurs in vivo. Using hybridization with locked nucleic acid probes, we directly detected abortive transcripts in bacteria. In addition, we show that in vivo abortive initiation shows characteristics of in vitro abortive initiation: Abortive initiation increases upon stabilizing interactions between RNAP and either promoter DNA or sigma factor, and also upon deleting elongation factor GreA. Abortive transcripts may have functional roles in regulating gene expression in vivo. PMID- 19443782 TI - MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. AB - A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS and ERK1/2 (extracellular signal-regulated kinases 1 and 2) are activated by an LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrate that C/EBPbeta (CCAAT/Enhancer-binding protein-beta) is a critical downstream mediator of ERK1/2 activation. Thus, ERK1/2 and C/EBPbeta constitute an in vivo LH regulated signaling pathway that controls ovulation- and luteinization-related events. PMID- 19443783 TI - Fictive reward signals in the anterior cingulate cortex. AB - The neural mechanisms supporting the ability to recognize and respond to fictive outcomes, outcomes of actions that one has not taken, remain obscure. We hypothesized that neurons in the anterior cingulate cortex (ACC), which monitors the consequences of actions and mediates subsequent changes in behavior, would respond to fictive reward information. We recorded responses of single neurons during performance of a choice task that provided information about the reward values of options that were not chosen. We found that ACC neurons signal fictive reward information and use a coding scheme similar to that used to signal experienced outcomes. Thus, individual ACC neurons process both experienced and fictive rewards. PMID- 19443785 TI - Smoking status and body mass index: a longitudinal study. AB - INTRODUCTION: The general consensus is that smoking cessation leads to some degree of weight gain, although considerable disagreement remains regarding the magnitude and duration of this gain. METHODS: We investigated the relationship between smoking status and change in body mass index (BMI) over time in a cohort of male participants recruited for a study of cardiovascular risk factors and assessed at multiple timepoints. We further investigated whether calorie consumption, recorded using food frequency questionnaires, mediated any effect of smoking cessation on change in BMI. RESULTS: Our results indicate that never smokers and ex-smokers differ in BMI from current smokers by an average of 1.6 kg/m2, based on a comparison at baseline. Moreover, smoking cessation between timepoints is associated with a corresponding average increase in BMI of 1.6 kg/m2. DISCUSSION: These results suggest that when cigarette smokers achieve long term abstinence, they revert to a mean BMI roughly equivalent to that of never smokers. Perhaps surprisingly, this difference in BMI was not substantially attenuated following adjustment for calorie and alcohol consumption, suggesting that the effects of smoking cessation on BMI are not mediated entirely by changes in dietary or alcohol consumption behavior. PMID- 19443786 TI - Tobacco control policy and adolescent cigarette smoking status in the United States. AB - INTRODUCTION: Tobacco policies that limit the sale of cigarettes to minors and restrict smoking in public places are important strategies to deter youth from accessing and consuming cigarettes. METHODS: We examined the relationship of youth cigarette smoking status to state-level youth access and clean indoor air laws, controlling for sociodemographic characteristics and cigarette price. Data were analyzed from the 2001 to 2002 U.S. Health Behavior in School-Aged Children survey, a cross-sectional survey conducted with a nationally representative sample of 13,339 students in the United States. RESULTS: Compared with students living in states with strict regulations, those living in states with no or minimal restrictions, particularly high school students, were more likely to be daily smokers. These effects were somewhat reduced when logistic regressions were adjusted for sociodemographic characteristics and cigarette price, suggesting that higher cigarette prices may discourage youth to access and consume cigarettes independent of other tobacco control measures. DISCUSSION: Strict tobacco control legislation could decrease the potential of youth experimenting with cigarettes or becoming daily smokers. The findings are consistent with the hypothesis that smoking policies, particularly clean indoor air provisions, reduce smoking prevalence among high school students. PMID- 19443787 TI - Progressive reduction using nicotine gum as a prelude to quitting. AB - INTRODUCTION: This uncontrolled study examined the outcome of a program of progressive cigarette reduction, using nicotine gum, as a prelude to complete cessation among 116 smokers (70 men, 46 women; mean age = 45.7 years, SD = 12.65; mean baseline smoking = 28.3 cigarettes/day) who sought treatment in a smokers' clinic but did not want to quit abruptly. METHODS: Subjects participated in a two stage program consisting of a 4-month reduction phase followed by a 6-month abstinence phase. The aim was to reduce the number of cigarettes smoked daily by at least 50% by Week 8 and to quit at the end of Week 16. During the reduction phase, subjects used nicotine gum (2 or 4 mg) to progressively decrease smoking. During the abstinence phase, subjects used any type of nicotine replacement therapy (NRT) to remain smoke free. Psychological treatment and NRT were provided at no cost to participants. RESULTS: At Month 2, 76 subjects (68%) achieved the target of 50% reduction. At the target quit date in Week 16, 66 subjects (57%) achieved carbon monoxide-validated abstinence and 45 subjects (39%) maintained continuous abstinence at the 6-month follow-up. No symptoms of nicotine overdose were detected. DISCUSSION: A program of progressive cigarette reduction using nicotine gum is feasible in practice and may be a useful strategy for smokers who are unable or unwilling to quit by abrupt cessation. PMID- 19443788 TI - Contingency management and motivational enhancement: a randomized clinical trial for college student smokers. AB - INTRODUCTION: The efficacy of contingency-management (CM) and motivational enhancement therapy (MET) for college student smoking cessation was examined. METHODS: Nontreatment-seeking daily smokers (N = 110) were randomly assigned to 3 weeks of CM versus noncontingent reinforcement (NR) and to three individual sessions of MET versus a relaxation control in a 2 x 2 experimental design. Expired carbon monoxide (CO) samples were collected twice daily for 3 weeks. Participants earned 5 US dollars for providing each sample; additionally, those randomized to CM earned escalating monetary rewards based on CO reductions (Week 1) and smoking abstinence (Weeks 2-3). RESULTS: Compared with NR, CM resulted in significantly lower CO levels and greater total and consecutive abstinence during the intervention. Those in the CM and MET groups reported greater interest in quitting smoking posttreatment, but rates of confirmed abstinence at follow-up were very low (4% at 6-month follow-up) and did not differ by group. DISCUSSION: Findings support the short-term efficacy of CM for reducing smoking among college students. Future research should explore enhancements to CM in this population, including a longer intervention period and the recruitment of smokers who are motivated to quit. PMID- 19443790 TI - Stent placement in acute cerebral artery occlusion. PMID- 19443791 TI - Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Antiplatelet medication use and reduced platelet activity may be associated with mortality after intracerebral hemorrhage (ICH). We tested the hypothesis that reduced platelet activity is associated with early ICH clot growth and worse outcomes. METHODS: We prospectively identified patients with spontaneous ICH, measured platelet activity (VerifyNow-ASA, Accumetrics) on admission, and recorded antiplatelet medication use. ICH volume was calculated using computerized volumetric analysis. Data were analyzed with nonparametric statistics and repeated measures ANOVA as appropriate. Patients were prospectively followed for functional outcomes. Data are presented as mean+/-SD or median [Q1 to Q3]. RESULTS: Reduced platelet activity (50 microbleeds on MRI, n=3) or low microbleed counts (<3 microbleeds, n=3). RESULTS: Plotted on a logarithmic scale, the volumes of 163 hemorrhagic lesions identified on scans from the 46 subjects fell in a distinctly bimodal distribution with mean volumes for the 2 modes of 0.009 cm(3) and 27.5 cm(3). The optimal cut point for separating the 2 peaks (determined by receiver operating characteristics) corresponded to a lesion diameter of 0.57 cm. On neuropathologic analysis, the high microbleed-count autopsied subjects showed significantly thicker amyloid positive vessel walls than the low microbleed-count subjects (proportional wall thickness 0.53+/-0.01 versus 0.37+/-0.01; P<0.0001; n=333 vessel segments analyzed). CONCLUSIONS: These findings suggest that cerebral amyloid angiopathy associated microbleeds and macrobleeds comprise distinct entities. Increased vessel wall thickness may predispose to formation of microbleeds relative to macrobleeds. PMID- 19443798 TI - Change in diffusion-weighted imaging infarct volume predicts neurologic outcome at 90 days: results of the Acute Stroke Accurate Prediction (ASAP) trial serial imaging substudy. AB - BACKGROUND AND PURPOSE: Predictive models of outcome after ischemic stroke have incorporated acute diffusion-weighted MRI (DWI) information with mixed results. We hypothesized that serial measurements of DWI infarct volume would be predictive of functional outcome after ischemic stroke. METHODS: The prospective Acute Stroke Accurate Prediction (ASAP) Study included a prespecified serial imaging subgroup who underwent DWI studies at baseline (<24 hours after symptom onset) and Day 5 (+/-2 days). DWI infarct volumes were calculated using the Analyze software (Rochester, Minn). Clinical outcomes were assessed at 3 months. Univariate and multivariable regression analysis was performed to assess the relationship between change in DWI lesion volume and excellent neurological outcome (modified Rankin Scale 0, 1, and Barthel Index >or=95). RESULTS: In total, 169 cases from the ASAP study had serial DWI scans with a measurable lesion at baseline, follow-up, or both. The median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 3 to 13). For each 10 cm(3) of growth in DWI infarct volume, the OR for achieving an excellent outcome by modified Rankin Scale was 0.52 (95% CI, 0.38 to 0.71) and for the Barthel Index was 0.64 (95% CI, 0.51 to 0.79). Adjusting for clinically important covariates, the OR for an excellent modified Rankin Scale outcome was 0.57 (95% CI, 0.37 to 0.88) and excellent Barthel Index outcome was 0.75 (95% CI, 0.56 to 1.01). CONCLUSIONS: Based on these data, the likelihood of achieving an excellent neurological outcome diminishes substantially with growth in DWI infarct volume in the first 5 days after ischemic stroke of mild to moderate severity. PMID- 19443799 TI - Cerebral white matter lesions are associated with the risk of stroke but not with other vascular events: the 3-City Dijon Study. AB - BACKGROUND AND PURPOSE: White matter lesions (WMLs) have been shown to be associated with the risk of stroke in previous studies but little is known about the prediction of other vascular events. We evaluated the risk of stroke and other vascular events according to WML volume in a large population-based sample. We also studied WML volume by type (deep or periventricular) in relation to these events. METHODS: The 3-City Study is a population-based prospective cohort of people aged >or=65 years followed up for, on average, 4.9 years. Among them, 1643 participants free of prevalent vascular events had quantitative measurements of WML volume at baseline using a fully automatic method. The risks of incident major vascular events according to WML volume were evaluated using Cox proportional hazards models. RESULTS: The risk of incident stroke significantly increased with increasing baseline WML volume and was multiplied by 5 for those in the highest quartile of WML volume. Nonstroke vascular events' incidence was not associated with WML volumes, whatever their type. CONCLUSIONS: WMLs are an independent predictor of stroke in the elderly. This association is specific because WMLs are not associated with the risk of other vascular events. PMID- 19443800 TI - Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? AB - BACKGROUND AND PURPOSE: Patent foramen ovale (PFO) is significantly associated with cryptogenic stroke (CS). However, even in patients with CS, a PFO can be an incidental finding. We sought to estimate the probability that a PFO in a patient with CS is incidental. METHODS: A systematic search identified 23 case-control studies examining the prevalence of PFO in patients with CS versus control subjects with stroke of known cause. Using simple assumptions and Bayes' theorem, we calculated the probability a PFO is incidental in patients with CS. Random effects meta-analyses estimated the odds ratio (OR) of a PFO in CS versus control subjects in different age populations, with or without atrial septal aneurysms, and were used to summarize across studies the probability that a PFO in CS is incidental. RESULTS: The summary OR (95% CIs) for PFO in CS versus control subjects was 2.9 (CI, 2.1 to 4.0). The corresponding ORs for young and old patients (< or >or=55 years) were 5.1 (3.3 to 7.8) and 2.0 (>1.0 to 3.7), respectively. The corresponding probabilities that a PFO in patients with CS is incidental were 33% (28% to 39%) in age-inclusive studies, 20% (16% to 25%) in younger patients, and 48% (34% to 66%) in older patients. These probabilities were much lower when an atrial septal aneurysm was present. CONCLUSIONS: In patients with otherwise CS, approximately one third of discovered PFOs are likely to be incidental and hence not benefit from closure. This probability is sensitive to patient characteristics such as age and the presence of an atrial septal aneurysm, suggesting the importance of patient selection in therapeutic decision-making. PMID- 19443804 TI - eNOS mediates TO90317 treatment-induced angiogenesis and functional outcome after stroke in mice. AB - BACKGROUND AND PURPOSE: TO901317, a synthetic liver X receptor agonist, elevates high-density lipoprotein cholesterol (HDL-C) in mice. We tested the hypothesis that TO901317 treatment of stroke promotes angiogenesis and vascular maturation and improves functional outcome after stroke by increasing endothelial nitric oxide synthase (eNOS) phosphorylation. METHODS: C57BL/6J mice were subjected to middle cerebral artery occlusion and were treated with or without TO901317 (30 mg/kg) starting 24 hours after middle cerebral artery occlusion and daily for 14 days. RESULTS: TO901317 significantly increased serum HDL-C level, promoted angiogenesis and vascular stabilization in the ischemic brain, and improved functional outcome after stroke. The increased HDL-C level significantly correlated with functional recovery after stroke. TO901317 also increased eNOS phosphorylation in the ischemic brain. Mechanisms underlying the TO901317-induced angiogenesis were investigated using eNOS knockout (eNOS-/-) mice. TO901317 treatment of eNOS-/- mice significantly increased HDL-C level but failed to increase angiogenesis and functional outcome after stroke. In vitro studies demonstrated that TO901317 and HDL-C significantly increased capillary tube formation and promoted eNOS phosphorylation activity in cultured mouse brain endothelial cells compared with nontreatment controls. However, TO901317 and high density lipoprotein treatment-induced capillary tube formation were absent in eNOS-deficient mouse brain endothelial cell. CONCLUSIONS: These data indicate that TO901317 treatment increases serum HDL-C level, which promotes angiogenesis through eNOS and leads to improvement of functional outcome after stroke. PMID- 19443806 TI - Predictors of smoking abstinence after first-ever ischemic stroke: a 3-month follow-up. AB - BACKGROUND AND PURPOSE: Predictors of smoking abstinence in stroke survivors remain largely unexplored. The present study addressed the relationship between degrees of nicotine dependence and smoking abstinence 3 months after ischemic stroke. METHODS: One hundred smokers with first-ever ischemic stroke were prospectively enrolled to the study. Correlates of nicotine dependence as well as sociodemographic and clinical characteristics were assessed during hospitalization. Smoking status was determined at 3-month follow-up. RESULTS: Significant predictors of smoking abstinence at follow-up included: the Fagerstrom Test for Nicotine Dependence score, the Barthel Index, the number of smoking household members, and the Geriatric Depression Scale score. CONCLUSIONS: Our results suggest that smoking cessation after ischemic stroke can be determined by the interplay of psychobiological and environmental factors. PMID- 19443805 TI - Recombinant T cell receptor ligand treats experimental stroke. AB - BACKGROUND AND PURPOSE: Experimental stroke induces a biphasic effect on the immune response that involves early activation of peripheral leukocytes followed by severe immunodepression and atrophy of the spleen and thymus. In tandem, the developing infarct is exacerbated by influx of numerous inflammatory cell types, including T and B lymphocytes. These features of stroke prompted our use of recombinant T cell receptor ligands (RTL), partial major histocompatibility complex Class II molecules covalently bound to myelin peptides. We tested the hypothesis that RTL would improve ischemic outcome in the brain without exacerbating defects in the peripheral immune system function. METHODS: Four daily doses of RTL were administered subcutaneously to C57BL/6 mice after middle cerebral artery occlusion, and lesion size and cellular composition were assessed in the brain and cell numbers were assessed in the spleen and thymus. RESULTS: Treatment with RTL551 (I-A(b) molecule linked to MOG-35-55 peptide) reduced cortical and total stroke lesion size by approximately 50%, inhibited the accumulation of inflammatory cells, particularly macrophages/activated microglial cells and dendritic cells, and mitigated splenic atrophy. Treatment with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide) similarly reduced the stroke lesion size in HLA-DR2 transgenic mice. In contrast, control RTL with a nonneuroantigen peptide or a mismatched major histocompatibility complex Class II moiety had no effect on stroke lesion size. CONCLUSIONS: These data are the first to demonstrate successful treatment of experimental stroke using a neuroantigen specific immunomodulatory agent administered after ischemia, suggesting therapeutic potential in human stroke. PMID- 19443807 TI - Brain magnetic resonance imaging abnormalities in adult patients with sickle cell disease: correlation with transcranial Doppler findings. AB - BACKGROUND AND PURPOSE: Brain imaging abnormalities were reported in up to 44% of children with sickle cell disease (SCD). The prevalence of neuroimaging abnormalities in adult patients with SCD and their relationship to transcranial Doppler is still unclear. Our objectives were to study the frequency of MRI and MR angiography abnormalities in adults with SCD and to define what transcranial Doppler velocities are associated with intracranial stenoses detected by MR angiography. METHODS: We examined all adult patients (>16 years) with SCD followed in the hematology outpatient clinic at our university hospital with MRI, MR angiography, and transcranial Doppler. RESULTS: We evaluated 50 patients. The overall prevalence of MRI abnormalities was 60%. Abnormal MRI findings were more frequent when vessel tortuosity or stenoses were present on MR angiography (P<0.01). Patients with intracranial stenoses had significantly higher time averaged maximum mean velocities (P=0.01). A time-averaged maximum mean velocity of 123.5 cm/s allowed the diagnosis of middle cerebral artery or internal carotid artery intracranial stenosis with sensitivity of 100% and specificity of 73% with an area under the receiver operator characteristic curve of 0.91 (CI, 0.79 to 1.00). CONCLUSIONS: The frequency of brain imaging abnormalities detected by MRI/MR angiography in adults with SCD was higher than that described for children. Transcranial Doppler velocities in adult patients with intracranial stenoses were lower than those described for the pediatric population with SCD. PMID- 19443810 TI - Health inequities: a global concern. PMID- 19443809 TI - Cardiac dysfunction after left permanent cerebral focal ischemia: the brain and heart connection. AB - BACKGROUND AND PURPOSE: Stroke can lead to cerebrogenic cardiac arrhythmias. We sought to investigate the effect of ischemic stroke on cardiac function in a mouse model of permanent middle cerebral artery occlusion (pMCAO). METHODS: Twenty-four hours after the induction of focal ischemia, cardiac function was measured in mice by endovascular catheterization of the heart. Immediately after hemodynamic measurements, mice were euthanized and brains were excised and sectioned to measure infarct volume and the severity of insular cortex injury. Myocardial damage was evaluated by hematoxylin-eosin staining. Serum and heart levels of norepinephrine (NE) were also determined. RESULTS: Cardiac dysfunction occurred in 9 out of 14 mice that underwent left pMCAO. In these 9 mice, the severity of left insular cortex lesion was greater than the mice with normal heart function. The serum and heart levels of NE were significantly higher in left pMCAO mice with heart dysfunction. Liner regression analysis indicates significant inverse correlation between the severity of left insular cortex damage and heart dysfunction. Mice that underwent right pMCAO did not exhibit cardiac dysfunction. CONCLUSIONS: This study shows that left focal cerebral ischemia can produce cardiac dysfunction, which is associated with the extent of left insular cortex damage. Furthermore, mice exhibiting cardiac dysfunction had elevated levels of NE in the serum and heart. PMID- 19443808 TI - Beta-amyloid, blood vessels, and brain function. AB - Cerebrovascular disease and Alzheimer disease are common diseases of aging and frequently coexist in the same brain. Accumulating evidence suggests that the presence of brain infarction, including silent infarction, influences the course of Alzheimer disease. Conversely, there is evidence that beta-amyloid can impair blood vessel function. Vascular beta-amyloid deposition, also known as cerebral amyloid angiopathy, is associated with vascular dysfunction in animal and human studies. Alzheimer disease is associated with morphological changes in capillary networks, and soluble beta-amyloid produces abnormal vascular responses to physiological and pharmacological stimuli. In this review, we discuss current evidence linking beta-amyloid metabolism with vascular function and morphological changes in animals and humans. PMID- 19443811 TI - Midian Othello Bousfield: advocate for the medical and public health concerns of Black Americans. PMID- 19443812 TI - The use and efficacy of child restraint devices. PMID- 19443813 TI - Smoking inside vehicles should be banned globally. PMID- 19443814 TI - Underserved communities have the highest need for built environment interventions targeting obesity. PMID- 19443816 TI - Nutrition content of food and beverage products on Web sites popular with children. AB - We assessed the nutritional quality of branded food and beverage products advertised on 28 Web sites popular with children. Of the 77 advertised products for which nutritional information was available, 49 met Institute of Medicine criteria for foods to avoid, 23 met criteria for foods to neither avoid nor encourage, and 5 met criteria for foods to encourage. There is a need for further research on the nature and extent of food and beverage advertising online to aid policymakers as they assess the impact of this marketing on children. PMID- 19443815 TI - Stealing a march in the 21st century: accelerating progress in the 100-year war against tobacco addiction in the United States. AB - Tobacco use in the United States has declined dramatically over the past 50 years, with the prevalence of cigarette smoking falling from about 42% of all adults to less than 20% by 2007. If this rate of decline continues, smoking could be eliminated in the United States by 2047. Framed in military parlance, we may be halfway through a 100-year war against the leading public health killer of our time. We describe factors that have contributed to progress over the last 50 years and identify policy and other initiatives that can contribute to the elimination of tobacco use in the United States. PMID- 19443817 TI - The relationship between living arrangement and preventive care use among community-dwelling elderly persons. AB - OBJECTIVES: We sought to examine the relationship between living arrangements and obtaining preventive care among the elderly population. METHODS: We obtained data on 13,038 community-dwelling elderly persons from the 2002 to 2005 Medical Expenditure Panel Survey and used multivariate logistic regression models to estimate the likelihood of preventive care use among elderly persons in 4 living arrangements: living alone (38%), living with one's spouse only (52%), living with one's spouse and with one's adult offspring (5%), and living with one's adult offspring only (5%). Preventive care services included influenza vaccination, physical and dental checkup, and screenings for hypertension, cholesterol, and colorectal cancer. RESULTS: After we controlled for age, gender, race, education, income, health insurance, comorbidities, self-reported health, physical function status, and residence location, we found that elderly persons living with a spouse only were more likely than were those living alone to obtain all preventive care services, except for hypertension screening. However, those living with their adult offspring were not more likely to obtain recommended preventive care compared with those living alone. These results did not change when the employment status and functional status of adult offspring were considered. CONCLUSIONS: Interventions to improve preventive care use should target not only those elderly persons who live alone but also those living with adult offspring. PMID- 19443818 TI - Perceived racial discrimination in health care: a comparison of Veterans Affairs and other patients. AB - OBJECTIVES: We compared rates of perceived racial discrimination in health care settings for veteran and nonveteran patients and for veterans who used the Veterans Affairs health care system and those who did not. METHODS: Data were drawn from the 2004 Behavioral Risk Factor Surveillance System. We used logistic regression to examine whether perceived racial discrimination in health care was associated with veteran status or use of Veterans Affairs health care, after adjusting for patient characteristics. RESULTS: In this sample of 35,902 people, rates of perceived discrimination were equal for veterans and nonveterans (3.4% and 3.5%, respectively; crude odds ratio [OR] = 1.00; 95% confidence interval [CI] = 0.77, 1.28; adjusted OR = 0.92; 95% CI = 0.66, 1.28). Among veterans (n = 3420), perceived discrimination was more prevalent among patients who used Veterans Affairs facilities than among those who did not (5.4% vs 2.7%; OR = 2.08; 95% CI = 1.04, 4.18). However, this difference was not significant after adjustment for patient characteristics (OR = 1.30; 95% CI = 0.54, 3.13). CONCLUSIONS: Perceived racial discrimination in health care was equally prevalent among veterans and nonveterans and among veterans who used the Veterans Affairs health care system and those who did not. PMID- 19443819 TI - Suicidal behavior among female sex workers in Goa, India: the silent epidemic. AB - OBJECTIVES: We sought to study suicidal behavior prevalence and its association with social and gender disadvantage, sex work, and health factors among female sex workers in Goa, India. METHODS: Using respondent-driven sampling, we recruited 326 sex workers in Goa for an interviewer-administered questionnaire regarding self-harming behaviors, sociodemographics, sex work, gender disadvantage, and health. Participants were tested for sexually transmitted infections. We used multivariate analysis to define suicide attempt determinants. RESULTS: Nineteen percent of sex workers in the sample reported attempted suicide in the past 3 months. Attempts were independently associated with intimate partner violence (adjusted odds ratio [AOR] = 2.70; 95% confidence interval [CI] = 1.38, 5.28), violence from others (AOR = 2.26; 95% CI = 1.15, 4.45), entrapment (AOR = 2.76; 95% CI = 1.11, 6.83), regular customers (AOR = 3.20; 95% CI = 1.61, 6.35), and worsening mental health (AOR = 1.05; 95% CI = 1.01, 1.11). Lower suicide attempt likelihood was associated with Kannad ethnicity, HIV prevention services, and having a child. CONCLUSIONS: Suicidal behaviors among sex workers were common and associated with gender disadvantage and poor mental health. India's widespread HIV-prevention programs for sex workers provide an opportunity for community-based interventions against gender-based violence and for mental health services delivery. PMID- 19443820 TI - The association of immigration and acculturation attributes with oral health among immigrants in New York City. AB - OBJECTIVES: We examined associations between immigration and acculturation attributes and oral disease among immigrants. METHODS: We conducted a large cross sectional study of 1318 immigrants in New York City. We performed comprehensive interviews and oral examinations of the participants and used linear regression models to assess differences in oral disease levels among immigrant subgroups. We also constructed proportional odds models to evaluate the association of oral disease level with length of stay in the United States, age at immigration, and language preference. RESULTS: After we controlled for most known risk factors, country of birth and age at immigration were associated with variations in oral disease prevalence and need for oral health care. Length of stay was inversely associated with need for treatment of dental caries but not with any other indicator of oral disease. Language preference was not associated with any indicator of oral disease. CONCLUSIONS: Immigrants' country of birth, length of stay in the United States, and age at immigration played important roles in their oral disease prevalence, independently of most known risk factors for oral diseases. Our findings emphasize the need for more studies to elucidate the complex relationships of ethnicity, socioeconomic status, and culturally influenced factors that impact immigrants' oral health. PMID- 19443821 TI - Screening and brief intervention for substance misuse among older adults: the Florida BRITE project. AB - OBJECTIVES: We developed and examined the effectiveness of the Florida Brief Intervention and Treatment for Elders (BRITE) project, a 3-year, state-funded pilot program of screening and brief intervention for older adult substance misusers. METHODS: Agencies in 4 counties conducted screenings among 3497 older adults for alcohol, medications, and illicit substance misuse problems and for depression and suicide risk. Screening occurred in elders' homes, senior centers, or other selected sites. Individuals who screened positive for substance misuse were offered brief intervention with evidence-based practices and rescreened at discharge from the intervention program and at follow-up interviews. RESULTS: Prescription medication misuse was the most prevalent substance use problem, followed by alcohol, over-the-counter medications, and illicit substances. Depression was prevalent among those with alcohol and prescription medication problems. Those who received the brief intervention had improvement in alcohol, medication misuse, and depression measures. CONCLUSIONS: The BRITE program effectively shaped state policy by responding to legislative mandates to address the needs of an increasing, but underserved, elder population. The pilot paved the way for obtaining a federally funded grant to expand BRITE to 27 sites in 17 counties in Florida. PMID- 19443822 TI - Childhood abuse and early menarche: findings from the black women's health study. AB - OBJECTIVES: We examined the association between childhood abuse and early menarche in a sample of US Black women. METHODS: We conducted multivariable log binomial regression on data from 35 330 participants in the Black Women's Health Study to estimate risk ratios and 95% confidence intervals for the relation of childhood physical and sexual abuse with early age at menarche (i.e., < 12 years). RESULTS: In adjusted analyses, sexual abuse was positively associated with early menarche, and the risk of early menarche increased with increasing frequency of sexual abuse incidents. We observed a weak but statistically significant association between physical abuse and early menarche. Associations between sexual abuse and early menarche were stronger when we used a more stringent cutpoint for early menarche (i.e., < 11 years). CONCLUSIONS: Our data suggest an increased risk of early menarche among Black women who experienced childhood sexual abuse. Evidence for an association between childhood physical abuse and early menarche was equivocal. PMID- 19443823 TI - Impact of social position on the effect of cardiovascular risk factors on self rated health. AB - OBJECTIVES: We assessed the impact of education level on the association between self-rated health and cardiovascular risk factors (blood pressure, glycosylated hemoglobin level, and total cholesterol and triglyceride levels). METHODS: We used data from the National Health and Nutrition Examination Survey for the years 2001 through 2004 (4015 men and 4066 women). Multivariate analyses were performed with a logistic regression model. RESULTS: After adjustment for age and ethnicity, among women with high glycosylated hemoglobin levels, the most educated women had poorer self-rated health compared with the least-educated women (odds ratio [OR] = 4.61; 95% confidence interval [CI] = 2.90, 7.34 vs OR = 2.59; 95% CI = 1.60, 4.20, respectively; interaction test, P = 0.06). The same was true among women with high cholesterol levels (OR = 2.23; 95% CI = 1.40, 3.56 vs OR = 1.13; 95% CI = 0.85, 1.49, respectively; interaction test, P = 0.06). Among men, the impact of education level on the association between self-rated health and any cardiovascular risk factors (measured or self-reported) was not significant. CONCLUSIONS: The impact of cardiovascular risk factors on self-rated health was higher for highly educated women, which could lead to underestimation of health inequalities between socioeconomic groups when self-rated health is used as an indicator of objective health. PMID- 19443824 TI - Disparities in dietary intake, meal patterning, and home food environments among young adult nonstudents and 2- and 4-year college students. AB - We examined whether young adult meal patterning, dietary intake, and home food availability differed among nonstudents, 2-year college students, and 4-year college students (N = 1687; mean age = 20.5 years). Unadjusted analyses showed that few young adults consumed optimal diets and, compared with 4-year college students, nonstudents and 2-year students consumed fewer meals and poorer diets. After controlling for sociodemographics and living arrangements, we found that over half of the observed associations remained significant (P < .05). Nutrition interventions are needed for young adults, particularly specific at-risk groups. PMID- 19443825 TI - Reducing the impact of the health care access crisis through volunteerism: a means, not an end. AB - In the absence of meaningful health reform, Florida implemented a volunteer health care program to strengthen the existing safety net. Since program implementation in 1992, over $1 billion of services have been provided to uninsured and underserved populations. Currently, over 20,000 volunteers participate statewide. Key incentives for provider participation have been an organized framework for volunteering and liability protection through state sponsored sovereign immunity. Volunteerism, although not a solution to the health care crisis, serves as a valuable adjunct pending full-scale health care reform. PMID- 19443826 TI - The StrongWomen-Healthy Hearts program: reducing cardiovascular disease risk factors in rural sedentary, overweight, and obese midlife and older women. AB - OBJECTIVES: We tested a community-based intervention designed to reduce cardiovascular disease risk in sedentary midlife and older women who were overweight or obese. METHODS: In a randomized controlled trial conducted in 8 counties in Arkansas and Kansas, counties were assigned to the intervention (a 12 week twice-weekly heart health program) group or to the delayed-intervention control group. Ten to fifteen women were selected from each site, and participants' weight, waist circumference, diet, physical activity, and self efficacy were measured before and after the intervention. Data were analyzed with multiple regressions. RESULTS: Compared with the control group, participants in the intervention group had a significant decrease in body weight (-2.1 kg; 95% confidence interval [CI] = -3.2, -1.0), waist circumference (-2.3 in; 95% CI = 4.2, -0.5), and energy intake (-390 kcal/day; 95% CI = -598, -183); an increase in activity (+1637 steps/day; 95% CI = 712, 2562); and an increase in self efficacy for dietary and physical activity behaviors. CONCLUSIONS: Our results suggest that a community-based program can improve self-efficacy, increase physical activity, and decrease energy intake, resulting in decreased waist circumference and body weight among at-risk women. PMID- 19443827 TI - Health disparities among Mexican American women aged 15-44 years: National Health and Nutrition Examination Survey, 1999-2004. AB - OBJECTIVES: We analyzed the health of Mexican American women aged 15 to 44 years, by generation and language preference, to guide planning for reproductive health services in this growing population. METHODS: We used personal interview and medical examination data from the 1999 to 2004 National Health and Nutrition Examination Surveys. We used SUDAAN for calculating age-adjusted prevalence estimates of demographic and health characteristics. The Satterthwaite adjusted F test and Student t test were used for subgroup comparisons. RESULTS: The women had different health profiles (P < .05) by generation and language preference. Second- and later-generation women and women who used more English were more likely to be sexually active, to have been younger at first intercourse, and to have had more male sexual partners than were first-generation women and women who used more Spanish. Compared with their first-generation counterparts, second- and later-generation women drank more alcohol, were better educated, had higher incomes, and were more likely to have health insurance. Third-generation women were more likely to have delivered a low-birthweight baby than were first generation women. CONCLUSIONS: Differences by generation and language preference suggest that acculturation should be considered when planning interventions to promote healthy reproductive behaviors among Mexican American women. PMID- 19443828 TI - The relationship between remittances and health care provision in Mexico. AB - OBJECTIVES: We examined whether remittances sent from the United States to Mexico were used to access health care in Mexico. METHODS: Data were from a 2006 survey of 2 localities in the municipal city of Tepoztlan, Morelos, Mexico. We used logistic regression to determine whether household remittance expenditure on health care was associated with type of health insurance coverage. RESULTS: Individuals who lacked insurance coverage or who were covered by the Seguro Popular program were significantly more likely to reside in households that spend remittances on health care than were individuals covered by an employer-based insurance program. CONCLUSIONS: Improving the coverage and quality of care within Mexico's health care system will help ensure that remittances serve as a complement, and not a substitute, to formal access to care. PMID- 19443829 TI - Health insurance coverage and medical expenditures of immigrants and native-born citizens in the United States. AB - OBJECTIVES: I examined insurance coverage and medical expenditures of both immigrant and US-born adults to determine the extent to which immigrants contribute to US medical expenditures. METHODS: I used data from the 2003 Medical Expenditure Panel Survey to perform 2-part multivariate analyses of medical expenditures, controlling for health status, insurance coverage, race/ethnicity, and other sociodemographic factors. RESULTS: Approximately 44% of recent immigrants and 63% of established immigrants were fully insured over the 12-month period analyzed. Immigrants' per-person unadjusted medical expenditures were approximately one half to two thirds as high as expenditures for the US born, even when immigrants were fully insured. Recent immigrants were responsible for only about 1% of public medical expenditures even though they constituted 5% of the population. After controlling for other factors, I found that immigrants' medical costs averaged about 14% to 20% less than those who were US born. CONCLUSIONS: Insured immigrants had much lower medical expenses than insured US born citizens, even after the effects of insurance coverage were controlled. This suggests that immigrants' insurance premiums may be cross-subsidizing care for the US-born. If so, health care resources could be redirected back to immigrants to improve their care. PMID- 19443830 TI - Outcomes of a breast health project for Hmong women and men in California. AB - OBJECTIVES: We used a community-based research approach to test a culturally based breast cancer screening program among low-income Hmong women in central and southern California. METHODS: We designed a culturally informed educational program with measures at baseline and 1-year follow-up in 2 intervention cities and 1 comparison city. Measures included changes in breast cancer screening, knowledge, and attitudes. RESULTS: Compared with women in the comparison community, women in the intervention community significantly improved their attitudes toward, and increased their knowledge and receipt of, breast cancer screenings. Odds of women in the intervention group having had a mammogram, having had a clinical breast examination, and having performed breast self examination was 6.75, 12.16, and 20.06, respectively, compared with women in the comparison group. CONCLUSIONS: Culturally informed education materials and intervention design were effective methods in conveying the importance of maintaining and monitoring proper breast health. The strength of community collaboration in survey development and intervention design highlighted the challenges of early detection and screening programs among newer immigrants, who face significant language and cultural barriers to care, and identified promising practices to overcome these health literacy challenges. PMID- 19443831 TI - Tackling health inequities in Chile: maternal, newborn, infant, and child mortality between 1990 and 2004. AB - OBJECTIVES: We analyzed trends in maternal, newborn, and child mortality in Chile between 1990 and 2004, after the introduction of national interventions and reforms, and examined associations between trends and interventions. METHODS: Data were provided by the Chilean Ministry of Health on all pregnancies between 1990 and 2004 (approximately 4,000,000). We calculated yearly maternal mortality ratios, stillbirth rates, and mortality rates for neonates, infants (aged > 28 days and < 1 year), and children aged 1 to 4 years. We also calculated these statistics by 5-year intervals for Chile's poorest to richest district quintiles. RESULTS: During the study period, the maternal mortality ratio decreased from 42.1 to 18.5 per 100,000 live births. The mortality rate for neonates decreased from 9.0 to 5.7 per 1000 births, for infants from 7.8 to 3.1 per 1000 births, and for young children from 3.1 to 1.7 per 1000 live births. The stillbirth rate declined from 6.0 to 5.0 per 1000 births. Disparities in these mortality statistics between the poorest and richest district quintiles also decreased, with the largest mortality reductions in the poorest quintile. CONCLUSIONS: During a period of socioeconomic development and health sector reforms, Chile experienced significant mortality and inequity reductions. PMID- 19443832 TI - Building alliances in unlikely places: progressive allies and the Tobacco Institute's coalition strategy on cigarette excise taxes. AB - The tobacco industry often utilizes third parties to advance its policy agenda. One such utilization occurred when the industry identified organized labor and progressive groups as potential allies whose advocacy could undermine public support for excise tax increases. To attract such collaboration, the industry framed the issue as one of tax fairness, creating a labor management committee to provide distance from tobacco companies and furthering progressive allies' interests through financial and logistical support. Internal industry documents indicate that this strategic use of ideas, institutions, and interests facilitated the recruitment of leading progressive organizations as allies. By placing excise taxes within a strategic policy nexus that promotes mutual public interest goals, public health advocates may use a similar strategy in forging their own excise tax coalitions. PMID- 19443833 TI - Patne en Aksyon: addressing cancer disparities in Little Haiti through research and social action. AB - Haitian women living in Miami, Florida, experience an increased risk of developing and dying from cervical cancer compared with women in other racial/ethnic minority and immigrant groups in the area. In response to this disparity, academic investigators from a local university-based cancer center and community leaders from Little Haiti, the predominately Haitian neighborhood in Miami, created Patne en Aksyon (Partners in Action), a campus-community partnership. We describe the partnership's effort to document the prevalence of lifetime and routine Papanicolau test use using community-based participatory research methods. Community health workers indigenous to the area recruited participants from various community venues throughout Little Haiti and administered informal, brief interviews to assess their screening practices. The results indicate that Haitian women are underscreened and underscore the importance of community involvement in study implementation. PMID- 19443834 TI - A rights-based approach to food insecurity in the United States. AB - Food insecurity is a serious public health problem associated with poor cognitive and emotional development in children and with depression and poor health in adults. Despite sizable continued investments in federal food assistance, food insecurity still affects 11.1% of US households--almost the same rate as in 1995, when annual measurement began. As a fresh approach to solving the problem of food insecurity, we suggest adoption of a human rights framework. This approach could actively engage those affected and would ensure that food security monitoring would be compared to benchmarks in national action plans. We describe key elements of a right-to-food approach, review challenges to implementing it, and suggest actions to foster its adoption. PMID- 19443835 TI - Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. AB - The therapeutic potential of vascular endothelial growth factor (VEGF)-C and VEGF D in skeletal muscle has been of considerable interest as these factors have both angiogenic and lymphangiogenic activities. Previous studies have mainly used adenoviral gene delivery for short-term expression of VEGF-C and VEGF-D in pig, rabbit, and mouse skeletal muscles. Here we have used the activated mature forms of VEGF-C and VEGF-D expressed via recombinant adeno-associated virus (rAAV), which provides stable, long-lasting transgene expression in various tissues including skeletal muscle. Mouse tibialis anterior muscle was transduced with rAAV encoding human or mouse VEGF-C or VEGF-D. Two weeks later, immunohistochemical analysis showed increased numbers of both blood and lymph vessels, and Doppler ultrasound analysis indicated increased blood vessel perfusion. The lymphatic vessels further increased at the 4-week time point were functional, as shown by FITC-lectin uptake and transport. Furthermore, receptor activation and arteriogenic activity were increased by an alanine substitution mutant of human VEGF-C (C137A) having an increased dimer stability and by a chimeric CAC growth factor that contained the VEGF receptor-binding domain flanked by VEGF-C propeptides, but only the latter promoted significantly more blood vessel perfusion when compared to the other growth factors studied. We conclude that long-term expression of VEGF-C and VEGF-D in skeletal muscle results in the generation of new functional blood and lymphatic vessels. The therapeutic value of intramuscular lymph vessels in draining tissue edema and lymphedema can now be evaluated using this model system. PMID- 19443836 TI - Synergistic activation of vascular TRPC6 channel by receptor and mechanical stimulation via phospholipase C/diacylglycerol and phospholipase A2/omega hydroxylase/20-HETE pathways. AB - TRPC6 is a non-voltage-gated Ca(2+) entry/depolarization channel associated with vascular tone regulation and remodeling. Expressed TRPC6 channel responds to both neurohormonal and mechanical stimuli, the mechanism for which remains controversial. In this study, we examined the possible interactions of receptor and mechanical stimulations in activating this channel using the patch clamp technique. In HEK293 cells expressing TRPC6, application of mechanical stimuli (hypotonicity, shear, 2,4,6-trinitrophenol) caused, albeit not effective by themselves, a prominent potentiation of cationic currents (I(TRPC6)) induced by a muscarinic receptor agonist carbachol. This effect was insensitive to a tarantula toxin GsMTx-4 (5 mumol/L). A similar extent of mechanical potentiation was observed after activation of I(TRPC6) by GTPgammaS or a diacylglycerol analog 1 oleoyl-2-acetyl-sn-glycerol (OAG). Single TRPC6 channel activity evoked by carbachol was also enhanced by a negative pressure added in the patch pipette. Mechanical potentiation of carbachol- or OAG-induced I(TRPC6) was abolished by small interfering RNA knockdown of cytosolic phospholipase A(2) or pharmacological inhibition of omega-hydroxylation of arachidonic acid into 20 HETE (20-hydroxyeicosatetraenoic acid). Conversely, direct application of 20-HETE enhanced both OAG-induced macroscopic and single channel TRPC6 currents. Essentially the same results were obtained for TRPC6-like cation channel in A7r5 myocytes, where its activation by noradrenaline or Arg8 vasopressin was greatly enhanced by mechanical stimuli via 20-HETE production. Furthermore, myogenic response of pressurized mesenteric artery was significantly enhanced by weak receptor stimulation dependently on 20-HETE production. These results collectively suggest that simultaneous operation of receptor and mechanical stimulations may synergistically amplify transmembrane Ca(2+) mobilization through TRPC6 activation, thereby enhancing the vascular tone via phospholipase C/diacylglycerol and phospholipase A(2)/omega-hydroxylase/20-HETE pathways. PMID- 19443837 TI - Antiarrhythmic drug-induced internalization of the atrial-specific k+ channel kv1.5. AB - Conventional antiarrhythmic drugs target the ion permeability of channels, but increasing evidence suggests that functional ion channel density can also be modified pharmacologically. Kv1.5 mediates the ultrarapid potassium current (I(Kur)) that controls atrial action potential duration. Given the atrial specific expression of Kv1.5 and its alterations in human atrial fibrillation, significant effort has been made to identify novel channel blockers. In this study, treatment of HL-1 atrial myocytes expressing Kv1.5-GFP with the class I antiarrhythmic agent quinidine resulted in a dose- and temperature-dependent internalization of Kv1.5, concomitant with channel block. This quinidine-induced channel internalization was confirmed in acutely dissociated neonatal myocytes. Channel internalization was subunit-dependent, activity-independent, stereospecific, and blocked by pharmacological disruption of the endocytic machinery. Pore block and channel internalization partially overlap in the structural requirements for drug binding. Surprisingly, quinidine-induced endocytosis was calcium-dependent and therefore unrecognized by previous biophysical studies focused on isolating channel-drug interactions. Importantly, whereas acute quinidine-induced internalization was reversible, chronic treatment led to channel degradation. Together, these data reveal a novel mechanism of antiarrhythmic drug action and highlight the possibility for new agents that selectively modulate the stability of channel protein in the membrane as an approach for treating cardiac arrhythmias. PMID- 19443838 TI - Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. AB - The peripheral apelin system plays a significant role in cardiovascular homeostasis and in the pathophysiology of cardiovascular diseases. However, the central effect of this neurohormonal system in neural control of cardiovascular function remains poorly understood. Thus, this study was undertaken to evaluate the effect of apelin in the rostral ventrolateral medulla (RVLM) on blood pressure, cardiac function, and sympathetic nerve activity. Apelin mRNA and protein levels were detected with real-time RT-PCR and Western blots, respectively. Expression of apelin was significantly enhanced in the RVLM of spontaneously hypertensive rat (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. To study the functional consequence of upregulated apelin expression, apelin was overexpressed by bilateral microinjection of the AAV2-apelin viral vector into the RVLM of WKY rats. Immunofluorescence staining and Western blots demonstrated that microinjection of AAV2-apelin into the RVLM resulted in a significant increase in apelin expression, which was associated with a chronic elevation in blood pressure and cardiac hypertrophy. In addition, direct microinjection of exogenous apelin-13 (200 pmol in 50 nL) into the RVLM caused a 20 mm Hg elevation in blood pressure and a 24% increase in sympathetic nerve activity. The present study is the first to show that apelin expression is enhanced in the RVLM of SHR versus WKY rats and that overexpression of this gene in the RVLM results in chronic blood pressure elevation and cardiac hypertrophy in normotensive rats. Thus, the apelin system in the RVLM may play a very important role in central blood pressure regulation and in the pathogenesis of hypertension. PMID- 19443839 TI - Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1. AB - Emerging evidence illustrates the importance of the positive transcription elongation factor (P-TEF)b in control of global RNA synthesis, which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl-terminal domain of RNA polymerase (Pol) II. We and others have shown that the activity of P-TEFb is inhibited by its association with cardiac lineage protein (CLP)-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of control of P-TEFb activity by CLP-1 in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by overexpression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC-cyclin T1/CLP-1(+/-)) by crossing MHC-cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy that is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of carboxyl-terminal domain and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced lifespan. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates derepression of P-TEFb activity and emphasizes the importance of the role of CLP-1 in the mechanism governing compensatory hypertrophy in cardiomyocytes. PMID- 19443840 TI - The recovery time course of the endothelial cell glycocalyx in vivo and its implications in vitro. AB - Compelling evidence continues to emerge suggesting that the glycocalyx surface layer on vascular endothelial cells plays a determining role in numerous physiological processes including inflammation, microvascular permeability, and endothelial mechanotransduction. Previous research has shown that enzymes degrade the glycocalyx, whereas inflammation causes shedding of the layer. To track the endogenous recovery of the glycocalyx in vivo, we used fluorescent microparticle image velocimetry (micro-PIV) in mouse cremaster muscle venules to estimate the hydrodynamically relevant glycocalyx thickness 1, 3, 5, and 7 days after enzymatic or cytokine-mediated degradation of the layer. Results indicate that after acute degradation of the glycocalyx, 5 to 7 days are required for the layer to endogenously restore itself to its native hydrodynamically relevant thickness in vivo. In light of these findings, and because demonstrable evidence has emerged that standard cell culture conditions are not conducive to providing the environment and/or cellular conditions necessary to produce and maintain a physiologically relevant cell surface glycocalyx in vitro, we sought to determine whether merely the passage of time would be sufficient to promote the production of a hydrodynamically relevant glycocalyx on a confluent monolayer of human umbilical vein endothelial cells (HUVECs). Using micro-PIV, we found that the hydrodynamically relevant glycocalyx was substantially absent 7 days postconfluence on HUVEC-lined cylindrical collagen microchannels maintained under standard culture conditions. Thus, it remains to be determined how a hydrodynamically relevant glycocalyx surface layer can be synthesized and maintained in culture before the endothelial cell culture model can be used to elucidate glycocalyx-mediated mechanisms of endothelial cell function. PMID- 19443841 TI - Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. AB - Rapid induction and maintenance of blood flow through new vascular networks is essential for successfully treating ischemic tissues and maintaining function of engineered neo-organs. We have previously shown that human endothelial progenitor cells (EPCs) form functioning vessels in mice, but these are limited in number and persistence; and also that human adipose stromal cells (ASCs) are multipotent cells with pericytic properties which can stabilize vascular assembly in vitro. In this study, we tested whether ASCs would cooperate with EPCs to coassemble vessels in in vivo implants. Collagen implants containing EPCs, ASCs, or a 4:1 mixture of both were placed subcutaneously into NOD/SCID mice. After a range of time periods, constructs were explanted and evaluated with regard to vascular network assembly and cell fate; and heterotypic cell interactions were explored by targeted molecular perturbations. The density and complexity of vascular networks formed by the synergistic dual-cell system was many-fold higher than found in implants containing either ASCs or EPCs alone. Coimplantation of ASCs and EPCs with either pancreatic islets or adipocytes produced neoorgans populated by these parenchymal cells, as well as by chimeric human vessels conducting flow. This study is the first to demonstrate prompt and consistent assembly of a vascular network by human ASCs and endothelial cells and vascularization by these cells of parenchymal cells in implants. Mixture of these 2 readily available, nontransformed human cell types provides a practical approach to tissue engineering, therapeutic revascularization, and in vivo studies of human vasculogenesis. PMID- 19443842 TI - Milk fat globule protein epidermal growth factor-8: a pivotal relay element within the angiotensin II and monocyte chemoattractant protein-1 signaling cascade mediating vascular smooth muscle cells invasion. AB - Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 months) and old (30 months) rats and identified 50 proteins that significantly change in abundance with aging. One novel protein, the milk fat globule protein epidermal growth factor 8 (MFG-E8), increases 2.3-fold in abundance in old aorta. Transcription and translation analysis demonstrated that aortic MFG-E8 mRNA and protein levels increase with aging in several mammalian species including humans. Dual immunolabeling shows that MFG-E8 colocalizes with both angiotensin II and monocyte chemoattractant protein (MCP)-1 within vascular smooth muscle cells (VSMCs) of the thickened aged aortic wall. Exposure of early passage VSMCs from young aorta to angiotensin II markedly increases MFG-E8 and enhances invasive capacity to levels observed in VSMCs from old rats. Treatment of VSMCs with MFG-E8 increases MCP-1 expression and VSMCs invasion that are inhibited by the MCP-1 receptor blocker vCCI. Silencing MFG-E8 RNA substantially reduces MFG-E8 expression and VSMCs invasion capacity. The data indicate that arterial MFG-E8 significantly increases with aging and is a pivotal relay element within the angiotensin II/MCP-1/VSMC invasion signaling cascade. Thus, targeting of MFG-E8 within this signaling axis pathway is a potential novel therapy for the prevention and treatment of the age-associated vascular diseases such as atherosclerosis. PMID- 19443843 TI - Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome. AB - OBJECTIVE: Increasing evidence suggests that chronic inflammation contributes to atherogenesis, and that acute inflammatory events cause plaque rupture, thrombosis, and myocardial infarction. The present studies examined how inflammatory factors, such as interferon-gamma (IFNgamma), cause increased sensitivity to apoptosis in vascular lesion cells. METHODS AND RESULTS: Cells from the fibrous cap of human atherosclerotic lesions were sensitized by interferon-gamma (IFNgamma) to Fas-induced apoptosis, in a Bcl-X(L) reversible manner. Microarray profiling identified 72 INFgamma-induced transcripts with potential relevance to apoptosis. Half could be excluded because they were induced by IRF-1 overexpression, which did not sensitize to apoptosis. IFNgamma treatment strongly reduced Mcl-1, phospho-Bcl-2 (ser70), and phospho-Bcl-X(L) (ser62) protein levels. Candidate transcripts were modulated by siRNA, overexpression, or inhibitors to assess the effect on IFNgamma-induced Fas sensitivity. Surprisingly, siRNA knockdown of PSMB8 (LMP7), an "immunoproteasome" component, reversed IFNgamma-induced sensitivity to Fas ligation and prevented Fas/IFNgamma-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl X(L). Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-X(L) levels after IFNgamma treatment. CONCLUSIONS: Although critical for antigen presentation, the immunoproteasome appears to be a key link between inflammatory factors and the control of vascular cell apoptosis and may thus be an important factor in plaque rupture and myocardial infarction. PMID- 19443844 TI - Rapamycin inhibition of the Akt/mTOR pathway blocks select stages of VEGF-A164 driven angiogenesis, in part by blocking S6Kinase. AB - OBJECTIVE: We evaluated the stages of VEGF-A(164) driven angiogenesis that are inhibited by therapeutic doses of rapamycin and the potential role of S6K1 in that response. METHODS AND RESULTS: We assessed the effects of rapamycin on the several stages of angiogensis and lymphangiogenesis induced with an adenovirus expressing VEGF-A(164) (Ad-VEGF-A(164)) in the ears of adult nude mice. Rapamycin (0.5 mg/kg/d) effectively inhibited mTOR and downstream S6K1 signaling and partially inhibited Akt signaling, likely through effects on TORC2. The earliest stages of angiogenesis, including mother vessel formation and increased vascular permeability, were strikingly inhibited by rapamycin, as was subsequent formation of daughter glomeruloid microvasular proliferations. However, later stage formation of vascular malformations and lymphangiogenesis were unaffected. Retrovirally delivered isoforms and shRNAs demonstrated that S6K1 signaling plays an important role in early VEGF-A(164)-angiogenesis. CONCLUSIONS: Rapamycin potently inhibited early and mid stages of VEGF-A(164)-driven angiogenesis, but not late-stage angiogenesis or lymphangiogenesis. Rapamycin decreased phosphorylation of both Akt and S6, suggesting that both the TORC1 and TORC2 pathways are impacted. Inhibition of S6K1 signaling downstream of mTOR is a major component of the antiangiogenesis action of rapamycin. PMID- 19443849 TI - Labour pains: giving birth to new mechanisms for the regulation of myometrial contractility. PMID- 19443850 TI - Unravelling the complexity of Cl- channels: how long is a piece of string? PMID- 19443851 TI - The evaluation of CBRN canisters for use by firefighters during overhaul. AB - Air-purifying respirators (APRs) have been proposed to provide an additional respiratory protection option for structural firefighters involved in overhaul operations and wildland firefighters, where particulate and aldehyde exposures have been documented. Previous studies (Anthony et al., 2007) developed test methods to evaluate APR cartridges and canisters for use in overhaul activities, where initial findings indicated that multi-gas cartridges may not be effective. This study evaluated the performance of three chemical, biological, radiological, and nuclear (CBRN) canisters (MSA, 3M, and Scott) and one multi-gas canister similar in appearance to CBRN canisters but without CBRN certification (3M FR 64040). Challenge concentrations typical of overhaul exposures were generated by combusting common household materials. Twelve tests were conducted, using random canister selection, where challenge air and air filtered by the canisters were tested. All tests examined penetration of CO; NO(2); SO(2); respirable dust; aldehydes, including formaldehyde, acrolein, and glutaraldehyde; and hydrogen cyanide. Six of the tests also investigated naphthalene, benzene, and hydrogen chloride, but challenge concentrations from the simulated overhaul smoke were near the limit of detection (LOD) and were two orders of magnitude below short term or ceiling concentrations of concern and were eliminated from further study with the combustion materials used in this study. In all tests, an irritant index was computed to evaluate the aggregate penetration of contaminants in the smoke mixture, using 15- and 30-min occupational exposure limits as well as assessing individual penetrations. In all cases, the challenge concentration irritant index exceeded unity, ranging from 2.3 to 21. For all 12 tests, the APR canister reduced the overall irritant index to levels below unity, indicating that these canisters would provide protection for firefighters working in overhaul environments. However, in some tests, levels of carbon monoxide were higher than recommended for persons wearing APRs. Since these canisters do not protect against carbon monoxide, firefighters must still rely on direct reading warning to indicate high CO levels, indicating the need to leave the area if wearing an APR, as these APR canisters would be inappropriate. PMID- 19443852 TI - Field and wind tunnel comparison of four aerosol samplers using agricultural dusts. AB - Occupational lung disease is a significant problem among agricultural workers exposed to organic dusts. Measurements of exposure in agricultural environments in the USA have traditionally been conducted using 37-mm closed-face cassettes (CFCs) and respirable Cyclones. Inhalable aerosol samplers offer significant improvement for dose estimation studies to reduce respiratory disease. The goals of this study were to determine correction factors between the inhalable samplers (IOM and Button) and the CFC and Cyclone for dusts sampled in livestock buildings and to determine whether these factors vary among livestock types. Determination of these correction factors will allow comparison between inhalable measurements and historical measurements. Ten sets of samples were collected in swine, chicken, turkey, and dairy facilities in both Colorado and Iowa. Pairs of each sampling device were attached to the front and back of a rotating mannequin. Laboratory studies using a still-air chamber and a wind tunnel provided information regarding the effect of wind speed on sampler performance. Overall, the IOM had the lowest coefficient of variation (best precision) and was least affected by changes in wind speed. The performance of the Button was negatively impacted in poultry environments where larger (feather) particulates clogged the holes in the initial screen. The CFC/IOM ratios are important for comparisons between newer and older studies. Wind speed and dust type were both important factors affecting ratios. Based on the field studies (Table 6), a ratio of 0.56 is suggested as a conversion factor for the CFC/IOM (average for all environments because of no statistical difference). Suggested conversion factors for the Button/IOM are swine (0.57), chicken (0.80), turkey (0.53), and dairy (0.67). Any attempt to apply a conversion factor between the Cyclone and inhalable samplers is not recommended. PMID- 19443853 TI - A single-copy IS5-like transposon in the genome of a bdelloid rotifer. AB - In the course of sequencing telomeric chromosomal regions of the bdelloid rotifer Adineta vaga, we encountered an unusual DNA transposon. Unlike other bdelloid and, more generally, eukaryotic transposable elements (TEs), it exhibits similarity to prokaryotic insertion sequences (ISs). Phylogenetic analysis indicates that this transposon, named IS5_Av, is related to the ISL2 group of the IS5 family of bacterial IS elements. Despite the apparent intactness of the single open reading frame coding for a DDE transposase and the perfect identity of its 213-bp terminal inverted repeats (TIRs), the element is present in only one copy per diploid genome. It does not exhibit any detectable levels of transcription, so that its transposase gene appears to be silent in the bdelloid host. Although horizontal transfers of TEs between kingdoms are not known to happen in nature, it appears likely that IS5_Av underwent integration into the A. vaga genome relatively recently, but was not successful in adapting to the new host and failed to increase in copy number. Alternatively, it might be the only known member of a novel eukaryotic DNA TE superfamily which is so rare that its other members, if any, have not yet been identified in eukaryotic genomes sequenced to date. PMID- 19443854 TI - Can GC content at third-codon positions be used as a proxy for isochore composition? AB - The isochore theory depicts the genomes of warm-blooded vertebrates as a mosaic of long genomic regions that are characterized by relatively homogeneous GC content. In the absence of genomic data, the GC content at third-codon positions of protein-coding genes (GC3) was commonly used as a proxy for the GC content of isochores. Oddly, in the postgenomic era, GC3 is still sometimes used as a proxy for the GC composition of isochores. Here, we use genic and genomic sequences from human, chimpanzee, cow, mouse, rat, chicken, and zebrafish to show that GC3 only explains a very small proportion of the variation in GC content of long genomic sequences flanking the genes (GCf), and what little correlation there is between GC3 and GCf was found to decay rapidly with distance from the gene. The coefficient of variation of GC3 was found to be much larger than that of GCf and, therefore, GC3 and GCf values are not comparable with each other. Comparisons of orthologous gene pairs from 1) human and chimpanzee and 2) mouse and rat show strong correlations between their GC3 values, but very weak correlations between their GCf values. We conclude that the GC content of third-codon position cannot be used as stand-in for isochoric composition. PMID- 19443855 TI - A machine-learning approach reveals that alignment properties alone can accurately predict inference of lateral gene transfer from discordant phylogenies. AB - Among the methods currently used in phylogenomic practice to detect the presence of lateral gene transfer (LGT), one of the most frequently employed is the comparison of gene tree topologies for different genes. In cases where the phylogenies for different genes are incompatible, or discordant, for well supported branches there are three simple interpretations for the result: 1) gene duplications (paralogy) followed by many independent gene losses have occurred, 2) LGT has occurred, or 3) the phylogeny is well supported but for reasons unknown is nonetheless incorrect. Here, we focus on the third possibility by examining the properties of 22,437 published multiple sequence alignments, the Bayesian maximum likelihood trees for which either do or do not suggest the occurrence of LGT by the criterion of discordant branches. The alignments that produce discordant phylogenies differ significantly in several salient alignment properties from those that do not. Using a support vector machine, we were able to predict the inference of discordant tree topologies with up to 80% accuracy from alignment properties alone. PMID- 19443856 TI - Domain shuffling and the evolution of vertebrates. AB - The evolution of vertebrates has included a number of important events: the development of cartilage, the immune system, and complicated craniofacial structures. Here, we examine domain shuffling as one of the mechanisms that contributes novel genetic material required for vertebrate evolution. We mapped domain-shuffling events during the evolution of deuterostomes with a focus on how domain shuffling contributed to the evolution of vertebrate- and chordate specific characteristics. We identified approximately 1000 new domain pairs in the vertebrate lineage, including approximately 100 that were shared by all seven of the vertebrate species examined. Some of these pairs occur in the protein components of vertebrate-specific structures, such as cartilage and the inner ear, suggesting that domain shuffling made a marked contribution to the evolution of vertebrate-specific characteristics. The evolutionary history of the domain pairs is traceable; for example, the Xlink domain of aggrecan, one of the major components of cartilage, was originally utilized as a functional domain of a surface molecule of blood cells in protochordate ancestors, and it was recruited by the protein of the matrix component of cartilage in the vertebrate ancestor. We also identified genes that were created as a result of domain shuffling in ancestral chordates. Some of these are involved in the functions of chordate structures, such as the endostyle, Reissner's fiber of the neural tube, and the notochord. Our analyses shed new light on the role of domain shuffling, especially in the evolution of vertebrates and chordates. PMID- 19443858 TI - Intestinal dipeptide absorption is preserved during thermal injury and cytokine treatment. AB - BACKGROUND: Intestinal barrier function is impaired during thermal injury; however, the effects of thermal injury on the absorption of dietary peptides are not well characterized. The purpose of this study was to determine the impact of thermal injury on dipeptide absorption in rats and to describe the influence of inflammatory cytokines on the expression of the oligopeptide transporter PEPT1 and dipeptide permeability in cultured intestinal cells (Caco-2 cells). METHODS: Sprague Dawley rats were assigned to 30% body surface area burn (n = 7) or sham (n = 8) groups. Twenty-four hours following burn/sham, the proximal jejunum was cannulated. The jejunal segment was perfused with buffer containing the dipeptide glycylsarcosine (Gly-Sar), and intestinal permeability (P(eff)) was calculated. For in vitro experiments, Caco-2 cells were grown on permeable supports and treated with tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 (10 ng/mL) alone and in combination for 48 hours. The effective apical-to-basolateral permeabilities (P(eff)) of Gly-Sar were measured, and PEPT1 expression was determined using reverse transcription-polymerase chain reaction. RESULTS: Gly Sar P(eff) was similar in burn and sham rats (6.67 +/- 2.27 x 10(-5) vs 7.58 +/- 2.20 x 10(-5) cm/s, respectively, P = .45). In Caco-2 cells, cytokine treatment did not alter PEPT1 expression (P = .954) or the P(eff) of Gly-Sar (P = .806). CONCLUSIONS: Intestinal absorption of the dipeptide Gly-Sar is preserved 24 hours following thermal injury in rats. Likewise, PEPT1 expression and peptide absorption are preserved following treatment with TNF-alpha, IL-6, and IL-10 in Caco-2 monolayers. These findings imply that intestinal dipeptide absorption may be preserved during burn injury. This may lead to new strategies to optimize enteral protein delivery in burn patients. PMID- 19443857 TI - MS-qFRET: a quantum dot-based method for analysis of DNA methylation. AB - DNA methylation contributes to carcinogenesis by silencing key tumor suppressor genes. Here we report an ultrasensitive and reliable nanotechnology assay, MS qFRET, for detection and quantification of DNA methylation. Bisulfite-modified DNA is subjected to PCR amplification with primers that would differentiate between methylated and unmethylated DNA. Quantum dots are then used to capture PCR amplicons and determine the methylation status via fluorescence resonance energy transfer (FRET). Key features of MS-qFRET include its low intrinsic background noise, high resolution, and high sensitivity. This approach detects as little as 15 pg of methylated DNA in the presence of a 10,000-fold excess of unmethylated alleles, enables reduced use of PCR (as low as eight cycles), and allows for multiplexed analyses. The high sensitivity of MS-qFRET enables one step detection of methylation at PYCARD, CDKN2B, and CDKN2A genes in patient sputum samples that contain low concentrations of methylated DNA, which normally would require a nested PCR approach. The direct application of MS-qFRET on clinical samples offers great promise for its translational use in early cancer diagnosis, prognostic assessment of tumor behavior, as well as monitoring response to therapeutic agents. PMID- 19443859 TI - Association between a g.+6723G-A SNP in the myostatin gene (MSTN) and carcass traits in New Zealand Texel sheep. PMID- 19443860 TI - Statistical power calculations: comment. PMID- 19443863 TI - Bone loss in inflammatory disorders. AB - Chronic inflammatory diseases of almost any cause are associated with bone loss. Bone loss is due to direct effects of inflammation, poor nutrition, reduced lean body mass, immobility and the effects of treatments, especially glucocorticoids. These mechanisms are complex and interrelated but are ultimately mediated through effects on the bone remodelling cycle. Inflammatory disease can increase bone resorption, decrease bone formation but most commonly impacts on both of these processes resulting in an uncoupling of bone formation from resorption in favour of excess resorption. This review will illustrate these interactions between inflammation and bone metabolism and discuss how these are, and might be, manipulated as therapies for inflammation related bone loss. PMID- 19443862 TI - Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm. AB - Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid (FA) oxidation is an important source of ATP. FA oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis. Here, we demonstrate that lipopolysaccharide (LPS) decreases FA oxidation and the expression of lipoprotein lipase (LPL), FA transport protein 1 (FATP-1), CD36, carnitine palmitoyltransferase beta, medium chain acyl-CoA dehydrogenase (MCAD), and acyl-CoA synthetase, key proteins required for FA uptake and oxidation, in the diaphragm. LPS also decreased mRNA levels of PPARalpha and beta/delta, RXRalpha, beta, and gamma, thyroid hormone receptor alpha and beta, and estrogen related receptor alpha (ERRalpha) and their coactivators PGC-1alpha, PGC-1beta, SRC1, SRC2, Lipin 1, and CBP. Zymosan resulted in similar changes in the diaphragm. Finally, in PPARalpha deficient mice, baseline CPT-1beta and FATP 1 levels were markedly decreased and were not further reduced by LPS suggesting that a decrease in the PPARalpha signaling pathway plays an important role in inducing some of these changes. The decrease in FA oxidation in the diaphragm may be detrimental, leading to decreased diaphragm contraction and an increased risk of respiratory failure during sepsis. PMID- 19443864 TI - Endovascular stent graft treatment of acute thoracic aortic transections due to blunt force trauma. AB - Endovascular stent graft treatment of acute thoracic aortic transections is an encouraging minimally invasive alternative to open surgical repair. Between 2006 and 2008, 16 patients with acute thoracic aortic transections underwent evaluation at our institution. Seven patients who were treated with an endovascular stent graft were reviewed. The mean Glasgow Coma Score was 13.0, probability of survival was .89, and median injury severity score was 32. The mean number of intensive care unit days was 7.7, mean number of ventilator support days was 5.4, and hospital length of stay was 10 days. Mean blood loss was 285 mL, and operative time was 143 minutes. Overall mortality was 14%. Procedure complications were a bleeding arteriotomy site and an endoleak. Endovascular treatment of traumatic thoracic aortic transections appears to demonstrate superior results with respect to mortality, blood loss, operative time, paraplegia, and procedure-related complications when compared with open surgical repair literature. PMID- 19443865 TI - Laparoscopic circular biomesh hiatoplasty during paraesophageal hernia repair. AB - Laparoscopic approaches for paraesophageal hernia repair and the use of prosthetic reinforcement materials during crural repair have become standard. However, the search for the optimal prosthetic material and techniques for placement and fixation methods are still controversial and under investigation. The authors aimed to determine the technical feasibility of the use of human acellular dermal matrix for hiatoplasty in a circular fashion during paraesophageal hernia repair in a small series of patients. The short-term outcomes of patients who underwent laparoscopic repair of large paraesophageal hernias with biomesh circular hiatal reinforcement were analyzed. Laparoscopic circular hiatal reinforcement with acellular dermal matrix is feasible and reproducible with no associated short-term morbidity. The acellular dermal matrix mesh is very elastic and has excellent intracorporeal handling characteristics during hiatoplasty. PMID- 19443866 TI - PGP 9.5 and cyclin D1 coexpression in cutaneous squamous cell carcinomas. AB - BACKGROUND: squamous cell carcinoma (SCC) consists of altered keratinocytes, presents variable differentiation, inexorably progresses, and on occasion metastasizes. OBJECTIVE: to investigate the biological activity of epidermal cells in SCCs by estimating the expression of PGP 9.5 and cyclin D1 using immunohistochemistry. METHODS: the sample included 13 well-differentiated cases of cutaneous SCC (grade I), 12 moderately differentiated tumors (grade II), and 7 poorly differentiated lesions (grade III). Four cases belonged to the distinct entity of pseudoadenoid SCC. RESULTS: PGP 9.5 expression was positively correlated with tumor stage (P < .001) and potential perineural invasion ( P < .001), whereas cyclin D1 expression correlated inversely with the degree of cellular differentiation (P < .001) and PGP 9.5 immunostaining (P < .001). CONCLUSION: PGP 9.5 and cyclin D1 coexpression was closely associated with tumor aggressiveness and can be classified as a marker for predicting the outcome of resection-treated skin cancer patients. PMID- 19443867 TI - "Dedifferentiated" adrenal cortical neoplasm. PMID- 19443868 TI - Colonic carcinoma metastatic to the endometrium: the importance of clinical history in averting misdiagnosis as a primary endometrial carcinoma. AB - Metastases to endometrium are a rare event. A case of a 53-year-old woman with a previous colon cancer presenting with a dysfunctional uterine bleeding is reported. The curettage specimens consisted of multiple fragments of proliferative endometrial tissue mixed with irregular glands, focally amputated, lined by very cells with elongated, hyperchromatic nuclei and solid sheets of neoplastic cells often filled with necrotic debris and inflammatory cells, resembling endometrioid adenocarcinoma. Neoplastic cells resulted positive at immunohistochemical reaction for CK20, CDX2, p53 and negative for CK7, vimentin, ER, and PR suggesting a metastatic colon adenocarcinoma. Absence of premalignant changes, such as hyperplasia, besides frankly malignant glands in an endometrial curette should be regarded as an alarming feature for a secondary nature mostly from large bowel. In these cases clinical history is crucial and an immunohistochemical panel made up of CK7, CK20, CDX2, p53, vimentin, ER, and PR is useful for the correct diagnosis. PMID- 19443869 TI - Lynch syndrome--related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types. AB - Although endometrial cancer (EC) represents the second most common cancer after colonic cancer in patients with Lynch syndrome (LS), the pathologic features and behavior of LS-related EC are not well recognized. ECs from 23 patients (mean age 46.2 years) with MSH2 (16), MLH1 (6), and MLH1/MSH2 (1) constitutional mutations were evaluated for histologic type, FIGO grade, FIGO stage, association with tumors in other sites, and survival. For every LS-associated tumor, 2 same-age cases from patients with no family history of LS-associated cancer were evaluated (sporadic group). In LS-associated EC there were 13 (56.5%) endometrioid (eec) and 10 (43.5%) nonendometrioid carcinomas (neec), and among the sporadic tumors there were 44 (95.7%) eec and 2 (4.3%) neec (P = .001). The eec in women with germline LS mutation had a significantly higher FIGO grade (P = .0378) and more frequent vascular invasion than the controls. The mean survival of the entire group of 23 patients with LS-related EC was 17.326 (14.066 to 20.585). Mean survival according to FIGO stage was significant (P = .010). Difference in mean survival according to age of the patient at the time of the diagnosis (patients >46 years vs <46 years) was not significant. The mean survival of the mutated patients with eec was 20.462 (17.564 to 23.359) and was not significantly different from that of the mutated patients with neec, which was 14.240 (9.119 to 19.361). Log-rank analysis showed that histology did not affect the survival. However, the hazard ratio of neec patients, although not significant, resulted higher. Mean survival of patients with a neec tumor combined with an endometrioid component (14.375 [8.084 to 20.666]) was not different from that of patients with pure neec cancers (14.250 [7.885 to 20.615]). When compared with the control population, LS-related ECs show a wider variety of histologic types; a higher frequency of neec types despite the younger age of the patients, and a higher frequency of high grades among the eec. PMID- 19443870 TI - Pleomorphic adenoma with mucinous and squamous differentiation: a mimicker of mucoepidermoid carcinoma. AB - Pleomorphic adenoma with foci of squamous and mucinous differentiation can potentially be misdiagnosed as low-grade mucoepidermoid carcinoma. The circumscribed borders of the tumor, gradual merging of mucoepidermoid foci into areas typical of pleomorphic adenoma, and presence of keratinization are features against the latter diagnosis. PMID- 19443871 TI - Strategies to change body shape among men and women who attend fitness centers. AB - The current study examined the association between exercise behaviors, disordered eating, and other behaviors to change body shape among fitness center attendees. The participants were 520 adults (245 men, 275 women) who attended fitness centers. Data were gathered using an anonymous questionnaire. Women who attended fitness centers were generally trying to lose weight and improve fitness; men were generally trying to increase their muscles and improve their fitness level. Reasons for exercise predicted the nature of the body change strategies adopted by respondents. Regression analyses demonstrated that exercises performed by people who attend fitness centers are a reflection of whether or not they want to lose weight, increase muscle or improve fitness. All groups were equally likely to engage in health risk behaviors, but the specific nature of these behaviors varied by group. The implications of these findings for health-related messages among people who attend fitness centers are discussed. PMID- 19443872 TI - Probable impacts of climate change on public health in Bangladesh. AB - The recent report of the Intergovernmental Panel on Climate Change confirmed that there is overwhelming evidence that the global climate will severely affect human health. Climate change might have severe consequences on public health in Bangladesh, especially in light of the poor state of the country's public health infrastructure. A number of possible direct and indirect impacts of climate change on public health in Bangladesh have been identified in this article. Adaptive measures that should be taken to reduce the negative consequences of climate change on public health have also been discussed. PMID- 19443874 TI - Review paper: epidemiology, evidence-based medicine, and public health. AB - This article reviews the relation between evidence-based medicine and epidemiology and the recent evolution of the former. The meaning of evidence and the international efforts to collect, summarize, and disseminate findings from scientific research that are relevant for medical decision making are discussed. Evidence, current resources, and people's values, all play a role in making evidence-based medical decisions. This also has important implications for public health practice. However, decision making differs considerably between clinical care of individual patients and public health decision and policies that normally apply to populations. Although more closely related to epidemiology than clinical medicine, public health should also adopt a more systematic approach to evidence based practice. PMID- 19443873 TI - An assessment of felt needs and expectations of people living with HIV/AIDS seeking treatment at NGOs in Delhi, India. AB - People living with HIV/AIDS (PLHAs) continue to face stigma and discrimination in society. The felt needs of PLHAs can be met by means of a comprehensive, holistic, and integrated approach by the concerned sectors. This study included 100 PLHAs admitted at 3 care homes run by nongovernmental organizations in New Delhi. As many as 22% of the patients had been diagnosed with pulmonary Koch's. Unemployment rates were found to increase after disease onset. Majority were satisfied with the medical treatment and overall care provided at these centers. About 25% expressed that they would like the government to provide them with suitable jobs. Less than one third (30%) of the PLHAs expressed satisfaction with their family life whereas the rest yearned for love and acceptance from society. Study findings highlight the important role of nongovernmental organizations and stresses on the need for a holistic approach toward the care of these people. PMID- 19443875 TI - Variation in the prevalence, awareness, and control of diabetes in a multiethnic population: a nationwide population study in Malaysia. AB - The purpose of this study was to determine the association between different ethnic groups and the prevalence, awareness, and control of diabetes in Malaysia. A population-based cross-sectional study using multistage sampling was conducted in Malaysia. Diabetes is defined as having a fasting blood glucose > or =7 mmol/L or a self-reported diabetic on treatment. Among the 7683 respondents aged > or =30 years, the prevalence of diabetes mellitus was 15.2% (95% CI = 14.1, 16.4). Multivariate analysis showed that compared with Malays, Chinese had lower odds (adjusted odds ratio [aOR] 0.71; 95% CI = 0.56, 0.91) and Indians had higher odds of having diabetes (aOR 1.54; 95% CI = 1.20, 1.98). The odds of diabetes increased with age, family history of diabetes, body mass index, and lower education levels. Among those with diabetes mellitus, 45.0% were aware and 42.7% were under treatment. Among treated diabetics, 25.1% had their fasting blood sugar under control. There is a significant association between prevalence of diabetes and different ethnic groups. PMID- 19443876 TI - A qualitative evaluation of the information, education, and communication component of the tuberculosis control program in Delhi, India. AB - Tuberculosis control programs have recognized and addressed those system components in which knowledge and behavior of the patient and the general population are key issues because they have a profound influence on the treatment seeking behavior and completion of course of treatment. As a part of the Revised National Tuberculosis Control Program, the ongoing information, education, and communication (IEC) efforts in Delhi were further intensified in the form of a multipronged media campaign. The objectives of this study are to evaluate (a) the impact of the campaign on awareness generation among the target audiences, (b) their opinion for making the campaign more effective and suited to their needs, and (c) perceptions of health personnel regarding the campaign. The study follows a descriptive cross-sectional design. The following qualitative methods were used: (a) focus group discussions of patients and the general population, (b) 3 key informant interviews of the health care personnel and a defaulter patient, and (c) in-depth interviews of 20 DOTS (directly observed treatment, short course) providers. The study observed that (a) different sociocultural segments of the population varied in terms of their observations of IEC messages, (b) stigma associated with tuberculosis is widely prevalent despite having a campaign, and ( c) television was voted as the most effective IEC medium. IEC strategies should be tailor-made and suited to the needs of a particular subpopulation. PMID- 19443877 TI - Vision-related quality of life among elders with cataract in Sri Lanka: findings from a study in Gampaha District. AB - The objective of this study was to establish the prevalence of cataract and measure vision related quality of life among elders in Sri Lanka. The 4-part study consisted of a survey to establish cataract prevalence, a case control study of risk factors, an assessment of the National Eye Institute Visual Functional Questionnaire (NEI-VFQ), and a comparison of quality of life among elders with and without cataract. Cataract prevalence was 56%. Significant risk factors were age, being female, occupational exposure, lower social class, presence of chronic illnesses, and smoking. The NEI-VFQ was validated for use in Sri Lanka and quality of life of elders with cataract was significantly lower on the NEI-VFQ and 2 other standard measures. The findings inform the development of public health strategies for treatment and prevention of cataract in Sri Lanka where the impact of cataract is increasingly being felt with rapid population aging and are applicable to other developing countries. PMID- 19443878 TI - Seven attributes of primary care in Thailand. AB - Primary care must be defined with a given country's contexts because primary care services vary across countries. This study aimed to define the concept of primary care in Thailand, which had not been systematically formulated. METHODS: of in depth interview, focus group discussion, and Delphi were used to derive the attributes of primary care from 66 participants, including primary care providers, community representatives, general population, and national experts.The study yielded a total of 7 attributes of primary care categorized into 3 dimensions: medical care services (accessibility, continuity, comprehensiveness, and coordination), individual and family (trust and patient centeredness), and population and community (population and community orientation).These 7 attributes provide a conceptual framework of how primary care in Thailand should be evaluated. RESULTS: of the evaluation will offer insights on which aspects of primary care need to be improved to achieve better health care. PMID- 19443879 TI - A study of the impact of tuberculosis on the quality of life and the effect after treatment with DOTS. AB - A prospective study was conducted on 90 patients of tuberculosis at 2 directly observed treatment short course (DOTS) cum microscopy centers in an urban area of Delhi. The WHOQOL-BREF (Hindi) questionnaire was used to assess the QOL at the onset of treatment, after 3 months of treatment under DOTS, and at completion of treatment. Patients with tuberculosis had significantly lower mean scores than controls for overall QOL. The most affected domains were physical and psychological. Women scored significantly better than men in the physical and environmental domains. Overall QOL scores were lowest for category II and significantly lower for the psychological and social domains. The mean scores after treatment were significantly lower than controls for overall QOL, the social and environmental domains. The DOTS regimen improves the QOL and its domains; however, they remain significantly affected compared to the healthy controls. PMID- 19443880 TI - Prevalence of primary infertility in the Islamic Republic of Iran in 2004-2005. AB - This study aimed to determine the prevalence of lifetime and current primary infertility in Iran. The study was conducted in 2004-5 in all the 28 provinces of Iran. A cluster sampling method was used to select 10 783 women aged 19 to 49 years for the survey. Lifetime primary infertility was defined based on 1 of 2 contraception scenarios immediately after marriage to find experience of infertility despite 1 year of unprotected intercourse. The term "current primary infertility" designated a woman who, in addition to meeting the definition of lifetime infertility, had been unable to conceive up to the study time. A complex sampling design and SVY commands in the software package STATA 8.0 were used to derive 95% confidence intervals. A history of lifetime primary infertility was present in 24.9% of the subjects (95% CI: 23.5-26.2), and the prevalence of current primary infertility was 3.4% (95% CI: 3.0-3.8). As for age trends in lifetime primary infertility, the highest prevalence rates were observed in individuals with the lowest age at marriage. Minimum prevalence (17.2%) occurred with marriage age of 21 to 26 years, and the rates rose with higher age at marriage. About one fourth of the Iranian couples experience primary infertility at some point in their lives and 3.4% suffer from this problem at any time. For a correct interpretation of prevalence rates and the implications in terms of health care and service delivery, factors such as age at marriage and the couple's fertility potential must be taken into consideration. PMID- 19443881 TI - Smoking knowledge, attitudes, and behaviors among rural-to-urban migrant women in Beijing, China. AB - BACKGROUND: China has the largest population of cigarette smokers worldwide; surveys suggest rising prevalence among young women. Migratory lifestyles may confer increased susceptibility. OBJECTIVES: we aimed to understand how migration relates to smoking among young women. METHODS: we implemented a cross-sectional behavioral survey of rural-to-urban Chinese women (n = 206) working in restaurants and commercial sex venues, assessing smoking attitudes, behaviors, and health-risk knowledge. RESULTS: rates of ever smoking and current smoking among restaurant workers were high compared with the rates in general population surveys (16.1% and 6.5%, respectively); rates were much higher among sex workers (54.9% and 33.3%, respectively). Multivariate analysis revealed education to be protective, whereas exposure to female-branded cigarettes was a risk for ever smoking. CONCLUSIONS: Chinese migrant women appear to be smoking at higher rates than nonmigrant women. Priorities for future research include representative studies in multiple cities examining reasons for uptake and stimuli to quit. PMID- 19443882 TI - Exposure to and attitudes regarding secondhand smoke among secondary students in Taiwan. AB - The 2003 School Health Act of Taiwan stipulated that school campuses of senior high and below should be smoke free, but data from the Global Youth Tobacco Survey show that the majority of students are exposed to smoke in public and at home. More than 50% of nonsmokers indicated that they had been exposed to secondhand smoke (SHS) in public places, with the exposure rate as high as 90% among smokers. More than 40% of junior and senior high school students were exposed to SHS at home. Support for banning smoking in public places ranged from almost 60% to almost 80%. More than 60% of current smokers and almost 90% of never smokers think that smoke from others is harmful to them. With a clear body of evidence detailing the harmful effects, reduction and eventual elimination of exposure to SHS should be the goal of the tobacco control community. PMID- 19443883 TI - Effects of oral health care on salivary flow rate in patients with type 2 diabetes: preliminary study. AB - The purpose of this study is to evaluate the effects of the authors' oral health care program on the stimulated whole salivary flow rate and buffer capacity before and after a 6-month intervention. The authors conducted the intervention study among 25 participants with diabetes. The salivary flow rate and buffer capacity were evaluated before and after this intervention. Overall, the results showed a significant increase in salivary flow rate and no significant change in buffer capacity. Also, it was likely that salivary flow rate significantly increased among patients with more than 20 remaining teeth and patients with well controlled diabetes. The findings suggest that this program for type 2 diabetes led to an increase in the stimulated whole salivary flow rate. PMID- 19443884 TI - Role of polysomy 17 in transitional cell carcinoma of the bladder: immunohistochemical study of HER2/neu expression and fish analysis of c-erbB-2 gene and chromosome 17. AB - This study investigates the potential clinical significance of c-erbB-2 gene and chromosome 17 alterations by fluorescence in situ hybridization (FISH) analysis and HER2/neu overexpression by immunohistochemical staining in transitional cell carcinoma (TCC) of urinary bladder correlating the results with tumor stage and grade categories and with clinical behavior. Sixty-three cases of TCC retrieved from the files of 2 institutions were analyzed for chromosome 17 aberrations and c-erbB-2 amplification by FISH analysis and evaluated immunohistochemically for HER2/neu overexpression. Five tumors were G1, 29 intermediate grade (G2), and 29 tumors high grade (G3); 32 tumors had stage Ta, 18 tumors T1, and 13 tumors T2. We found polysomy of chromosome 17 in 58.7% of TCC with average chromosome copy number >2.26; increased number of HER2/neu gene copy was observed in 66.7% of tumors. C-erbB-2 amplification occurred in 6.3% of tumors. Immunohistochemically, 60.3% of TCC overexpressed HER2/neu and 39.7% of tumors were negative. All tumors with polysomy showed simultaneously increase of HER2/neu gene copy number of which 34/37 with protein overexpression. A statistically significant correlation between polysomy of chromosome 17 and tumor stage (P = .0003) and tumor grade (P < .0001) was found; polysomy was not seen in G1 tumors; however, 8/29 G2 tumors and 29/29 G3 tumors revealed polysomy of chromosome 17; in 8/32 Ta tumors, 14/18 T1 and 13/13 of deeply invasive tumors (T2) polysomy 17 was observed. Moreover, it was found that 7 superficial tumors (1 Ta and 6 T1) showed high polysomy with average of chromosome 17 copy number > or =3.76 as observed in all invasive tumors. The data suggest that although HER2/neu amplification, found in high grade and invasive tumors, is a rare event in TCC, polysomy of chromosome 17 is an important factor correlated with tumor stage and grade categories and could be considered a molecular marker of tumor progression with interesting diagnostic implications. PMID- 19443885 TI - A reevaluation of the clinical significance of histological subtyping of non- small-cell lung carcinoma: diagnostic algorithms in the era of personalized treatments. AB - The classification of lung cancer has always been primarily based on the morphologic assessment of routinely stained histological sections, but this approach may be difficult or even unfeasible in cytological preparations or small biopsies. Moreover, the simplistic dichotomization between small-cell carcinoma and non-small cell carcinoma (NSCLC) should be overcome, as new drugs have been discovered that are effective in specific subtypes of lung cancer. A more accurate characterization of NSCLC, however, may be hard in carcinomas lacking clear-cut signs of differentiation. The incorporation into the diagnostic algorithm of poorly differentiated carcinomas of an immunohistochemical panel including markers of squamous (high-molecular-weight cytokeratins, p63) and glandular (TTF-1, cytokeratin 7) cell differentiation seems the most promising approach. The evaluation of lung cancer for gene mutations, gene amplification, tumor-related angiogenesis, expression levels of DNA repair genes and genomic or proteomic profiles represents an exciting challenge for the pathologist in the near future. PMID- 19443886 TI - The histology of pulmonary sarcoidosis: a review with particular emphasis on unusual and underrecognized features. AB - The pathologist is frequently involved in the diagnostic approach to the patient with suspected sarcoidosis. Although the histologic diagnosis is generally not difficult, atypical and underrecognized features may occasionally occur and may result in diagnostic problems. The authors review the histology of pulmonary sarcoidosis, focusing particularly on these unusual problematic findings. PMID- 19443887 TI - Tissue eosinophilia and its association with tumoral invasion of oral cancer. AB - This study investigated if tumor-associated tissue eosinophilia (TATE) could be associated with the process of tissue invasion in oral squamous cell carcinomas (OSCCs) and its influence on patient's prognosis. Forty-three patients treated for OSCCs with or without lymph nodes involvement, at A. C. Camargo Cancer Hospital, Brazil, were selected for TATE analysis. Two degrees of tissue eosinophilia were established in OSCC: absent/mild and intense. The TATE was evaluated in relation to the clinicopathological features and prognostic value using chi( 2) test and the Kaplan-Meier method. Most of the patients with OSCC in advanced clinical stage presented muscular infiltration and significantly intense TATE whereas those with tumors in early stage frequently showed absent/mild eosinophilia (P = .009). The TATE showed no prognostic value for 5-year and 10 year survival rates of the OSCC. These findings suggest that intense TATE seems to reflect the stromal invasion of the OSCCs that occur in advanced clinical stage. PMID- 19443888 TI - Extrapleural solitary fibrous tumor: a clinicopathologic study of 19 cases. AB - This study reports a series of 19 extrapleural solitary fibrous tumors. The patients included 6 men and 13 women with age ranging from 27 to 86 years. Three patients showed local recurrence. In 2 tumors, a diagnosis of malignancy was made. All of the tumors were strongly positive for CD34, and 3 of them expressed high levels of progesterone receptor. Solitary fibrous tumors are fairly rare, occurring in many parts of the body, and their behavior is unpredictable. PMID- 19443889 TI - The correlation of the World Health Organization histologic classification of thymic epithelial tumors and its prognosis: a clinicopathologic study of 108 patients from China. AB - This study retrospectively reviewed the clinicopathological features of thymic epithelial tumors in 108 patients, and evaluated World Health Organization (WHO) histologic classification of thymic tumors. Other prognostic factors, including age, gender, clinical stage, and completeness of tumor resection were also analyzed. Seven type A tumors, 19 type AB, 23 type B1, 19 type B2, 27 type B3, and 13 thymic carcinomas were studied. The 5-year and 10-year survival rates were 100% after resection of tumor types A and AB; 93% and 81% for B1; 83% and 70% for B2; and 43% and 33% for B3. The overall 5-year and 10-year survival rates were 72.0% and 63.0%, respectively. Tumor classification was highly significant in predicting survival (P .001) and also reflected the clinical behavior of tumors. The Masaoka stage was the most important independent prognostic index in thymomas. The WHO histologic subtype and completeness of resection were also important prognostic factors. PMID- 19443890 TI - Images in pathology. "Giant" solid cell rest of the thyroid: a hyperplastic change? PMID- 19443891 TI - Living in a world of change. PMID- 19443892 TI - Double trouble: infection and ischemia in the diabetic foot. PMID- 19443893 TI - The impact of interventional management on healing of ischemic foot lesions. PMID- 19443894 TI - Woundcare R&D in the credit crunch. PMID- 19443895 TI - Risk factors for ipsilateral reamputation in patients with diabetic foot lesions. AB - This study aimed to examine the rates and risk factors for ipsilateral re amputation in 121 patients with diabetic foot and prior amputation. Twenty-six (21.5%) patients required re-amputation during a mean follow-up of 18 months. Most re-amputations were performed within the first 6 months of the initial amputation. Re-amputation was more common among patients in whom the initial amputation had only affected one or two toes. Age (hazard ratio: 1.06) and heel lesions (hazard ratio: 2.69) were significantly associated with re-amputation. There is a high risk of re-amputation in the diabetic foot, especially within the first 6 months of the initial amputation, mainly due to poor selection of the original amputation level in an effort to save a greater part of the lower extremity. Patients 70 years and those with heel lesions are at greatest risk of re-amputation. PMID- 19443896 TI - Peripheral arterial disease and diabetes: a clinical update. AB - Peripheral arterial disease is characterized by a gradual reduction in blood to the extremities secondary to atherosclerosis. In diabetes, the pattern of atherosclerotic occlusion typically shows a propensity toward the infrapopliteal vessels. Additionally, impairment of the microcirculation manifests in diminished vasoreactivity and a functional ischemia that is not always correctable with surgery. However, when a nonhealing wound is complicated by peripheral arterial disease, revascularization is paramount to wound healing. Revascularization can be accomplished through traditional bypass surgery or newer endovascular interventions, such as angioplasty and stenting. These less invasive techniques of revascularization offer the advantages of quicker recovery and lower morbidity but durability may be compromised. Ultimately, the choice of revascularization procedure should be based on the clinical characteristics of the atherosclerotic lesion along with the individual patient history. PMID- 19443897 TI - Emerging evidence for neuroischemic diabetic foot ulcers: model of care and how to adapt practice. AB - Although neuropathic ulceration remains the commonest type of foot ulcers among patients with diabetes, recent data suggest that ischemic (and therefore, neuroischemic) ulcers are on the rise. The high prevalence and incidence of diabetes and its attendant foot complications, coupled with the current trend where increasingly diabetes care is being provided by general practitioners (primary care physicians) would mean that primary care practices are expected to see greater numbers of diabetic foot ulcer patients. Unfortunately, these settings are frequently ill-equipped to appropriately manage diabetic foot ulcers either due to lack of adequately trained personnel and access to multidisciplinary foot care teams. Whereas neuropathic foot ulceration may appear to be less challenging, neuroischemic or ischemic ulcers portend a higher risk of adverse outcomes, including non-healing, infection, amputation, and death. The last 2 decades have witnessed a paradigm shift from neuropathy as the main etiological factor in diabetic foot disease to an ever-increasing preponderance of ischemic and/or neuroischemic ulceration. Available literature does not always consider the limited access primary care practices have to specialized multidisciplinary foot care teams. Additionally, in the case of neuroischemic and/or ischemic ulcers, existing guidelines on their diagnosis and management are varied and unclear. This review aimed at providing a simple understanding to the complex evidence base for diagnosing and treating neuroischemic and/or ischemic ulcers in a primary care setting. It emphasizes the need for urgent vascular review in all patients with ischemic/ neuroischemic ulcers and advocates effective participation of vascular specialists in diabetic foot clinics and combined ward rounds. PMID- 19443898 TI - Altered molecular mechanisms of diabetic foot ulcers. AB - The continuously increasing worldwide prevalence of diabetes will be accompanied by a greater incidence of diabetic foot ulcer, a complication in which many of the morphological processes involved in normal wound healing are disrupted. The highly complex and integrated process of wound healing is regulated by a large array of molecular factors. These often have overlapping functions, ensuring a certain degree of tolerance through redundancy. In diabetes, changes to the expression of a large number of molecular factors have been observed, overwhelming this inbuilt redundancy. This results in delayed healing or incomplete healing as in ulceration. Understanding the relationship between altered levels of molecular factors and the inhibited healing process in such ulcers will permit the development of targeted treatments aimed to greatly improve the quality of life of patients, at the same time helping to reduce the huge costs associated with treating this diabetic condition and its long-term consequences. This short review examines how changes in the expression of molecular factors are related to altered morphology in diabetic foot ulceration and very briefly considers treatment strategies at molecular level. PMID- 19443900 TI - A case series describing 118 patients with lower limb necrotizing fasciitis. AB - Necrotizing fasciitis of the lower limb is not uncommon, with poor outcome. This study reviewed 118 cases (78 males and 40 females) with mean age of 45 + 16.5 years (range 12-95 years) of lower limb necrotizing fasciitis admitted to the Department of Surgery, BHU in India between 1995 and 2007. Most patients (n = 97) presented with fever. Other presenting symptoms included painful swelling, bullae, erythema, ulcer, and necrosis. Comorbid conditions such as diabetes, tuberculosis, malignancy, and immunosuppressive therapy were associated in 72 (61%) cases. Amputations were done in 24 patients. Thirty one patients developed septic shock. Renal dialysis was done in 16 patients and ventilatory support was needed in 12 patients. The most common organism identified was beta-hemolytic streptococci (n = 42). Eighteen patients died, a mortality of 15%. The authors consider early diagnosis and aggressive surgical intervention to be crucial for the successful treatment of disease. PMID- 19443899 TI - Evidence-based recommendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. AB - Topical oxygen therapy provides another tool in the armamentarium of clinicians treating refractory lower extremity wounds. Devices suitable for providing topical oxygen therapy in a clinical setting have recently become available. This article reviews the evidence to justify the use of this treatment modality, including in vitro, preclinical data, and clinical data. It also provides a protocol for how to administer topical oxygen therapy as well as guidance on patient selection and management to optimize outcomes. Randomized controlled trials are not yet reported and clearly necessary. The current body of evidence suggests that topical oxygen therapy may be considered as a second line of therapy for refractory wounds. PMID- 19443901 TI - A case report of the eradication of pseudomonas aeruginosa from leg ulcer in a patient with essential thrombocythemia. AB - A patient treated with hydroxyurea had a lower extremity ulcer that was found infected with Pseudomonas aeruginosa. Drug discontinuation and ceftazidime treatment did not initially lead to resolution due to misidentification of inducible betalactamases expressed by the organism and subsequent clinical failure of the cephalosporin in eradicating infection. These class C enzymes may be strongly induced after betalactam exposure and confer resistance to penicillins, cephalosporins, betalactamase inhibitors but not to carbapenems. Though hydroxyurea represents a major cause of essential thrombocythemia-related ulcers, lesion infections by difficult-to-treat organisms should be eradicated to promote wound healing. PMID- 19443902 TI - Kaposi's sarcoma misdiagnosed as a diabetic plantar foot ulcer. AB - In this report, the authors describe the case of a patient with Kaposi's sarcoma that was initially misdiagnosed as a plantar ulcer. The ulcer typically appeared as a neuropathic foot ulceration located on the plantar aspect of the first metatarsal head. There was hyperkeratosis on the plantar surfaces of the other metatarsal heads. However, the lesion had mushrooming granulation tissue, without undermined perilesional edges. A wound biopsy revealed the presence of Kaposi's sarcoma. The presence of cancerous lesions on the plantar aspect of the foot is an infrequent event in diabetic patients. However, given the malignant nature of some skin cancers careful clinical examination and biopsy of the wound are advisable. PMID- 19443904 TI - Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma. AB - The human hMYH and NEIL1 genes encode DNA glycosylases involved in repair of oxidative base damage and mutations in these genes are associated with certain cancers. Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease characterized by inflammatory destruction of the biliary tree, is often complicated by the development of cholangiocarcinoma (CCA). Here, we aimed to investigate the influence of genetic variations in the hMYH and NEIL1 genes on risk of CCA in PSC patients. The hMYH and NEIL1 gene loci in addition to the DNA repair genes hOGG1, NTHL1 and NUDT1 were analyzed in 66 PSC patients (37 with CCA and 29 without cancer) by complete genomic sequencing of exons and adjacent intronic regions. Several single-nucleotide polymorphisms and mutations were identified and severe impairment of protein function was observed for three non synonymous variants. The NEIL1 G83D mutant was dysfunctional for the major oxidation products 7,8-dihydro-8-oxoguanine (8oxoG), thymine glycol and dihydrothymine in duplex DNA, and the ability to perform delta-elimination at abasic sites was significantly reduced. The hMYH R260Q mutant had severe defect in adenine DNA glycosylase activity, whereas hMYH H434D could excise adenines from A:8oxoG pairs but not from A:G mispairs. We found no overall associations between the 18 identified variants and susceptibility to CCA in PSC patients; however, the impaired variants may be of significance for carcinogenesis in general. Our findings demonstrate the importance of complete resequencing of selected candidate genes in order to identify rare genetic variants and their possible contribution to individual susceptibility to cancer development. PMID- 19443905 TI - Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase. AB - Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin. PRL prevented cisplatin-induced G(2)/M cell cycle arrest and apoptosis. In the presence of PRL, significantly less cisplatin was bound to DNA, as determined by mass spectroscopy, and little DNA damage was seen by gamma-H2AX staining. PRL dramatically increased the activity of glutathione-S-transferase (GST), which sequesters cisplatin in the cytoplasm; this increase was abrogated by Jak and mitogen-activated protein kinase inhibitors. PRL upregulated the expression of the GSTmu, but not the pi, isozyme. A GST inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL. In conclusion, PRL confers resistance against cisplatin by activating a detoxification enzyme, thereby reducing drug entry into the nucleus. These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer, which is characterized by high expression of both PRL and its receptor. Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options. PMID- 19443906 TI - Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress. AB - Endometrial cancer, the most common gynecological malignancy in western countries, is characterized by a favorable prognosis. Nonetheless, deep myometrial invasion correlates with more undifferentiated tumors, lymph-vascular invasion, node involvement and decreased global survival. We have described previously the Ets family member ERM/ETV5 specifically upregulated in endometrial endometrioid carcinoma (EEC) associated with myometrial infiltration. To understand the role of this transcription factor during myometrial infiltration, we analyzed by two-dimension differential gel electrophoresis (2D-DIGE) technology those proteins whose expression was altered in endometrial cell lines stably overexpressing ERM/ETV5. Pathway analysis pointed to actin regulation and transforming growth factor beta and progesterone signaling as processes regulated by ERM/ETV5. In addition, we characterized the specific upregulation of the nuclear dehydrogenase/reductase Hep27 as well as its ERM/ETV5-dependent mitochondrial localization. Further functional studies demonstrated a protective role of Hep 27 against apoptosis induced by oxidative stress. Overall, the ETV5 related proteomic approach performed in the Hec-1A cell line reinforces a role of this transcription factor in the regulation of the migratory and invasive tumor behavior and points to a modulated response to oxidative stress associated with the promotion of invasion in endometrial cancer. Unraveling the molecular events in EEC associated with the initiation of tumor invasion would represent an obvious improvement in the pursuit of rational targets for the onset of metastasis. This knowledge would also be a valuable tool for the molecular stratification of patients since myometrial affectation determines an increase in the rate of recurrence after a first surgical treatment and a decrease in 5 year survival. PMID- 19443907 TI - Longer (TA)n repeat but not A49T and V89L polymorphisms in SRD5A2 gene may confer prostate cancer risk in South Indian men. AB - Testosterone is converted to 5 alpha-dihydrotestosterone (DHT) by 5 alpha reductase enzyme, which is encoded by the SRD5A2 gene. DHT is the main androgen responsible for prostate growth. We have analyzed the complete coding region of the SRD5A2 gene in 87 histologically confirmed prostate cancer (PC) patients, 40 benign prostatic hyperplasia (BPH) cases, and 96 control samples from southern parts of India. The study revealed the A49T site to be monomorphic, the V89L site to be highly polymorphic, and the (TA)(n) repeat site to be polymorphic with only 2 alleles in our populations. The distribution of V89L alleles between PC cases and controls was not significantly different; however, (TA)(9) alleles distributed differently between the 2 groups. BPH cases exhibited alleles similar to controls at all polymorphic sites. The sequencing of the whole coding region did not reveal any other known or novel polymorphism in this gene. Our study emphasizes that the (TA)(9) allele might confer certain PC risk but that A49T and V89L polymorphisms do not confer PC risk in South Indian men. PMID- 19443908 TI - Total sperm per ejaculate of men: obtaining a meaningful value or a mean value with appropriate precision. AB - We retrospectively mined and modeled data to answer 3 questions. 1) Relative to an estimate based on approximately 20 semen samples, how imprecise is an estimate of an individual's total sperm per ejaculate (TSperm) based on 1 sample? 2) What is the impact of abstinence interval on TSperm and TSperm/h? 3) How many samples are needed to provide a meaningful estimate of an individual's mean TSperm or TSperm/h? Data were for 18-20 consecutive masturbation samples from each of 48 semen donors. Modeling exploited the gamma distribution of values for TSperm and a unique approach to project to future samples. Answers: 1) Within-individual coefficients of variation were similar for TSperm or TSperm/h abstinence and ranged from 17% to 51%; average approximately 34%. TSperm or TSperm/h in any individual sample from a given donor was between -20% and +20% of the mean value in 48% of 18-20 samples per individual. 2) For a majority of individuals, TSperm increased in a nearly linear manner through approximately 72 hours of abstinence. TSperm and TSperm/h after 18-36 hours' abstinence are high. To obtain meaningful values for diagnostic purposes and maximize distinction of individuals with relatively low or high sperm production, the requested abstinence should be 42-54 hours with an upper limit of 64 hours. For individuals producing few sperm, 7 days or more of abstinence might be appropriate to obtain sperm for insemination. 3) At least 3 samples from a hypothetical future subject are recommended for most applications. Assuming 60 hours' abstinence, 80% confidence limits for TSperm/h for 1, 3, or 6 samples would be 70%-163%, 80%-130%, or 85%-120% of the mean for observed values. In only approximately 50% of cases would TSperm/h for a single sample be within -16% and +30% of the true mean value for that subject. CONCLUSIONS: Pooling values for TSperm in samples obtained after 18-36 or 72-168 hours' abstinence with values for TSperm obtained after 42-64 hours is inappropriate. Reliance on TSperm for a single sample per subject is unwise. PMID- 19443909 TI - Considerations in evaluating human spermatogenesis on the basis of total sperm per ejaculate. AB - Total number of sperm per ejaculate (TSperm) is an important measure for clinicians to provide advice to patient couples. However, TSperm per hour of abstinence (TSperm/h) is a better measure for epidemiologist-andrologist teams or clinicians to evaluate spermatogenesis because it is a rate function. This review looks at the interplay and impacts of rate of sperm accumulation in the excurrent duct system, abstinence interval, sexual arousal, and masturbation vs intercourse on observed TSperm. It also examines why and when TSperm/h might provide a meaningful quantitative evaluation of spermatogenesis (ie, rate of sperm production). There is no doubt that TSperm increases with longer abstinence, and in different men plateaus after 2-9 days. Clinicians wishing to maximize number of fully functional sperm available during intercourse, or for artificial insemination, might wish to recommend 6-7 days of abstinence. Diagnostically, the important feature is TSperm/h. After abstinence interval exceeds 64-72 hours, TSperm/h has started to decline in most nonoligozoospermic men as rate of sperm accumulation in the excurrent ducts approaches zero; apparently increasingly more sperm are voided in urine. Clinicians or epidemiologist-andrologist teams wishing to have optimal distinction among individuals with high, typical, or low sperm production (ie, normal or abnormal spermatogenesis) should accurately measure TSperm/h for samples provided after 42-54 hours' abstinence (never 64 hours). Longer abstinence intervals reward men with poor sperm production, because sperm accumulate in the excurrent ducts for 7 days or more of abstinence, and penalize men with good sperm production, because after 3 days or less of abstinence their excurrent ducts probably are full. PMID- 19443910 TI - Evaluating spermatogenesis using semen: the biology of emission tells why reporting total sperm per sample is important, and why reporting only number of sperm per milliliter is irrational. PMID- 19443911 TI - Angiotensin-converting enzyme and adducin-1 polymorphisms in women with preeclampsia and gestational hypertension. AB - The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the Adducin-1 (ADD1) G460W nonsense single nucleotide polymorphism (SNP) have previously been associated to hypertension, whereas their association with preeclampsia (PE) and gestational hypertension (GH) is still controversial. We genotyped ACE I/D, ADD1 G460W, and ADD1 S586C polymorphisms in 672 unrelated pregnant women: 204 PE (81/204 mild PE), 56 GH, and 412 controls, evaluating both their single and combined effects on these pathologies. The genotype combination of the 3 polymorphisms was not statistically different in cases versus controls, nor were ACE and ADD1 polymorphisms in GH. Nevertheless, the distribution of ACE genotypes was different in PE. This was confirmed in mild PE, whereas no significance was found in severe PE. This could suggest that different factors may lead to mild and severe PE, with ACE polymorphism playing a more important role in the mild form. PMID- 19443912 TI - In vitro assessment of mouse uterine and fetoplacental vascular function. AB - Adequate blood flow provision through alterations in maternal vascular function is essential during pregnancy for optimal fetal development. Abnormal uterine vasculature adaptation, resulting in aberrant blood flow to the placenta, has been implicated as a possible cause of fetal growth restriction (FGR). Our study aimed to develop strategies to evaluate murine vascular function in pregnancy using wire myography. Main uterine artery loop and branch vessels isolated from near-term pregnant mice showed significant contraction to phenylephrine (PE). Endothelial-dependent relaxation was noted with acetylcholine (ACH). U46619 elicited significant contraction of umbilical arteries and veins, but relaxation was only demonstrable with the nitric oxide (NO) donor sodium nitroprusside (SNP). In conclusion, our data suggest that murine uteroplacental and fetoplacental arteries show distinct responses to vasoactive agents. Furthermore, this study indicates that wire myography represents a robust technique for the assessment of murine uteroplacental and fetoplacental vascular function, which will aid evaluation of mouse genetic models of FGR. PMID- 19443913 TI - Surgical training using simulation. PMID- 19443915 TI - Classification based on hybridization of parametric and nonparametric classifiers. AB - Parametric methods of classification assume specific parametric models for competing population densities (e.g., Gaussian population densities can lead to linear and quadratic discriminant analysis) and they work well when these model assumptions are valid. Violation in one or more of these parametric model assumptions often leads to a poor classifier. On the other hand, nonparametric classifiers (e.g., nearest-neighbor and kernel-based classifiers) are more flexible and free from parametric model assumptions. But, the statistical instability of these classifiers may lead to poor performance when we have small numbers of training sample observations. Nonparametric methods, however, do not use any parametric structure of population densities. Therefore, even when one has some additional information about population densities, that important information is not used to modify the nonparametric classification rule. This paper makes an attempt to overcome these limitations of parametric and nonparametric approaches and combines their strengths to develop some hybrid classification methods. We use some simulated examples and benchmark data sets to examine the performance of these hybrid discriminant analysis tools. Asymptotic results on their misclassification rates have been derived under appropriate regularity conditions. PMID- 19443914 TI - Effect of virtual reality training on laparoscopic surgery: randomised controlled trial. AB - OBJECTIVE: To assess the effect of virtual reality training on an actual laparoscopic operation. DESIGN: Prospective randomised controlled and blinded trial. SETTING: Seven gynaecological departments in the Zeeland region of Denmark. PARTICIPANTS: 24 first and second year registrars specialising in gynaecology and obstetrics. INTERVENTIONS: Proficiency based virtual reality simulator training in laparoscopic salpingectomy and standard clinical education (controls). MAIN OUTCOME MEASURE: The main outcome measure was technical performance assessed by two independent observers blinded to trainee and training status using a previously validated general and task specific rating scale. The secondary outcome measure was operation time in minutes. RESULTS: The simulator trained group (n=11) reached a median total score of 33 points (interquartile range 32-36 points), equivalent to the experience gained after 20-50 laparoscopic procedures, whereas the control group (n=10) reached a median total score of 23 (22-27) points, equivalent to the experience gained from fewer than five procedures (P<0.001). The median total operation time in the simulator trained group was 12 minutes (interquartile range 10-14 minutes) and in the control group was 24 (20-29) minutes (P<0.001). The observers' inter-rater agreement was 0.79. CONCLUSION: Skills in laparoscopic surgery can be increased in a clinically relevant manner using proficiency based virtual reality simulator training. The performance level of novices was increased to that of intermediately experienced laparoscopists and operation time was halved. Simulator training should be considered before trainees carry out laparoscopic procedures. TRIAL REGISTRATION: ClinicalTrials.gov NCT00311792. PMID- 19443916 TI - Combining slanted-frame classifiers for improved HMM-based Arabic handwriting recognition. AB - The problem addressed in this study is the offline recognition of handwritten Arabic city names. The names are assumed to belong to a fixed lexicon of about 1,000 entries. A state-of-the-art classical right-left hidden Markov model (HMM) based recognizer (reference system) using the sliding window approach is developed. The feature set includes both baseline-independent and baseline dependent features. The analysis of the errors made by the recognizer shows that the inclination, overlap, and shifted positions of diacritical marks are major sources of errors. In this paper, we propose coping with these problems. Our approach relies on the combination of three homogeneous HMM-based classifiers. All classifiers have the same topology as the reference system and differ only in the orientation of the sliding window. We compare three combination schemes of these classifiers at the decision level. Our reported results on the benchmark IFN/ENIT database of Arabic Tunisian city names give a recognition rate higher than 90 percent accuracy and demonstrate the superiority of the neural network based combination. Our results also show that the combination of classifiers performs better than a single classifier dealing with slant-corrected images and that the approach is robust for a wide range of orientation angles. PMID- 19443917 TI - A constant-time algorithm for finding neighbors in quadtrees. AB - Quadtrees and linear quadtrees are well-known hierarchical data structures to represent square images of size 2(r) x 2(r). Finding the neighbors of a specific leaf node is a fundamental operation for many algorithms that manipulate quadtree data structures. In quadtrees, finding neighbors takes O(r) computational time for the worst case, where r is the resolution (or height) of a given quadtree. Schrack [1] proposed a constant-time algorithm for finding equal-sized neighbors in linear quadtrees. His algorithm calculates the location codes of equal-sized neighbors; it says nothing, however, about their existence. To ensure their existence, additional checking of the location codes is needed, which usually takes O(r) computational time. In this paper, a new algorithm to find the neighbors of a given leaf node in a quadtree is proposed which requires just O(1) (i.e., constant) computational time for the worst case. Moreover, the algorithm takes no notice of the existence or nonexistence of neighbors. Thus, no additional checking is needed. The new algorithm will greatly reduce the computational complexities of almost all algorithms based on quadtrees. PMID- 19443918 TI - Preprocessing of low-quality handwritten documents using Markov random fields. AB - This paper presents a statistical approach to the preprocessing of degraded handwritten forms including the steps of binarization and form line removal. The degraded image is modeled by a Markov Random Field (MRF) where the hidden-layer prior probability is learned from a training set of high-quality binarized images and the observation probability density is learned on-the-fly from the gray-level histogram of the input image. We have modified the MRF model to drop the preprinted ruling lines from the image. We use the patch-based topology of the MRF and Belief Propagation (BP) for efficiency in processing. To further improve the processing speed, we prune unlikely solutions from the search space while solving the MRF. Experimental results show higher accuracy on two data sets of degraded handwritten images than previously used methods. PMID- 19443919 TI - Context-aware visual tracking. AB - Enormous uncertainties in unconstrained environments lead to a fundamental dilemma that many tracking algorithms have to face in practice: Tracking has to be computationally efficient, but verifying whether or not the tracker is following the true target tends to be demanding, especially when the background is cluttered and/or when occlusion occurs. Due to the lack of a good solution to this problem, many existing methods tend to be either effective but computationally intensive by using sophisticated image observation models or efficient but vulnerable to false alarms. This greatly challenges long-duration robust tracking. This paper presents a novel solution to this dilemma by considering the context of the tracking scene. Specifically, we integrate into the tracking process a set of auxiliary objects that are automatically discovered in the video on the fly by data mining. Auxiliary objects have three properties, at least in a short time interval: 1) persistent co-occurrence with the target, 2) consistent motion correlation to the target, and 3) easy to track. Regarding these auxiliary objects as the context of the target, the collaborative tracking of these auxiliary objects leads to efficient computation as well as strong verification. Our extensive experiments have exhibited exciting performance in very challenging real-world testing cases. PMID- 19443920 TI - A fast 2D shape recovery approach by fusing features and appearance. AB - In this paper, we present a fusion approach to solve the nonrigid shape recovery problem, which takes advantage of both the appearance information and the local features. We have two major contributions. First, we propose a novel progressive finite Newton optimization scheme for the feature-based nonrigid surface detection problem, which is reduced to only solving a set of linear equations. The key is to formulate the nonrigid surface detection as an unconstrained quadratic optimization problem that has a closed-form solution for a given set of observations. Second, we propose a deformable Lucas-Kanade algorithm that triangulates the template image into small patches and constrains the deformation through the second-order derivatives of the mesh vertices. We formulate it into a sparse regularized least squares problem, which is able to reduce the computational cost and the memory requirement. The inverse compositional algorithm is applied to efficiently solve the optimization problem. We have conducted extensive experiments for performance evaluation on various environments, whose promising results show that the proposed algorithm is both efficient and effective. PMID- 19443921 TI - Minimum distance between pattern transformation manifolds: algorithm and applications. AB - Transformation invariance is an important property in pattern recognition, where different observations of the same object typically receive the same label. This paper focuses on a transformation-invariant distance measure that represents the minimum distance between the transformation manifolds spanned by patterns of interest. Since these manifolds are typically nonlinear, the computation of the manifold distance (MD) becomes a nonconvex optimization problem. We propose representing a pattern of interest as a linear combination of a few geometric functions extracted from a structured and redundant basis. Transforming the pattern results in the transformation of its constituent parts. We show that, when the transformation is restricted to a synthesis of translations, rotations, and isotropic scalings, such a pattern representation results in a closed-form expression of the manifold equation with respect to the transformation parameters. The MD computation can then be formulated as a minimization problem whose objective function is expressed as the difference of convex functions (DC). This interesting property permits optimally solving the optimization problem with DC programming solvers that are globally convergent. We present experimental evidence which shows that our method is able to find the globally optimal solution, outperforming existing methods that yield suboptimal solutions. PMID- 19443922 TI - A novel algorithm for detecting singular points from fingerprint images. AB - Fingerprint analysis is typically based on the location and pattern of detected singular points in the images. These singular points (cores and deltas) not only represent the characteristics of local ridge patterns but also determine the topological structure (i.e., fingerprint type) and largely influence the orientation field. In this paper, we propose a novel algorithm for singular points detection. After an initial detection using the conventional Poincare Index method, a so-called DORIC feature is used to remove spurious singular points. Then, the optimal combination of singular points is selected to minimize the difference between the original orientation field and the model-based orientation field reconstructed using the singular points. A core-delta relation is used as a global constraint for the final selection of singular points. Experimental results show that our algorithm is accurate and robust, giving better results than competing approaches. The proposed detection algorithm can also be used for more general 2D oriented patterns, such as fluid flow motion, and so forth. PMID- 19443923 TI - An O(N(2)) square root unscented Kalman Filter for visual simultaneous localization and mapping. AB - This paper develops a Square Root Unscented Kalman Filter (SRUKF) for performing video-rate visual simultaneous localization and mapping (SLAM) using a single camera. The conventional UKF has been proposed previously for SLAM, improving the handling of nonlinearities compared with the more widely used Extended Kalman Filter (EKF). However, no account was taken of the comparative complexity of the algorithms: In SLAM, the UKF scales as O(N;{3}) in the state length, compared to the EKF's O(N;{2}), making it unsuitable for video-rate applications with other than unrealistically few scene points. Here, it is shown that the SRUKF provides the same results as the UKF to within machine accuracy and that it can be reposed with complexity O(N;{2}) for state estimation in visual SLAM. This paper presents results from video-rate experiments on live imagery. Trials using synthesized data show that the consistency of the SRUKF is routinely better than that of the EKF, but that its overall cost settles at an order of magnitude greater than the EKF for large scenes. PMID- 19443924 TI - Sign language spotting with a threshold model based on conditional random fields. AB - Sign language spotting is the task of detecting and recognizing signs in a signed utterance, in a set vocabulary. The difficulty of sign language spotting is that instances of signs vary in both motion and appearance. Moreover, signs appear within a continuous gesture stream, interspersed with transitional movements between signs in a vocabulary and nonsign patterns (which include out-of vocabulary signs, epentheses, and other movements that do not correspond to signs). In this paper, a novel method for designing threshold models in a conditional random field (CRF) model is proposed which performs an adaptive threshold for distinguishing between signs in a vocabulary and nonsign patterns. A short-sign detector, a hand appearance-based sign verification method, and a subsign reasoning method are included to further improve sign language spotting accuracy. Experiments demonstrate that our system can spot signs from continuous data with an 87.0 percent spotting rate and can recognize signs from isolated data with a 93.5 percent recognition rate versus 73.5 percent and 85.4 percent, respectively, for CRFs without a threshold model, short-sign detection, subsign reasoning, and hand appearance-based sign verification. Our system can also achieve a 15.0 percent sign error rate (SER) from continuous data and a 6.4 percent SER from isolated data versus 76.2 percent and 14.5 percent, respectively, for conventional CRFs. PMID- 19443925 TI - A stochastic filtering technique for fluid flow velocity fields tracking. AB - In this paper, we present a method for the temporal tracking of fluid flow velocity fields. The technique we propose is formalized within a sequential Bayesian filtering framework. The filtering model combines an Ito diffusion process coming from a stochastic formulation of the vorticity-velocity form of the Navier-Stokes equation and discrete measurements extracted from the image sequence. In order to handle a state space of reasonable dimension, the motion field is represented as a combination of adapted basis functions, derived from a discretization of the vorticity map of the fluid flow velocity field. The resulting nonlinear filtering problem is solved with the particle filter algorithm in continuous time. An adaptive dimensional reduction method is applied to the filtering technique, relying on dynamical systems theory. The efficiency of the tracking method is demonstrated on synthetic and real-world sequences. PMID- 19443926 TI - Supervised learning of quantizer codebooks by information loss minimization. AB - This paper proposes a technique for jointly quantizing continuous features and the posterior distributions of their class labels based on minimizing empirical information loss such that the quantizer index of a given feature vector approximates a sufficient statistic for its class label. Informally, the quantized representation retains as much information as possible for classifying the feature vector correctly. We derive an alternating minimization procedure for simultaneously learning codebooks in the euclidean feature space and in the simplex of posterior class distributions. The resulting quantizer can be used to encode unlabeled points outside the training set and to predict their posterior class distributions, and has an elegant interpretation in terms of lossless source coding. The proposed method is validated on synthetic and real data sets and is applied to two diverse problems: learning discriminative visual vocabularies for bag-of-features image classification and image segmentation. PMID- 19443927 TI - 3D shape recovery of smooth surfaces: dropping the fixed-viewpoint assumption. AB - We present a new method for recovering the 3D shape of a featureless smooth surface from three or more calibrated images illuminated by different light sources (three of them are independent). This method is unique in its ability to handle images taken from unconstrained perspective viewpoints and unconstrained illumination directions. The correspondence between such images is hard to compute and no other known method can handle this problem locally from a small number of images. Our method combines geometric and photometric information in order to recover dense correspondence between the images and accurately computes the 3D shape. Only a single pass starting at one point and local computation are used. This is in contrast to methods that use the occluding contours recovered from many images to initialize and constrain an optimization process. The output of our method can be used to initialize such processes. In the special case of fixed viewpoint, the proposed method becomes a new perspective photometric stereo algorithm. Nevertheless, the introduction of the multiview setup, self occlusions, and regions close to the occluding boundaries are better handled, and the method is more robust to noise than photometric stereo. Experimental results are presented for simulated and real images. PMID- 19443928 TI - A new distance measure for model-based sequence clustering. AB - We review the existing alternatives for defining model-based distances for clustering sequences and propose a new one based on the Kullback-Leibler divergence. This distance is shown to be especially useful in combination with spectral clustering. For improved performance in real-world scenarios, a model selection scheme is also proposed. PMID- 19443929 TI - Generalized risk zone: selecting observations for classification. AB - In this paper, we extend the risk zone concept by creating the Generalized Risk Zone. The Generalized Risk Zone is a model-independent scheme to select key observations in a sample set. The observations belonging to the Generalized Risk Zone have shown comparable, in some experiments even better, classification performance when compared to the use of the whole sample. The main tool that allows this extension is the Cauchy-Schwartz divergence, used as a measure of dissimilarity between probability densities. To overcome the setback concerning pdf's estimation, we used the ideas provided by the Information Theoretic Learning, allowing the calculation to be performed on the available observations only. We used the proposed methodology with Learning Vector Quantization, feedforward Neural Networks, Support Vector Machines, and Nearest Neighbors. PMID- 19443930 TI - A novel feature selection methodology for automated inspection systems. AB - This paper proposes a new feature selection methodology. The methodology is based on the stepwise variable selection procedure, but, instead of using the traditional discriminant metrics such as Wilks' Lambda, it uses an estimation of the misclassification error as the figure of merit to evaluate the introduction of new features. The expected misclassification error rate (MER) is obtained by using the densities of a constructed function of random variables, which is the stochastic representation of the conditional distribution of the quadratic discriminant function estimate. The application of the proposed methodology results in significant savings of computational time in the estimation of classification error over the traditional simulation and cross-validation methods. One of the main advantages of the proposed method is that it provides a direct estimation of the expected misclassification error at the time of feature selection, which provides an immediate assessment of the benefits of introducing an additional feature into an inspection/classification algorithm. PMID- 19443931 TI - Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. AB - This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy. PMID- 19443932 TI - Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity. AB - Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. Rimonabant is also being tested as a potential anti smoking treatment since endocannabinoids are related to the pleasurable effect of nicotine. Thus, rimonabant constitutes a new therapeutic approach to obesity and cardiovascular risk factors. Studies show effectiveness in weight loss; however, side effects such as psychiatric alterations have been reported, including depression and anxiety. These side effects have led the FDA (Food and Drug Administration) to not approve this drug in the United States. For a more complete evaluation on the safety of this drug, additional studies are in progress. PMID- 19443933 TI - Pharmacology of dimethyl sulfoxide in cardiac and CNS damage. AB - The pharmacological effects of dimethyl sulfoxide (DMSO) administration include some desirable properties that may be useful in the treatment of medical disorders resulting in tissue injury and compromised organ systems. These properties include the reported effects of DMSO on impaired blood flow, suppression of cytotoxicity from excess glutamate release that may result in lethal NMDA-AMPA activation, restriction of cytotoxic Na(+) and Ca(2+) entry into damaged cells, blocking tissue factor (TF) from contributing to thrombosis, reduction of intracranial pressure, tissue edema, and inflammatory reactions, and inhibition of vascular smooth muscle cell migration and proliferation that can lead to atherosclerosis of the coronary, peripheral, and cerebral circulation. A review of the basic and clinical literature on the biological actions of DMSO in cardiac and central nervous system (CNS) damage or dysfunction indicates that this agent, alone or in combination with other synergistic molecules, has been reported to neutralize or attenuate pathological complications that harmed or can further harm these two organ systems. The effects of DMSO make it potentially useful in the treatment of medical disorders involving head and spinal cord injury, stroke, memory dysfunction, and ischemic heart disease. PMID- 19443934 TI - Influence of bupropion and calcium channel antagonists on the nicotine-induced memory-related response of mice in the elevated plus maze. AB - In this study, we investigated the effects of acute administration of nicotine on memory-related behavior in mice using the elevated plus maze test. In this test, the time necessary for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. Our results revealed that nicotine (0.035 and 0.175 mg/kg, base, sc) shortened the transfer latency relative to the saline-treated group. Moreover, we investigated the effects of bupropion (10, 20 and 40 mg/kg, ip) and L-type voltage-dependent calcium channel antagonists (nimodipine, flunarizine, verapamil, diltiazem - 5, 10 and 20 mg/kg, ip) on memory-related behavior. At all tested doses, bupropion, did not significantly affect transfer latency. However, flunarizine and verapamil (both at 10 mg/kg) resulted in a slight decrease in transfer latency, whereas nimodipine (10 mg/kg) increased transfer latency. Interestingly, both bupropion (20 mg/kg) and calcium channel blockers (5 mg/kg) attenuated the improvement of memory induced by nicotine. Our findings indicate that the cholinergic nicotinic system may play an important role in memory consolidation, and that neural calcium-dependent mechanisms can be involved in the modulation of memory-related responses induced by nicotine. The results of these studies have revealed neuronal mechanisms that are important for nicotinic modulation of cognition and will be useful for the treatments of human disorders in which cholinergic pathways have been implicated, such as psychiatric disorders and addiction. PMID- 19443935 TI - Characterization of the anticonvulsant activity of doxepin in various experimental seizure models in mice. AB - In this paper, the anticonvulsant characteristics of doxepin were evaluated in numerous experimental seizure models, including maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, isoniazid (ISO)-, 3-mercaptopropionic acid (3-MP)-, bicuculline (BIC)-, thiosemicarbazide (THIO)-, and strychnine (STR)-induced seizures. In addition, the acute adverse-effect profile of doxepin with respect to impairment of motor coordination was assessed with a mouse rotarod test. The evaluation of the time-course and dose-response relationships for doxepin provided evidence that the peak maximum anticonvulsant activity and acute adverse effects occurred 5 min after intraperitoneal (ip) administration. The results also revealed that doxepin had excellent anticonvulsant activity against maximal electroshock-induced seizures in mice with a median effect value (ED(50)) of 6.6 mg/kg. The assessment of acute adverse effects in the rotarod test revealed that doxepin induced acute neurotoxicity, and its median toxic dose (TD(50)) was 26.4 mg/kg. Additionally, doxepin showed anticonvulsant activity in several chemically induced seizure models, including ISO, 3-MP, BIC, and THI. Based on this study, we can conclude that the antidepressant drug doxepin may be useful for treatment of depression in patients with epilepsy due to its short time to peak maximum anticonvulsant activity after ip administration (5 min) and remarkable anticonvulsant activity (6.6 mg/kg). PMID- 19443936 TI - Influence of agmatine on the protective action of numerous antiepileptic drugs against pentetrazole-induced seizures in mice. AB - The aim of this study was to assess the influence of agmatine (an endogenous neuromodulator/neurotransmitter in the brain) on the protective action of numerous classical and second-generation antiepileptic drugs (clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, vigabatrin, and valproate) in the mouse pentetrazole-induced clonic seizure model. The results indicate that agmatine (up to 100 mg/kg, ip, 45 min before the test) did not alter the threshold for pentetrazole-induced clonic seizures in mice. However, agmatine (100 mg/kg, ip) significantly attenuated the anticonvulsant effects of vigabatrin against pentetrazole-induced clonic seizures by elevating the ED(50) value of vigabatrin from 517.5 to 790.3 mg/kg (p < 0.01). In contrast, agmatine at a dose of 50 mg/kg did not significantly affect the anticonvulsant action of vigabatrin, although an increase in the ED(50) value of the antiepileptic drug from 517.5 to 629.1 mg/kg was documented. Moreover, agmatine at doses of 50 and 100 mg/kg (ip) had no significant impact on the anticonvulsant action of clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, or valproate in pentetrazole induced seizures in mice. In conclusion, the combination of agmatine with vigabatrin seems to be unfavorable due to the reduction of the anticonvulsant effect of vigabatrin after concomitant administration of agmatine in the pentetrazole-induced seizure model. Therefore, the utmost caution is advised when combining agmatine with vigabatrin in further clinical settings. PMID- 19443937 TI - 5-HT-induced depression of the spinal monosynaptic reflex potential utilizes different types of 5-HT receptors depending on Mg2+ availability. AB - Receptor subtypes involved in the 5-hydroxytryptamine (5-HT)-induced depression of synaptic transmission in neonatal rat spinal cords in vitro were evaluated in the absence or presence of Mg(2+) in the medium. Stimulation of a dorsal root evoked monosynaptic reflex potential (MSP) and polysynaptic reflex potential (PSP) in the segmental ventral root in Mg(2+)-free medium where the voltage dependent blockade of NMDA receptors is absent. The 5-HT (0.3-50 microM) in the Mg(2+)-free medium depressed the MSP and PSP in a concentration-dependent manner. At 30 microM of 5-HT, the depression was 57% and 95% for MSP and PSP, respectively, and no further depression was seen at 50 microM. The 5-HT-induced depression of the reflexes in the Mg(2+)-free medium was blocked by ondansetron (5-HT(3) receptor antagonist), but not by spiperone (5-HT(2A/2C) antagonist). In the Mg(2+)-free medium, phenylbiguanide (5-HT(3) agonist) also depressed the MSP and PSP in a concentration-dependent manner and was blocked by ondansetron. Addition of Mg(2+) (1.3 mM) to the medium abolished the PSP and decreased the MSP by 30%. In the presence of Mg(2+), 5-HT (1-50 microM) also depressed the MSP in a concentration-dependent manner. At 10 microM of 5-HT, there was approximately 20% depression and at 50 microM the depression was 100%. The 5-HT-induced depression of MSP in the Mg(2+)-containing medium was antagonized by spiperone (p < 0.05, two-way ANOVA), but not by ondansetron. The results indicate that the 5-HT induced depression of MSP involves 5-HT(3) receptors in the Mg(2+)-free medium and 5-HT(2A/2C) in the presence of Mg(2+) when NMDA receptors are in the closed state. PMID- 19443938 TI - Lack of effect of naltrexone on the spinal synergism between morphine and non steroidal anti-inflammatory drugs. AB - To enhance analgesia, the combinatorial use of analgesic drugs with proven efficacies is a widely-used strategy to reduce adverse side effects. The present study characterizes the antinociceptive interaction of intrathecal morphine co administered with different NSAIDs using isobolographic analysis.Antinoceptive activity was evaluated using a model for acute visceral pain, the writhing test of mice. The possible involvement of opioid receptors in the mechanism of action of the intrathecal co-administration of morphine and NSAIDs was investigated using the non-selective receptor antagonist naltrexone. The study demonstrated a synergistic antinociception of intrathecal administered combinations of morphine with the following NSAIDs: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supra additive effect was obtained with very low doses of each drug and it appeared to be independent of the COX-1 or COX-2 inhibition selectivity of each NSAID and was not significantly modified by intrathecal naltrexone. The findings of the present work suggest that the combination of opioids and NSAIDs has a direct action on spinal nociceptive processing, which may be achieved via mechanisms that are independent of the activation of opioid receptors. The ineffectiveness of naltrexone to reverse the analgesic activity of opioids + NSAIDs combinations indicates that other complex pain regulatory systems are involved in this effect. PMID- 19443939 TI - Role of potassium channels in the relaxant effect of levosimendan in guinea pig tracheal preparations. AB - We investigated both the effect of levosimendan and the role of various potassium channels in carbachol-precontracted tracheal preparations samples obtained from guinea pig. The tracheas were cut into 0.5 cm wide rings and suspended in a 20 ml organ bath. Isometric tension was continuously measured with an isometric force transducer connected to a computer-based data acquisition system. Levosimendan or cromakalim produced concentration-dependent relaxation responses in guinea pig tracheal rings precontracted by carbachol. Incubation of guinea pig tracheal rings with the ATP-dependent potassium channel (K(ATP)) blocker glibenclamide for 30 min significantly inhibited the relaxant responses to both levosimendan and cromakalim. The large conductance Ca(2+)-activated potassium channel (BK(Ca)) blocker iberiotoxin also caused a significant inhibition on relaxant responses to levosimendan. However, incubation of the tracheal rings with the voltage dependent potassium channel blocker 4-aminopyridine for 10 min did not cause significant alterations on relaxant responses to levosimendan. The present findings suggested that the relaxant effect induced by levosimendan might be partially due to K(ATP) and BK Ca in isolated guinea pig tracheal rings. PMID- 19443940 TI - IL-1beta, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis patients with leflunomide. AB - Leflunomide is an isoxazole derivative that is structurally and functionally unrelated to other known immunomodulatory drugs. Previous studies have revealed that therapy with leflunomide causes decreased production of mediators such as IL 1beta, IL-6, and TNF-alpha, which are involved in inflammatory process. The aim of the present study was to examine whether the polymorphisms in genes IL1B, IL6, and TNF may affect treatment outcomes in RA patients treated with leflunomide. The study was carried out on 129 patients (106 women, 23 men, mean age 52.9 +/- 11.03) diagnosed with RA and treated with leflunomide 20 mg daily. Clinical improvement was evaluated according to the American College of Rheumatology (ACR) 20% and 50% response criteria. There were no statistically significant associations between the studied genotypes and improvement of disease activity parameters. The results of the present study suggest that IL1beta, IL6, and TNF gene polymorphisms are not significant factors influencing the therapy outcome of RA patients with leflunomide. PMID- 19443941 TI - Antitumor effects of a selenium heteropoly complex in K562 cells. AB - The aim of this study was to investigate the anti-tumor effects and mechanism of the selenium heteropoly compound (C(2)H(10)N(2))(5)(NH(4))(4)H(2)[Se(2)W(10)V(8)O(62)].9H(2)O (SeWV) in K562 cells. The results showed that 0.32-10.15 x 10(-3) mmol/l SeWV could significantly inhibit the proliferation of K562 cells in vitro, as determined by the MTT assay, with IC(50) values of 3.07 and 2.69 x 10(-3) mmol/l after 48 and 72 h of treatment with SeWV, respectively. Studies of the cell cycle indicated that SeWV could induce K562 cells gathered in the G(2)/M phase upon treatment for 24 and 48 h, and a significant sub-G1 peak was evident at 0.32 and 2.54 x 10(-3) mmol/l after treatment for 24 h. Morphological observations revealed typical apoptotic features. SeWV caused the accumulation of Ca(2+), Mg(2+) and ROS, and the reduction of pH and mitochondrial membrane potential (MMP) in K562 cells as evidenced by confocal laser scanning microscopy. Experiments also showed that the expression of Bcl-2 was significantly inhibited, but Bax was increased by SeWVat 5.07 x 10(-3) mmol/l. Additionally, the content of cytochrome-C was increased after treatment for 24 h. The experiment implied that SeWV had anti-tumor activity and that its mechanism was partially attributable to the induction of cell cycle distribution and apoptosis that was induced by a change in intracellular ion homeostasis. PMID- 19443943 TI - Effects of the cannabinoid CB1 receptor antagonist AM 251 on the reinstatement of nicotine-conditioned place preference by drug priming in rats. AB - Tobacco and cannabis are among the most widely abused drugs in humans, and recently, the functional interaction between nicotine and cannabinoids has been reported. The aim of the present studies is to evaluate the role of CB1 cannabinoid receptors in the reinstatement of nicotine-induced conditioned place preference. Nicotine-induced conditioned place preference was established (three day nicotine sessions, 0.5 mg/kg), extinguished and reinstated by a priming dose of nicotine. It was shown that the CB1 receptor antagonist AM 251 (0.25 and 0.5 mg/kg) in a dose-dependent manner attenuates the reinstatement of nicotine place conditioning. These studies suggest a role for CB1 cannabinoids receptors in preventing the reinstatement of nicotine addiction. PMID- 19443942 TI - Antigenotoxic effect of genistein against 7,12-dimethylbenz[a]anthracene induced genotoxicity in bone marrow cells of female Wistar rats. AB - Carcinogen induced mutation in somatic cells leads to genetic instability, which is considered as an important facet of carcinogenesis. Agents that inhibit DNA adduct formation, stimulate DNA repair mechanisms, and possess antioxidant functions are considered as antigenotoxic agents. Genistein, the major isoflavone of soy products, protects animals against experimentally induced mammary and prostate cancers. 7,12-Dimethylbenz[a]anthracene (DMBA), a potent site-specific carcinogen, induce mutations in DNA through its active metabolite, dihydrodiol epoxide, what is a crucial step in cancer initiation. The antigenotoxic effect of genistein against DMBA-induced genotoxicity has been investigated in the present study by analyzing the frequency of micronucleated polychromatic erythrocytes (MnPCEs) and chromosomal aberrations as cytogenetic end-points. The status of lipid peroxidation, antioxidants and detoxication agents were used as biochemical end-points to assess the antigenotoxic effect of genistein. Elevated MnPCEs frequency, marked chromosomal aberrations and enhanced status of lipid peroxidation, antioxidants and detoxication agents were observed in DMBA-treated animals. Oral pretreatment of genistein (20 mg/kg b.w.) for 5 days to DMBA treated animals significantly reduced the frequency of micronucleus formation and chromosomal abnormalities as well as reversed the status of biochemical variables. Our results suggest that genistein has potent antigenotoxic effect against DMBA-induced genotoxicity. PMID- 19443945 TI - Investigation of the acute effect of leptin on the inhibition of glycogen catabolism by insulin in rat liver perfused in situ. AB - Leptin, a cytokine secreted by adipose tissue, has been implicated in the insulin resistance associated with obesity. Here we examined the acute influence of leptin at physiological (10 ng/ml) and supraphysiological (50 ng/ml and 100 ng/ml) concentrations on the inhibition of glycogen catabolism promoted by insulin in rat liver perfusion experiments. Perfusion of the liver with insulin (20 microU/ml) decreased the activation of glucose production (p < 0.05) and glycogenolysis by cAMP (3 microM). However, the infusion of leptin, at concentrations similar to those found in non-obese (10 ng/ml), obese (50 ng/ml), and morbidly obese (100 ng/ml) individuals did not influence the acute inhibitory effect of insulin (20 microU/ml) on glucose production and glycogenolysis stimulated by cAMP (p > 0.05).We conclude that neither physiological nor supraphysiological concentrations of leptin directly influence the inhibition of glycogen catabolism promoted by insulin in rat liver perfused in situ. PMID- 19443944 TI - Neonatal co-lesion by DSP-4 and 5,7-DHT produces adulthood behavioral sensitization to dopamine D(2) receptor agonists. AB - To assess the possible modulatory effects of noradrenergic and serotoninergic neurons on dopaminergic neuronal activity, the noradrenergic and serotoninergic neurotoxins DSP-4 N-(2-chlorethyl)-N-ethyl-2-bromobenzylamine (50.0 mg/kg, sc) and 5,7-dihydroxytryptamine (5,7-DHT) (37.5 microg icv, half in each lateral ventricle), respectively, were administered toWistar rats on the first and third days of postnatal ontogeny, and dopamine (DA) agonist-induced behaviors were assessed in adulthood. At eight weeks, using an HPLC/ED technique, DSP-4 treatment was associated with a reduction in NE content of the corpus striatum (> 60%), hippocampus (95%), and frontal cortex (> 85%), while 5,7-DHT was associated with an 80-90% serotonin reduction in the same brain regions. DA content was unaltered in the striatum and the cortex. In the group lesioned with both DSP-4 and 5,7-DHT, quinpirole-induced (DA D(2) agonist) yawning, 7-hydroxy-DPAT-induced (DA D(3) agonist) yawning, and apomorphine-induced (non-selective DA agonist) stereotypies were enhanced. However, SKF 38393-induced (DA D(1) agonist) oral activity was reduced in the DSP-4 + 5,7-DHT group. These findings demonstrate that DA D(2)- and D(3)-agonist-induced behaviors are enhanced while DA D(1) agonist-induced behaviors are suppressed in adult rats in which brain noradrenergic and serotoninergic innervation of the brain has largely been destroyed. This study indicates that noradrenergic and serotoninergic neurons have a great impact on the development of DA receptor reactivity (sensitivity). PMID- 19443946 TI - Use of transgenic (knockout) mice reveals a site distinct from the alpha2A adrenoceptors for agmatine in the vas deferens. AB - The inhibitory effect of agmatine on electrically induced contractions was studied in vas deferens of Adra 2a transgenic mice lacking alpha(2A) adrenoceptors. Agmatine and clonidine caused a concentration-dependent inhibition of twitches. However, while agmatine showed a similar pIC(50) value in control and transgenic mice, the pIC(50) value for clonidine was about 30-fold lower in knockout mice. In both strains, yohimbine shifted the curve for clonidine, but not for agmatine, even when a 100-fold higher concentration of yohimbine was employed. Our results indicate that inhibition by agmatine in mouse vas deferens is not simply due to interactions with alpha(2)-adrenoceptors in our experimental conditions. PMID- 19443947 TI - Contribution of NO, ATP-sensitive K+ channels and prostaglandins to adenosine receptor agonists-induced relaxation of the rat tail artery. AB - The mechanism of relaxation in the rat tail artery induced by the adenosine A(1) receptor-selective agonist N(6)-cyclohexyladenosine (CHA, 10 nM-300 microM) and the adenosine A1/A(2a) receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA, 10 nM-300 microM) has been characterized. To do this, we used alpha(1)-receptor agonist phenylephrine to evoke contraction (10 microM), and inhibitors of nitric oxide synthase (L-NAME, 10 microM), ATP-sensitive K(+) channels (glibenclamide, 10 microM) and prostaglandin synthesis (indomethacin, 10 microM). CHA and NECA induced relaxation of rat-tail artery by 80% and 70% in a concentration-dependent manner, respectively. The relaxation effect of NECA was completely abolished in the presence of L-NAME, while glibenclamide and indomethacin prevented CHA induced relaxation of the rat tail artery by approximately 25% and 40%, respectively. Our results indicate that nonspecific effects such nitric oxide and prostaglandins release or the activation of potassium channels significantly contributed to the effects of CHA and NECA. PMID- 19443948 TI - Acute doxorubicin pulmotoxicity in rats with malignant neoplasm is effectively treated with fullerenol C60(OH)24 through inhibition of oxidative stress. AB - The aim of this study was to investigate the possible protective role of fullerenol (FLR, C(60)(OH)(24) on doxorubicin (DOX)-induced lung toxicity using biochemical and histopathological approaches. Rats (Sprague-Dawley outbred) were randomly divided into five groups. The healthy control group received no medication (saline only). The other four groups had chemically induced breast cancer (1-methyl-1-nitrosourea; 50 mg/kg, ip). The second group was the cancer control group (saline only). The other three groups were DOX (8 mg/kg, ip), FLR/DOX (100 mg/kg, ip, 30 min before DOX; 8 mg/kg, ip), and FLR (100 mg/kg, ip), respectively. The levels of malondialdehyde (MDA) and oxidized glutathione (GSSG) in the lung tissue were higher in the group treated with DOX alone than in the control groups. The activities of catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), and lactate dehydrogenase (LDH) were found to be increased in the lung tissue of the animals in the DOX group over all the other groups, while GSH-Px significantly decreased in activity compared with the control and FLR groups. There was no significant difference in MDA and GSSG levels and enzyme activities in either control (healthy; cancer) or FLR (FLR/DOX; FLR) groups. The acute change found in the DOX group was subpleural edema. In contrast, the groups treated with FLR appeared to be virtually histopathologically normal. In conclusion, this study clearly indicates that DOX treatment markedly impairs pulmonary function and that pre-treatment with FLR might prevent this toxicity in rats through inhibition of oxidative stress. PMID- 19443949 TI - 4-Thio-uridylate (UD29) interferes with the function of protein -SH and inhibits HIV replication in vitro. AB - In this short communication, it is shown that 4-thio-uridylate (s(4)UMP, designated as UD29) inhibits glyceraldehyde 3-phosphate dehydrogenase (GAPDH), suggesting that the enol-form of the thiolated nucleotide may interfere with the function of the essential -SH group in the active center of the enzyme. Since HIV entry requires thiol/disulfide exchange processes, this activity prompted us to study the anti-HIV activity of the nucleotide. Indeed, UD29 inhibited the replication of HIV-1(IIIB) in the MT-4 cell line and HIV-1(Ada-M) in peripheral blood mononuclear cells (PBMC). Furthermore, UD29 was not toxic in PBMCs in vitro or in mice when the compound was administered intravenously. PMID- 19443950 TI - Folding pathways explored with artificial potential functions. AB - This paper considers the generation of trajectories to a given protein conformation and presents a novel approach based on artificial potential functions--originally proposed for multi-robot navigation. The artificial potential function corresponds to a simplified energy model, but with the novelty that--motivated by work on robotic navigation--a nonlinear compositional scheme of constructing the energy model is adapted instead of an additive formulation. The artificial potential naturally gives rise to a dynamic system for the protein structure that ensures collision-free motion to an equilibrium point. In cases where the equilibrium point is the native conformation, the motion trajectory corresponds to the folding pathway. This framework is used to investigate folding in a variety of protein structures, and the results are compared with those of other approaches including experimental studies. PMID- 19443951 TI - An active pixel sensor x-ray diffraction (APXRD) system for breast cancer diagnosis. AB - This paper describes the potential application of an active pixel sensor-based x ray diffraction (APXRD) system in the field of breast cancer diagnosis. The design and initial testing of the system was reported previously (Bohndiek et al 2008b Phys. Med. Biol. 53 655-72). The system has potential both as a 'diffraction enhanced breast imager' (DEBI) and as a probe for quantitative analysis of breast biopsy samples. The resolution of the system in a DEBI arrangement is 1 mm and the contrast available using a material-specific x-ray diffraction image was found to be up to seven times greater than that of a transmission image. Scatter signatures from a series of biopsy-equivalent samples, ranging in composition from 100% fat to 100% fibrous tissue, were acquired with the APXRD system. Multivariate data analysis was used to produce a partial least squares (PLS) model sensitive to sample fat content. The final model is able to accurately predict the fat content of a series of unknown samples and is robust to significant added noise. This suggests that the APXRD system could provide a simple, semi-automated, quantitative measurement system for analysis of breast biopsy samples. Training on a range of scatter signatures from real breast biopsy samples covering various stages of disease is now needed to test this hypothesis. PMID- 19443952 TI - The diaphragm as an anatomic surrogate for lung tumor motion. AB - Lung tumor motion due to respiration poses a challenge in the application of modern three-dimensional conformal radiotherapy. Direct tracking of the lung tumor during radiation therapy is very difficult without implanted fiducial markers. Indirect tracking relies on the correlation of the tumor's motion and the surrogate's motion. The present paper presents an analysis of the correlation between tumor motion and diaphragm motion in order to evaluate the potential use of diaphragm as a surrogate for tumor motion. We have analyzed the correlation between diaphragm motion and superior-inferior lung tumor motion in 32 fluoroscopic image sequences from ten lung cancer patients. A simple linear model and a more complex linear model that accounts for phase delays between the two motions have been used. Results show that the diaphragm is a good surrogate for tumor motion prediction for most patients, resulting in an average correlation factor of 0.94 and 0.98 with each model respectively. The model that accounts for delays leads to an average localization prediction error of 0.8 mm and an error at the 95% confidence level of 2.1 mm. However, for one patient studied, the correlation is much weaker compared to other patients. This indicates that, before using diaphragm for lung tumor prediction, the correlation should be examined on a patient-by-patient basis. PMID- 19443954 TI - The genetics and clinical characteristics of constitutional ring chromosomes. AB - Constitutional ring chromosomes are generally believed to be the result of de novo breakage of both end-segments of a chromosome during meiosis or early postzygotic mitosis, with the ends joining to give a continuous ring. This mechanism presumes the loss of some genetic material during ring formation. Ring chromosomes thus represent deletions of genetic material. But an accurate delineation of identifiable syndromes is not possible in the majority of cases even when the patients have apparently identical ring chromosomes and phenotypic charactristics. In many patients with a ring, independent of the chromosome involved, there is a similar clinical phenotype characterized by the presence of extreme growth failure without major malformation, with only a few or no minor anomalies and mild to moderate mental retardation. This phenotype is generally referred to as "ring syndrome." The description of the features of this chromosome anomaly has to-date been based on standard cytogenetic banding techniques. However, recent observations made with novel molecular techniques have brought new insights into the nature of ring chromosomes, contributing to the understanding of the genetic and clinical consequences. This review examines constitutional rings and is based on the generally accepted "classical" knowledge but also takes into consideration new molecular findings. PMID- 19443953 TI - A novel, SiPM-array-based, monolithic scintillator detector for PET. AB - Silicon photomultipliers (SiPMs) are of great interest to positron emission tomography (PET), as they enable new detector geometries, for e.g., depth-of interaction (DOI) determination, are MR compatible, and offer faster response and higher gain than other solid-state photosensors such as avalanche photodiodes. Here we present a novel detector design with DOI correction, in which a position sensitive SiPM array is used to read out a monolithic scintillator. Initial characterization of a prototype detector consisting of a 4 x 4 SiPM array coupled to either the front or back surface of a 13.2 mm x 13.2 mm x 10 mm LYSO:Ce(3+) crystal shows that front-side readout results in significantly better performance than conventional back-side readout. Spatial resolutions <1.6 mm full-width-at half-maximum (FWHM) were measured at the detector centre in response to an approximately 0.54 mm FWHM diameter test beam. Hardly any resolution losses were observed at angles of incidence up to 45 degrees , demonstrating excellent DOI correction. About 14% FWHM energy resolution was obtained. The timing resolution, measured in coincidence with a BaF(2) detector, equals 960 ps FWHM. PMID- 19443955 TI - Prevalence and prognosis of asymptomatic coronary artery disease in patients with abdominal aortic aneurysm and minor or no perioperative risks. AB - BACKGROUND: According to the AHA/ACC guideline 2002, patients with abdominal aortic aneurysm (AAA) with minor or no clinical risk for perioperative cardiovascular events require no preoperative coronary assessment if they have functional capacity greater than 4 METS. Further coronary assessment is not often performed, even after the operation, because of absence of symptoms. The aim of this study was to clarify the prevalence, and prognosis of asymptomatic coronary artery disease (CAD) in such AAA patients. METHODS AND RESULTS: From 2002 to 2006, 201 patients (161 men; mean age 73.1 +/-7.7 years) were classified as minor or no clinical risk for perioperative cardiovascular events. Medical history, and physical, laboratory, plus imaging examinations were evaluated. Prognosis was assessed by telephone canvass. Asymptomatic CAD was found in 59 patients (29.4%). By multivariate analysis, advanced age (> or =75 years: odds ratio (OR) 2.43, P=0.018) and family history of CAD (OR 5.27, P=0.001) independently predicted asymptomatic CAD. Asymptomatic CAD did not significantly affect death or cardiac events when treated appropriately. CONCLUSIONS: A high prevalence of asymptomatic CAD requiring treatment was shown in these AAA patients. Under appropriate therapies, prognosis was as well preserved as in patients without asymptomatic CAD, which underscored the importance of appropriate assessment and management of asymptomatic CAD. PMID- 19443956 TI - Comparison of drug-eluting stents and coronary artery bypass grafting for the treatment of multivessel coronary artery disease in patients with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a strong predictor of mortality after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), but the relative efficacy of the 2 revascularization strategies in this context remains unknown. METHODS AND RESULTS: The 1,069 patients with CKD undergoing revascularization for multivessel coronary disease were evaluated. Of them, 532 patients were treated for 2-vessel disease (97 CABG, 435 PCI) and 537 for 3-vessel disease (248 CABG, 289 PCI). CKD was defined as estimated glomerular filtration rate <60 ml/min. No differences between the PCI and CABG groups in the 2-vessel population were observed in the composite of death, myocardial infarction (MI) or cerebrovascular events (10.6% vs 8.2%, P=0.493) and repeat revascularization (6.7% vs 3.1%, P=0.181) during the 2-year follow-up. In the 3 vessel population, patients undergoing PCI showed similar rate for the composite endpoint (6.7% vs 3.1%, P=0.181), but had a higher incidence of repeat revascularization (12.5% vs 4.4%, P=0.001) compared with the CABG group. After multivariate adjustment, revascularization strategy was not an independent predictor of the composite endpoint. CONCLUSIONS: Compared with PCI with a drug eluting stent, CABG showed a similar incidence of death, MI or cerebrovascular events in patients with multivessel disease and CKD, but was associated with decreased repeat revascularization in the 3-vessel population. PMID- 19443957 TI - High-density lipoprotein-cholesterol and ischemic heart disease risk in Korean men with cardiac risk. AB - BACKGROUND: Although many epidemiological studies have suggested that a decreased level of high-density lipoprotein-cholesterol (HDL-C) is a risk factor for heart disease; this relationship remains uncertain in relation to triglycerides (TG). This study examined the effects of serum TG and HDL-C on the incidence of ischemic heart disease (IHD) in Korean men. METHODS AND RESULTS: A 14-year prospective cohort study was carried out with 29,171 Korean men who received insurance from the National Health Insurance Corporation and underwent a second screening for their cardiovascular risks. The main outcome measures were incidence of IHD. During 379,539 person-years of follow-up, 1,634 IHD (227 fatal IHD) events occurred. In the age-adjusted models, men in the lowest level of HDL C (<30 mg/dl) showed a higher risk [hazard ratio (HR) 1.57; 95% confidence interval (CI) 1.26-1.95] when compared with men with the highest concentration (HDL-C > or =60 g/dl), defined as the reference group. When TG were included in the multivariate adjusted Cox model, the relationship of HDL-C with IHD was weakened but remained (HR 1.38; 95%CI 1.10-1.73). The results were similar for TG in the multivariate model including HDL-C. CONCLUSIONS: These findings indicate that elevated TG and reduced HDL-C are independent risk factors for IHD risk in Korean men with cardiovascular risks. PMID- 19443959 TI - [Analysis of the mechanism underlying formation of the endocochlear potential in the inner ear]. PMID- 19443958 TI - Paraoxonase 1 polymorphisms and risk of myocardial infarction in women and men. AB - BACKGROUND: Previous studies of genetic variants of paraoxonase 1 (PON1) and coronary heart disease (CHD) have been conflicting and the modifying effects of lifestyle factors that affect PON1 activity are uncertain. METHODS AND RESULTS: In parallel nested case-control studies, the prospective associations between PON1 polymorphisms Q192R and L55M and incident CHD were examined among participants in the Nurses' Health and Health Professionals Follow-up Studies. Women were followed for 8 years and men for 6 years, and 249 women and 266 men were documented with incident CHD. Neither polymorphism was associated with risk of CHD in either sex, and neither monounsaturated fat intake nor smoking interacted with genotype. Among women, there was a possible interaction of Q192R with alcohol intake (P interaction 0.06) and a suggestion of a similar interaction with the L55M genotype (P interaction 0.11). In analyses of both polymorphisms, alcohol intake > or =2.5 g/day was associated with lower risk among all women (odds ratio 0.45), except those with the Q192Q/L55M genotype (OR 1.33; P 3-way interaction 0.07). CONCLUSIONS: PON1 polymorphisms are not associated with the risk of CHD nor do they interact with smoking or monounsaturated fat intake. A possible gene-alcohol interaction should be considered in future studies of PON1 and CHD. PMID- 19443960 TI - [Possible involvement of HRD1 (ubiquitin E3 ligase) in neurodegenerative diseases]. PMID- 19443961 TI - [Discovery and neuroprotective mechanisms of serofendic acid derived from fetal tissues]. PMID- 19443962 TI - [In vitro and in vivo angiogenesis assays]. PMID- 19443963 TI - [Optimization of intestinal drug absorption by drug delivery system (DDS) technology]. PMID- 19443964 TI - [Physicochemical profiling and drug absorption at the drug discovery stage]. PMID- 19443965 TI - [Pharmacological properties and clinical efficacy of the long-active angiotensin receptor blocker (ARB) irbesartan]. PMID- 19443966 TI - [Pharmacological and clinical profile of ramosetron hydrochloride (Irribow), a novel therapeutic agent for irritable bowel syndrome with diarrhea]. PMID- 19443967 TI - Imaging of nonalcoholic steatohepatitis: advantages and pitfalls of ultrasonography and computed tomography. AB - OBJECTIVE: The present study was performed to clarify the ability of ultrasonography (US) and computed tomography (CT) to detect steatosis and advanced fibrosis in nonalcoholic steatohepatitis (NASH) patients, and to assess the influence of steatosis, fibrosis, and obesity on the radiological detection of steatosis and advanced fibrosis. METHODS: One hundred and eighteen biopsy proven NASH patients underwent US and CT within 6 months before or after biopsy. The ability of US and CT to detect histological steatosis and advanced fibrosis was assessed. To evaluate whether fibrosis and obesity interfered with the detection of moderate to severe histological steatosis by US and CT, we analyzed 88 NASH patients with moderate to severe steatosis. To evaluate interference with the detection of advanced fibrosis by steatosis and obesity, we analyzed 59 NASH patients with advanced fibrosis. RESULTS: The sensitivity of US for detecting moderate to severe histological steatosis in patients with mild histological fibrosis was 100%, but this was reduced to 77.8% in patients with advanced histological fibrosis (p=0.001). The sensitivity of CT was 69.8% in patients with mild histological fibrosis and 48.9% in those with advanced histological fibrosis (p=0.047). The sensitivity of US and CT for moderate to severe histological steatosis was similar in each body mass index group. The sensitivity for detecting advanced fibrosis was markedly decreased by severe steatosis and obesity in the case of both US and CT. CONCLUSION: If we are aware of these disadvantages of US and CT, it is useful for diagnosing steatosis and fibrosis in NAFLD patients. PMID- 19443968 TI - Partial splenic embolization reverses insulin resistance in patients with liver cirrhosis. AB - BACKGROUND: It is well known that patients with liver cirrhosis often develop insulin resistance and diabetes mellitus. Recently, we encountered a liver cirrhosis patient in whom partial splenic embolization (PSE) improved insulin sensitivity. Therefore, we conducted further investigation about PSE and insulin resistance. METHODS: Thirty-seven consecutive patients with liver cirrhosis underwent PSE. Hemodynamic changes, blood counts, and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed before and 2 weeks after PSE. RESULTS: PSE resulted in decreased splenic venous flow and increased intestinal venous flow to the liver. Platelet counts before and after PSE were 7.7+/-0.5 x 10(4) /microL, 15.0+/-1.4 x 10(4) /microL, respectively (p<0.01). HOMA-IR before and after PSE were 6.5+/-2.1, 3.3+/-0.6, respectively (p<0.05). HCV core antigen before and after PSE were 6,340+/-1,296 fmol/L, 4,112+/-873 fmol/L, respectively (p<0.05). Conclusion PSE significantly reverses insulin resistance in patients with liver cirrhosis. The increase in intestinal venous flow to the liver and reduced HCV viral load were thought to be mechanisms of improvement in insulin sensitivity after PSE. PMID- 19443969 TI - Nonspecific interstitial pneumonia associated with collagen vascular disease: analysis of CT features to distinguish the various types. AB - OBJECTIVE: The purpose of this study was to analyze the CT findings of interstitial lung diseases that are associated with collagen vascular disease (CVD), with particular attention to nonspecific interstitial pneumonia (NSIP), and to examine whether it is possible to predict the clinical diagnosis of CVDs based on the CT findings alone. METHODS: CT scans of 49 patients with NSIP associated with CVD (15 males, 34 females; mean age, 55+/-10 years; age range, 25 76 years) were included in this retrospective study. All patients underwent a surgical biopsy. The clinical diagnosis comprised rheumatoid arthritis (RA) (n=15), systemic sclerosis (SSc) (n=8), polymyositis and dermatomyositis (PM/DM) (n=18), Sjogren's syndrome (SjS) (n=4), and mixed connective tissue disease (MCTD) (n=4). Each CT was reviewed by two independent observers who made a clinical diagnosis based on the CT findings alone. RESULTS: The observers made a correct diagnosis for 22 (45%) of the 49 patients. A correct diagnosis was made for: RA in 7 (47%) of 15 patients; SSc in 3 (38%) of 8 patients; PM/DM in 11 (61%) of 18 patients; SjS in 1 (25%) of 4 patients. None of the 4 MCTD cases was diagnosed. CONCLUSION: It is difficult to make a correct clinical diagnosis of the various types of CVDs based solely on CT findings. However, it is probable to make a reasonably accurate clinical diagnosis in cases that show the typical CT findings, especially for PM/DM patients. PMID- 19443970 TI - Correlation of decreased survival and IL-18 in bone metastasis. AB - OBJECTIVE: Previous studies have reported that serum IL-18 levels are increased in some cancers. We investigated whether IL-18 production is increased in sera and cancer cells of patients with non-small cell lung cancer (NSCLC). PATIENTS OR MATERIALS: Serum levels of IFN-gamma and IL-18 and thioredoxin 1 (TRX1) were measured in 79 patients (51 males, 28 females, median age 67 years) with advanced NSCLC (57 adenocarcinoma, 22 squamous cell carcinoma; TNM stages IIIA [n=11], IIIB [n=24], and IV [n=44]) and 75 healthy age-matched controls (44 males, 31 females, median age 65 years) by enzyme-linked immunosorbent assay. We examined IL-18 production in the lungs and sites of bone metastasis of adenocarcinoma by immunohistochemistry. RESULTS: Serum IL-18, IFN-gamma, and TRX1 levels in NSCLC patients were significantly (p<0.0001, p=0.0031, and p<0.0001, respectively) higher than in control subjects, while serum IFN-gamma levels in NSCLC were slightly increased. Serum IL-18, but not IFN-gamma or TRX1, levels were significantly (p=0.0102) and negatively associated with overall survival in NSCLC. The serum IL-18 level was identified as an independent prognostic factor for overall survival in multivariate survival analysis. Moreover, serum IL-18 levels were significantly (p=0.049) higher in NSCLC with bone metastasis than in NSCLC without bone metastasis. Based on immunohistochemistry, we observed that cancer cells in the lungs and bone metastases markedly produced IL-18. CONCLUSION: Our results suggest that elevated serum IL-18 levels may be associated with IL-18 producing cancer cells in advanced NSCLC. PMID- 19443971 TI - Analysis of triglyceride value in the diagnosis and treatment response of secondary hemophagocytic syndrome. AB - BACKGROUND/AIMS: Secondary hemophagocytic syndrome (hemophagocytic lymphohistiocytosis, HLH) follows viral infection, malignant disorders, and autoimmune disease. Criteria for HLH diagnosis, which were proposed in 2004, include hypertriglyceridemia. However, some studies reported the absence of hypertriglyceridemia in patients with secondary HLH, differing from those with primary HLH. SUBJECTS AND METHODS: In this study, we investigated the presence or absence of hypertriglyceridemia in 28 patients who were diagnosed with secondary HLH between 1997 and 2007 retrospectively. There were no patients undergoing treatment for those with a history of hyperlipidemia. RESULTS: The subjects consisted of 14 patients with lymphoma-associated HLH, 11 with virus-associated HLH, 2 with autoimmune disease-associated HLH, and 1 with post transplantation HLH. In 19 patients (68%), hypertriglyceridemia was noted on diagnosis or during the disease period (mean: 242 mg/dL). Furthermore, the triglyceride (TG) level decreased with the treatment-related amelioration of HLH (mean level before and after treatment: 297 and 136 mg/dL, respectively, p=0.0001). CONCLUSION: These results suggest that the TG level is useful for diagnosing HLH and evaluating the treatment response. TG measurement is simple and inexpensive; therefore, this parameter can be determined several times to evaluate the treatment response. PMID- 19443972 TI - Intravenous immunoglobulin therapy for autoantibody-positive cerebellar ataxia. AB - OBJECTIVE: It has been reported that autoimmune cerebellar ataxias, such as anti glutamic acid decarboxylase (GAD)-antibody-positive cerebellar ataxia and gluten ataxia, are treatable. Here, we examined the therapeutic efficacy of intravenous immunoglobulin (IVIg) on autoantibody-positive cerebellar ataxia. PATIENTS AND METHODS: IVIg therapy was administered in seven autoantibody-positive cerebellar ataxia patients. Therapeutic efficacy was examined in terms of its effects on clinical symptoms and changes in brain perfusion using single photon emission computed tomography (SPECT). RESULTS: Treatment was effective in four cerebellar cortical atrophy patients (two anti-GAD antibody-positive and two anti-gliadin antibody-positive) and in one anti-thyroid antibody-positive spinocerebellar ataxia type 3 (SCA3) patient, but not in two multiple system atrophy (MSA) patients. All four IVIg effective patients who underwent SPECT showed apparent increases in cerebellar perfusion. CONCLUSION: If cerebellar ataxia with an autoimmune mechanism is suspected and radiological findings do not reveal MSA, it is worth considering immunotherapy including IVIg. PMID- 19443973 TI - Nosocomial bacteremia caused by biofilm-forming Bacillus cereus and Bacillus thuringiensis. AB - OBJECTIVE: Bacterial biofilms cause serious problems, such as antibiotic resistance and medical device-related infections. Recent reports indicate that Bacillus species potentially form biofilms and cause nosocomial bacteremia via catheter infection. Our objective was to investigate the relationship between nosocomial bacteremia caused by Bacillus species and biofilm formations. METHODS: Between 2001 and 2006, Bacillus cereus and Bacillus thuringiensis were isolated from blood samples of 21 patients with nosocomial bacteremia in two hospitals. The patients had underlying diseases such as cerebrovascular damage, malignant disease, or chronic obstructive lung disease and had high fever at the onset of bacteremia. After investigation, B. cereus and B. thuringiensis were isolated from patient's catheter tip, gauze, and hospital environment. Pulsed-field gel electrophoresis (PFGE) on 32 B. cereus and 7 B. thuringiensis isolates, microtiter biofilm assay and scanning electron microscopy (SEM) on 22 B. cereus isolates from patient's blood were performed. RESULTS: Molecular analysis by PFGE showed that 32 B. cereus strains had 21 patterns and 7 B. thuringiensis strains had 3 patterns. The PFGE patterns of B. thuringiensis and B. cereus in blood samples from 2 patients blood were similar to those from the same patient's catheter tip. The PFGE pattern of B. cereus from a hospital environment was similar to that from 2 patients' blood samples, and the PFGE pattern of B. thuringiensis from 2 hospital environments was similar to that from 2 patients' blood. The biofilm formations by 22 B. cereus isolates from patients' blood were confirmed by microtiter biofilm assay and SEM even at 24 hours. CONCLUSION: Our data indicate that various types of Bacillus species exist in hospital environments and the biofilm-forming strains potentially cause nosocomial bacteremia by catheter infection. PMID- 19443974 TI - Molecular epidemiological study of Moraxella catarrhalis isolated from nosocomial respiratory infection patients in a community hospital in Japan. AB - BACKGROUND: Moraxella catarrhalis, occasionally, plays the essential role in nosocomial respiratory infection (NRI). Few studies have reported the route by which this organism spreads in a nosocomial infection outbreak. We identified characteristics of the strains isolated from NRI and attempted to reveal the potential nosocomial transmission routes. METHODS: A follow-up study has been performed in a Japanese community hospital between July 2002 and January 2003. M. catarrhalis clinical isolates were identified and beta-lactamase production test as well as the minimal inhibitory concentrations (MICs) have been examined. Pulsed-field gel electrophoresis (PFGE) and the multi locus sequence typing method (MLST) have been introduced as the effective "fingerprinting" methods. RESULTS: A total of 29 strains were isolated from 17 participants; 7 independent DNA fragment patterns were detected by PFGE. Pattern B (defined in this study) was dominant, and was detected both in strains from a health care worker (HCW) and inpatients. In the 9 selected strains analyzed by MLST, 7 unique MLST types were identified, which showed the congruence with the results of PFGE results. CONCLUSION: Epidemiological analysis proved the transmission route from patient to patient, and suggested that more studies should be focused on identifying the possible transmission route between HCWs and inpatients. PMID- 19443975 TI - Diffuse large B-cell lymphoma with massive portal vein tumor thrombosis in a patient with alcoholic cirrhosis: a case report and literature review. AB - We describe a case of diffuse large B-cell lymphoma with massive portal vein tumor thrombosis in a patient with alcoholic cirrhosis. The tumor was detected only in the intrahepatic portal vein and the spermatic cord by FDG-PET/CT. Percutaneous liver biopsy and orchiectomy were performed and histological examination revealed diffuse large B-cell lymphoma. The tumor showed complete response after six courses of the combination chemotherapy. Portal vein tumor thrombosis of malignant lymphoma is extremely rare; moreover, it is possible that this is the first case of malignant lymphoma originating from the spermatic cord producing portal vein tumor thrombosis. PMID- 19443976 TI - Endoscopic biliary plastic stenting and successful intentional stent retrieval in a benign biliary stricture with mural spherical calcification and porcelain gallbladder. AB - We report a very rare case of benign biliary stricture with calcification and porcelain gallbladder, causing difficulty in differential diagnosis. A 64-year old man was referred for further examination of jaundice. Computed tomography showed calcifications in the gallbladder wall and the common bile duct. Endoscopic retrograde cholangiopancreatography revealed narrowing and a filling defect in the distal common bile duct. Peroral cholangioscopy showed a protruded lesion and stricture, and pathological examinations revealed no evidence of malignancy. The stricture was resolved after temporary insertion of progressively larger of plastic stents. Patients with benign biliary stricture and/or porcelain gallbladder should be followed carefully, because malignancy can occur as a complication, although infrequent. PMID- 19443977 TI - Hepatocellular carcinoma and Crohn's disease: a case report and review. AB - Hepatocellular carcinoma (HCC) is usually known to develop in patients with underlying high-risk liver diseases such as viral hepatitis, cirrhosis and alcohol abuse, whereas reports dealing with HCC in Crohn's disease (CD) are limited. We present a case of HCC, which developed sequentially within a short period in a 52-year-old Japanese man with a 36-year history of CD without risky conditions for HCC. He also had not taken immunosuppressants such as azathioprine. Although the definitive etiological factors contributing to hepatocarcinogenesis in the present case could not be elucidated, further close surveillance is required. PMID- 19443978 TI - Primary systemic amyloidosis with bloody pericardial effusion. AB - A 73-year-old woman was admitted due to exertional dyspnea. It was considered that a large amount of pericardial effusion caused diastolic heart failure; pericardial paracentesis showed bloody effusion. There were no findings of malignancy or other abnormal findings in the examination. Further examinations were planned but she died of ventricular tachycardia attack. Pathological autopsy revealed primary systemic amyloidosis. Pathologically it was possible that the local inflammation (epicarditis) due to the deposition of amyloid in the epicardium and perivascular tissue caused the bloody effusion. There are no reports of primary systemic amyloidosis with hemorrhagic pericardial effusion. We report this rare case with pathological consideration. PMID- 19443979 TI - Desquamative interstitial pneumonia (DIP) in a patient with rheumatoid arthritis: is DIP associated with autoimmune disorders? AB - Desquamative interstitial pneumonia (DIP) is a rare pattern of diffuse parenchymal lung disease known as one of the idiopathic interstitial pneumonias and is considered to be a smoking- or dust inhalation-related interstitial pneumonia in the majority of cases. This report presents the first case of DIP in which the pulmonary manifestation preceded the onset of rheumatoid arthritis. This case and our review of twenty-four DIP cases (nineteen cases previously reported from Japan, plus five cases in our departments) indicate the possibility that the DIP pattern is an additional form of diffuse interstitial pneumonia that may develop in association with autoimmune diseases. PMID- 19443980 TI - Early ultrasonographic diagnosis and clinical follow-up of hepatic veno-occlusive disease after allogeneic bone marrow transplantation in a patient with acute lymphoblastic leukemia. AB - Hepatic veno-occlusive disease (VOD) is a typical complication occurring soon after allogeneic hematopoietic stem cell transplantation (HST), characterized by jaundice, painful liver enlargement, and weight gain due to fluid retention. The study reported here concerns a patient with VOD after allogeneic HST. Hemodynamic evaluation using ultrasonography revealed reversed portal venous flow before elevation of serum bilirubin, in addition to gallbladder wall thickening, ascites, and hepatomegaly. Quantitative evaluation using abdominal ultrasonography showed improvement in the reversed portal venous flow before the peaking of the serum bilirubin level and coagulopathy. This analysis was useful for both early diagnosis and clinical follow-up of VOD. PMID- 19443981 TI - Multisystem failure due to three coexisting autoimmune diseases. AB - Systemic lupus erythematosis (SLE) is a potentially fatal, autoimmune disease, which can affect different organs and can present with protean clinical manifestations. It may be associated with many other autoimmune conditions and two rare such conditions are myelofibrosis and acquired haemophilia. Autoimmune myelofibrosis is a bone marrow disorder characterized by pancytopenia, which can occur in conjunction with the presenting features, or an exacerbation of previously established SLE. Acquired haemophilia is another rare disorder of haemostasis, which can be life threatening without prompt and appropriate treatment. The management of these different conditions in itself poses a difficult problem but when the three conditions present simultaneously in the same individual, the accurate diagnosis and indeed the appropriate management becomes extremely challenging. This report describes a young woman who presented with pancytopenia secondary to myelofibrosis and panserositis with no identifiable precipitating factors. Her condition deteriorated rapidly and she required intensive care support for respiratory failure and renal impairment. A presumed diagnosis of SLE was considered and treatment was initiated which improved and stabilised her condition. However, she developed bleeding complications from acquired haemophilia which required further specialist intervention. Multidisciplinary management of the patient helped in the resolution of the complications and stabilisation of her autoimmune conditions. This report should make physicians aware of the rare presentations of SLE and its complex management. PMID- 19443982 TI - Acute autonomic, sensory and motor neuropathy: successful treatment with IVIg. AB - Acute autonomic, sensory and motor neuropathy (AASMN) is a rare peripheral nerve disorder characterized by prominent dysautonomia with somatic sensory and motor impairment. Dysautonomia in AASMN is intractable even with corticosteroid therapy or plasmapheresis. Here we report a case of AASMN with severe orthostatic hypotension. Although the effectiveness of corticosteroid was insufficient, high dose intravenous immunoglobulin therapy (IVIg) was effective for not only sensorimotor symptoms but also autonomic symptoms. This is the first case of AASMN showing favorable responses to IVIg treatment, suggesting that IVIg should be considered when corticosteroid therapy or plasmapheresis is ineffective or insufficient. PMID- 19443983 TI - Adult onset Schonlein-Henoch purpura associated with Helicobacter pylori infection. AB - Schonlein-Henoch purpura (SHP) is a systemic vasculitis, primarily involving the skin, gastrointestinal (GI) tract, joints, and kidneys. A wide variety of different conditions may be implicated in the pathogenesis of SHP. We report a 33 year-old man who presented with SHP accompanied by gastric Helicobacter pylori (Hp) infection. The GI manifestations and purpuric rashes were dramatically resolved after Hp eradication therapy. To date, very few publications have focused on the possible pathogenetic relationship between Hp infection and SHP. PMID- 19443984 TI - Epidural abscess caused by Haemophilus aphrophilus misidentified as Pasteurella species. AB - Haemophilus aphrophilus is one of the normal oropharyngeal flora and rarely implicated as a pathogen of spinal infection. A case of H. aphrophilus bacteremia complicated with epidural abscess, psoas muscle abscess, and spondylodiscitis is described in this report. The pathogen was mis-identified as Pasteurella spp. at the very start, and was confirmed by the molecular method. He was successfully treated with adequate antibiotics and surgery. The clinical features of sixteen previously reported cases of spinal infection caused by H. aphrophilus are reviewed. PMID- 19443985 TI - Pictures in clinical medicine. Huge apertures in the aortic valve due to Libman Sachs endocarditis. PMID- 19443986 TI - Pictures in clinical medicine. Brain magnetic resonance imaging in chronic trichloroethylene and toluene exposure. PMID- 19443987 TI - Pictures in clinical medicine. Recovery of cerebral blood perfusion from transient hypo-perfusion due to acute benzodiazepine poisoning coinciding with generalized convulsion as withdrawal syndrome. PMID- 19443988 TI - Pictures in clinical medicine. "Concretio cordis" and systemic sclerosis. PMID- 19443989 TI - Relations between cyclin D1 and chromosome 11 in thyroid carcinoma: analysis by dual stain using FISH and immunostaining method. AB - Cyclin D1 is an important cell-cycle regulator that drives the cell cycle from the G1 phase to the S phase. Elevated nuclear cyclin D1 expression has been found in human tumors, including thyroid carcinoma. Protein production is known to require DNA amplification in each cell, but reports of such amplification have not been published. This study aimed to analyze the relationship between cyclin D1 protein production and chromosome 11 in cultured cells by means of dual staining with fluorescence in situ hybridaization (FISH) and immunostaining. In addition, we immunostained anaplastic thyroid carcinoma tissue. The results indicate that cyclin D1 is not related to chromosome 11 in cultured cells. Furthermore, tissue study showed that cyclin D1 is produced in the cytoplasm and in nuclei in various ratios. PMID- 19443990 TI - Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. AB - Stem cell based therapies for the repair and regeneration of various tissues and organs offer a paradigm shift that may provide alternative therapeutic solutions for a number of diseases. Although embryonic stem cells and induced pluripotent stem cells are theoretically highly beneficial, there are various limitations to their use imposed by cell regulations, ethical considerations, and genetic manipulation. Adult stem cells, on the other hand, are more easily available, with neither ethical nor immunoreactive considerations, as long as they are of autologous tissue origin. Much research has focused on mesenchymal stem cells isolated from bone marrow stroma which have been shown to possess adipogenic, osteogenic, chondrogenic, myogenic, and neurogenic potential in vitro. However bone marrow procurement is extremely painful for patients and yields low numbers of harvested cells. When compared with bone marrow-derived mesenchymal stem cells, adipose-derived stem cells are equally capable of differentiating into cells and tissues of mesodermal origin. Because human adipose tissue is ubiquitous and easily obtainable in large quantities under local anesthesia with little patient discomfort, it may provide an alternative source of stem cells for mesenchymal tissue regeneration and engineering. Based on our previous experimental findings, this review highlights the molecular characteristics, the potential for differentiation, the potential for wound healing, and the future role of adipose-derived stem cells in cell-based therapies and tissue engineering. PMID- 19443991 TI - Evaluation of the usefulness of spectral analysis of inspiratory lung sounds recorded with phonopneumography in patients with interstitial pneumonia. AB - PURPOSE: We investigated whether spectral analysis with fast Fourier transform (FFT) of inspiratory lung sounds is useful in the diagnosis and evaluation of the severity of interstitial pneumonia (IP). SUBJECTS AND METHODS: The study population included 10 healthy volunteers (healthy group) and 21 patients with IP (IP group). We generated inspiratory averaged linear intensities using FFT and determined frequency at maximum sound intensity (Fmax), and quartile frequencies (f25, f50, and f75), compared these values between the groups, generated receiver operating characteristic curves to compare the detectability of IP between the indices and auscultation in all cases, and tested for the correlation of these indices with pulmonary function tests and the fibrosis scores from high resolution computed tomography images assessed by 3 observers. RESULTS: Both f50 and f75 were significantly higher in the IP group, but their ability to detect IP was inferior to that of auscultation. They had negative correlations with percent vital capacity and had positive correlations with the fibrosis scores calculated by the 3 different observers. DISCUSSION: These results were considered to reflect the presence of fine crackles and alterations in pulmonary sound conduction characteristics caused by IP and indicate that spectral analysis of lung sounds is useful in the diagnosis and evaluation of the severity of IP, although future study is necessary to improve its utility. PMID- 19443992 TI - Sympathetic excitation during exercise as a cause of attenuated heart rate recovery in patients with myocardial infarction. AB - BACKGROUND: Heart rate recovery (HRR) after exercise is known as a predictor of cardiac death in patients with heart disease. The mechanism is not fully understood, although a parasympathetic mechanism has been reported. To elucidate the factors that influence HRR, we evaluated the relationship of HRR with exercise performance and plasma norepinephrine (NE), lactic acid and B-type natriuretic peptide (BNP) responses to exercise testing. METHODS: The study population consisted of 52 male patients (age 58 +/- 9.6 years) who had experienced myocardial infarction without residual ischemia, uncompensated heart failure or atrial fibrillation. All subjects underwent a symptom-limited cardiopulmonary exercise test without a cool-down period and echocardiography. NE, lactic acid and BNP were measured at rest and at peak exercise. RESULTS: HRR did not correlate with the left ventricular ejection fraction, peak VO(2), lactic acid and BNP. HRR significantly correlated with the increment in heart rate (HR) from rest to peak exercise (DeltaHR) (r=0.30, p<0.05). When we divided DeltaHR into two phases at the anaerobic threshold (AT), HRR significantly correlated with DeltaHR (peak-AT) (r=0.409, p<0.01), but not with DeltaHR (AT-rest). There was a significant negative correlation between HRR and NE both at rest and at peak exercise (r=-0.286, p<0.05, r=-0.310, p<0.05). HRR was also correlated significantly with DeltaHR/logDeltaNE as an index of sensitivity to NE (r=0.421, p<0.01). Based on multiple regression analysis, DeltaHR and logDeltaNE predicted HRR (R(2)=0.467, p=0.0027). CONCLUSIONS: Present findings suggest that enhanced sympathetic excitation at maximum exercise suppresses parasympathetic reactivation and results in attenuation of HRR. PMID- 19443993 TI - Bronchoalveolar lavage fluid analysis provides diagnostic information on pulmonary Langerhans cell histiocytosis. AB - Histiocytes of Langerhans cell type are recovered from the bronchoalveolar lavage fluid (BALF) of patients with interstitial lung diseases in a nonspecific manner. Langerhans cells (LCs) can be identified through immunostaining for S-100, CD1a, and, more specifically, langerin. To evaluate the diagnostic value of BALF in pulmonary Langerhans cell histiocytosis (PLCH), we performed a retrospective clinicopathological study of 5 patients with biopsy-confirmed PLCH or Hand Schuller-Christian disease involving the lung. As a control study, we examined BALF cells from 23 patients with various diseases, including sarcoidosis, hypersensitivity pneumonitis, collagen vascular disease, idiopathic pulmonary fibrosis, and adenocarcinoma of the lung. Cytospins obtained from BALF were stained with Giemsa or Papanicoloau and others were immunostained. In general, cytospins showed a monomorphous and dispersed cell population containing mononucleated or binucleated and occasionally multinucleated histiocytes. LCs recovered from BALF were characterized by clear and velvety cytoplasm; oval or kidney-shaped, vesicular nuclei with irregular shapes; nucleoli; and frequent grooves and indentations. Radiography and high-resolution computed tomography showed multiple bilateral nodular or cystic lesions in the middle and upper lung zones. The mean percentage of LCs in 9 lavages from the 5 patients was 8.0%, whereas that from the control group was only 0.3% (maximum, 1.6%). The percentage of cells positive for S-100 or CD1a was comparable to the percentage of Langerhans-like histiocytes stained with Giemsa stain. The present results indicate that the survey of LCs in BALF with the aid of immunocytochemical evaluation and corresponding clinical data could play a critical role in establishing the diagnosis of PLCH, thus providing a less invasive approach than lung biopsy, which carries a risk of complications. PMID- 19443994 TI - A case of monochorionic-diamniotic twin pregnancy with polyhydramnios polyhydramnios sequence. AB - We present a case of monochorionic-diamniotic (MD) twin pregnancy with polyhydramnios-polyhydramnios sequence. A 20-year-old woman, gravida 1, para 0, was referred to our hospital at 31 weeks and 6 days' gestation for consultation about a high-risk pregnancy due to the presence of discordant fetal growth pattern (26% of fetal growth discordance) with polyhydramnios in MD twin pregnancy. Ultrasound examination at admission showed a maximal vertical pocket (MVP) of 11.4 cm in twin A and an MVP of 4.7 cm in twin B. At 33 weeks' gestation, the MVPs had increased to 22.2 cm and 10.2 cm, respectively. At 33 weeks and 2 days' gestation, Cesarean section was performed because of uncontrolled uterine contractions associated with polyhydramnios. Twin A was a female weighing 2,280 g, and twin B was a female weighing 1,782 g (22% growth discordance). The estimated amniotic fluid volumes of twins A and B were 5,000 and 1,000 mL, respectively. PMID- 19443995 TI - Krukenberg tumor: metastasis of Meckel's diverticular adenocarcinoma to ovaries. AB - A 56-year-old female presented with abdominal pain, weight loss and fatigue. Computed tomography revealed an abdominopelvic mass and ascites. At surgery she had carcinomatosis and bilateral ovarian metastases arising from a cancer in a Meckel's diverticulum. Histology identified the primary to be a signet-ring cell adenocarcinoma within the Meckel's with ovarian metastases. This is the first report of a Krukenberg tumor from a Meckel's diverticulum. A discussion of malignancies within a Meckel's diverticulum is provided. PMID- 19443996 TI - Liver cyst with biliary communication successfully treated with laparoscopic deroofing: a case report. AB - A 56-year-old woman visited our hospital because of high fever and right hypochondralgia. Abdominal computed tomography showed a liver cyst 10 cm in diameter and dilatation of the intrahepatic bile duct. Percutaneous transhepatic drainage of the cyst guided by ultrasonography disclosed that the cyst contained a brown milky fluid, and cystography showed biliary communication. Thus, the cyst was diagnosed as an infectious hepatic cyst with biliary communication. Treatments for liver cysts include aspiration therapy, alcoholic sclerotherapy, laparoscopic fenestration, fenestration by laparotomy, cystojejunostomy, cystectomy, and hepatectomy. Because a simple liver cyst is benign, treatments should be low-risk and minimally invasive; thus, we performed laparoscopic fenestration. Fenestration should not be performed if the case is complicated by infection or biliary communication. Although cystography showed biliary communication, the cyst was not visualized with endoscopic retrograde cholangiography, and we concluded that the biliary communication was small. Operation time was 95 minutes, and blood loss was 10 g. Pathological findings of the liver cyst were consistent with a simple cyst. The postoperative course was good, and the patient left the hospital 10 days after the operation. Eighteen months have passed since the operation, and no recurrent cysts have been detected with computed tomography. This is the second report of liver cyst with biliary communication successfully treated with laparoscopic deroofing. Laparoscopic fenestration is a useful method for treating simple benign liver cysts because of its minimal invasiveness and may be useful in cases with small biliary communication. PMID- 19443997 TI - Experimental analysis of silicone leakage. AB - We analyzed whether gel bleed, the leakage of silicone gel from breast implants, occurs in the human body. We simulated the phenomenon with olive oil. Silicone breast implants were submerged in olive oil, and the concentration of silicone polymers in the olive oil was measured periodically with nuclear magnetic resonance spectroscopy. We found no increase in the silicone concentration. However, clinical conditions might not be adequately simulated because of the shortness of the experimental period and the lack of external stress. However, when clinical experiences and our data are considered, we think that silicone implant durability is an important factor to prevent leakage or gel bleeding. PMID- 19443998 TI - Endothelium-derived nitric oxide contributes to the vasorelaxant response induced by mesoionic 2-(4-chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1;3-thiazolium-5 thyolate (CMMTT) in rats. AB - This study was performed to investigate the mechanisms involved in the vasorelaxation induced by mesoionic 2-(4-chlorophenyl)-3-methyl-4-(4 methoxyphenyl)-1;3-thiazolium-5-thyolate (CMMTT), a newly synthesized mesoionic compound, in rat superior mesenteric arteries. In phenylephrine (10 microM)-pre contracted mesenteric rings, CMMTT (10(-14) - 10(-6) M) induced a concentration dependent relaxation [pD(2) = 10.26 +/- 0.05, E(max) = 80.8 +/- 5.8%], and this effect was almost abolished after either removal of the vascular endothelium [E(max) = 17.7 +/- 4.2%, P<0.001], removal of the vascular endothelium plus100 microM N(omega)-nitro-L-arginine methyl esther (L-NAME) [E(max) = 21.0 +/- 2.0 %, P<0.001], or after pre-treatment of the rings with 100 microM L-NAME [E(max) = 13.3 +/- 2.4%, P<0.001] or 10 microM 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) [E(max) = 13.6 +/- 4.8%, P<0.001]. However, endothelium-dependent relaxation induced by CMMTT was not significantly modified after 1 microM indomethacin plus 1 nM atropine [pD(2) = 11.12 +/- 0.08, E(max) = 73.8 +/- 5.15%] or 100 nM charybdotoxin (ChTX) plus 100 nM apamin [pD(2) = 10.89 +/- 0.08, E(max) = 58.91 +/- 9.8%]. In mesenteric rings, CMMTT (10(-6) M) was able to increase nitric oxide (NO)(x) levels, and this effect was abolished after removal of the vascular endothelium. In conclusion, the present study, using combined functional and biochemical approaches, demonstrated that CMMTT induced a significant vasorelaxant effect, almost completely mediated by the endothelium, likely via NO release and activation of the NO-cGMP pathway. PMID- 19443999 TI - Comparison of five benzodiazepine-receptor agonists on buprenorphine-induced mu opioid receptor regulation. AB - In this study, we compared the effects of five short-, medium-, or long-acting benzodiazepine-receptor agonists (BZDs) [alprazolam (APZ), clonazepam (CLZ), flunitrazepam (FLZ), loprazolam (LPZ), zolpidem (ZLP)], at two distinct doses, 0.2 and 2 mg/kg, on the cell surface regulation of mu-opioid receptor induced by 0.15 mg/kg buprenorphine (BPN) in specific regions of the rat brain. Using 0.312 5 nM [(3)H]-DAMGO concentrations and Scatchard plot analysis, B(max) (maximal receptor density) and K(d) (dissociation constant) were determined at different brain regions of interest (amygdala, cortex, hippocampus, hypothalamus, thalamus). Acute BPN induced an expected down-regulation and addition of each of the BZDs to BPN induced less down-regulation than did BPN alone, sometimes while altering affinity. Some significant differences in the intensity of these effects were observed between BZDs. FLZ that is widely abused and enlarges BPN toxicity appeared the most potent to increase mu-cell surface receptor density at the lowest dose of 0.2 mg/kg. Besides, LPZ for which the effect on mu-opioid-receptor regulation appeared lower is considered to have a low risk of dependence in the epidemiological data banks. CLZ and ZLP (2 mg/kg) induced the strongest modification on mu-opioid-receptor density, but a substantial decrease in affinity could minimize the functional consequences. The reported changes were maximal in the amygdala, hippocampus, and thalamus. Among people using BPN and BZDs, the effects described here are likely to influence addictive behaviors and induce toxic effects that could be quantitatively different due to the quality of the BZD. PMID- 19444000 TI - Regulation of ryanodine receptor-mediated Ca(2+) release in vas deferens smooth muscle cells. AB - Ca(2+) release from intracellular store sites via the ryanodine receptor (RyR) and hormonal regulation by flutamide, an androgen-receptor (AR) antagonist, on it were examined in vas deferens (VD) smooth muscle cells (SMCs). VD and VDSMCs were obtained from two groups of male rats that were treated p.o. with 100 mg/kg flutamide (Flu) or vehicle (Vehicle). Both spontaneous and caffeine-induced Ca(2+) releases were markedly smaller in single VDSMCs from Flu than in those from Vehicle. Interestingly, [Ca(2+)](i) rise by 100 muM norepinephrine in VDSMCs from Flu was larger than that in those from Vehicle. The contractions induced by direct electrical stimulation in tissue preparations from Flu showed lower susceptibility to 30 muM ryanodine than those from Vehicle. Real-time PCR analyses revealed that the transcripts of ryanodine receptor (RyR) type 2 and type 3 (RyR2 and RyR3) were expressed in VD and markedly reduced in Flu. The protein expression of total RyR was significantly reduced by flutamide treatment, but that of inositol 1,4,5-trisphosphate receptor (IP3R) was not affected. It can be strongly suggested that long term block of AR by flutamide reduced the expression of RyR and its contribution to the contraction, but not those of IP3R in VDSMCs. PMID- 19444001 TI - Pharmacokinetics and efficacy of fluvoxamine and amitriptyline in depression. AB - Although often necessary for obtaining remission following major depressive disorder, combined antidepressant treatment is frequently associated with drug interactions and enhanced adverse drug effects. We investigated pharmacokinetic interactions following combined fluvoxamine and amitriptyline treatment and their impact on therapeutic efficacy and tolerability. Twenty-two inpatients with major depression [Hamilton Depression Scale (HAM-D) rating > or =18] were treated with either amitriptyline (75 mg/day), fluvoxamine (100 mg/day) or both. Blood samples, for determination of amitriptyline, its major metabolite nortritpyline, and fluvoxamine, were obtained after single dose administration and in steady state. Therapeutic efficacy was evaluated using HAM-D and adverse drug effects were evaluated using the clinical global impression scale. Following combined treatment, steady-state plasma levels of nortriptyline were significantly decreased compared to monotherapy. HAM-D scores after two-week treatment showed that there was a better response to combined treatment. There was no significant difference in severity of adverse effects among groups. We observed a pharmacokinetic interaction between fluvoxamine and amitritpyline resulting in impaired metabolism of the later. However, no significant impact of the interaction on treatment safety was observed. Moreover, concomitant use of amitriptyline at 75 mg/day and fluvoxamine at 100 mg/day was well tolerated with a more prompt and stronger onset of clinical response compared to monotherapy in patients with major depression. PMID- 19444002 TI - Effects of postnatal administration of diethylstilbestrol on puberty and thyroid function in male rats. AB - To examine the effects of diethylstilbestrol (DES) on male pubertal development and thyroid function, juvenile male Sprague-Dawley rats were given DES daily by oral intubation at doses of 10, 20 and 40 microg/kg/day from postnatal day 33 for 20 days. Prepuce separation was significantly delayed at the dose of 20 microg/kg/day and above in the DES-treated rats. DES treatment induced a significant reduction in the weights of testes, epididymides, the ventral prostate, seminal vesicles plus coagulating glands and fluid, levator ani bulbocavernosus muscles, Cowper's glands and the glans penis. The weights of the liver and adrenals increased in the DES-treated animals. DES caused a dose dependent reduction in germ cells; in particular the spermatids were mainly affected. The serum levels of testosterone and luteinizing hormone were significantly reduced in the DES-treated groups, but that of estradiol decreased. No differences were observed in the serum thyroxine levels of the control and DES treated groups. In microscopic observation of the DES-treated animals, degeneration of germ cells and tubular atrophy in the testis were noted, but there were no microscopic changes in the thyroid. These results indicate that DES affected the pubertal development of juvenile male rats and that its mode of action may be related to alterations in hormone levels. PMID- 19444004 TI - Removal of acrosomal membrane from sperm head improves development of rat zygotes derived from intracytoplasmic sperm injection. AB - When intracytoplasmic sperm injection (ICSI) is applied in the rat, sperm chromatin is introduced into the oocyte together with the acrosome, which does not enter the cytoplasm of the oocyte during normal fertilization, resulting in the rat giving birth to pups. Since successful ICSI was reported in rats, but with low efficiency, it has been observed that the acrosome of the sperm head seems to have detrimental effects on the embryonic development of ICSI oocytes. To improve ICSI in rats, the effects of removal of the acrosomal membrane from rat sperm on the development of ICSI oocytes were examined. While most control (non-treated) sperm had an intact acrosomal membrane, the Triton X-100 (TX)- and lysolecithin (LL)-treated groups showed high percentages of sperm with a removed acrosomal membrane. The timing of pronuclear formation in ICSI-oocytes using TX- or LL-treated sperm was significantly accelerated compared with that of the control sperm (P<0.05). However, neither TX nor LL treatment affected amounts of PLCzeta in rat sperm. The rates of offspring derived from TX- (20.3 +/- 4.4%) and LL-treated sperm (19.0 +/- 2.8%) were also significantly higher than that of the control group (7.6 +/- 2.3%; P<0.05). Our data clearly indicate that removal of acrosomal membranes from sperm by reagents is effective for generation of offspring via ICSI in rats. PMID- 19444003 TI - Localization of the chromatin remodelling protein, ATRX in the adult testis. AB - Mutations in ATRX (alpha-thalassaemia and mental retardation on the X-chromosome) can give rise to ambiguous or female genitalia in XY males, implying a role for ATRX in testicular development. Studies on ATRX have mainly focused on its crucial role in brain development and alpha-globin regulation; however, little is known about its function in sexual differentiation and its expression in the adult testis. Here we show that the ATRX protein is present in adult human and rat testis and is expressed in the somatic cells; Sertoli, Leydig, and peritubular myoid cells, and also in germ cells; spermatogonia and early meiotic spermatocytes. The granular pattern of ATRX staining is consistent with that observed in other cell-types and suggests a role in chromatin regulation. The findings suggest that ATRX in humans may play a role in adult spermatogenesis as well as in testicular development. PMID- 19444005 TI - Dickkopf-1 expression during early bovine placentation and its down-regulation in somatic cell nuclear transfer (SCNT) pregnancies. AB - The precise role of Dickkopf-1 (Dkk-1) during early bovine trophoblast development and subsequent placentation is not fully understood. Using somatic cell nuclear transfer (SCNT) generated pregnancies as a model of poor placentation we have found that mean levels of Dkk-1 mRNA were 1.5 fold lower in SCNT fetal cotyledon tissue at Day 50 of gestation than those resulting from artificial insemination (AI) and 2 fold lower at Days 100 and 150 (P<0.004). Dkk 1 expression in cotyledon tissue was localized by in situ hybridization to fetal binucleate cells (BNCs). Examining conceptuses from blastocyst stage we show that Dkk-1 mRNA was first evident between Days 15-20 of gestation in trophoblast tissue (when BNCs first appear) prior to the initial expression of the BNC specific bovine placental lactogen (bPL) on Day 20. Dkk-1 mRNA levels were higher than bPL in trophoblast tissue throughout the pre-attachment period (Days 24-31), however, this reversed during cotyledon development with only a subset of the bPL immunoreactive BNCs also containing Dkk-1 protein, suggesting a specific role for Dkk-1 during early placentation. One function of Dkk-1 is as an antagonist of the Wnt signaling pathway and, although Wnt5A and Wnt7A mRNAs were expressed in Day 50 bovine cotyledons, their expression levels were similar between AI and SCNT. In addition, the nuclear localization of beta-catenin, which is an indicator of activation of the Wnt pathway, was also similar between AI and SCNT cotyledon tissue. Transcriptional control of Dkk-1 was not due to changes in DNA methylation levels in the promoter region as methylation levels were no different when comparing AI and SCNT tissues. The decreased expression of Dkk-1 in SCNT cotyledons that are prone to abnormal placentation suggests a role in cotyledon formation but the mechanism and regulatory control is yet to be revealed. PMID- 19444006 TI - Regulation of porcine pituitary glycoprotein hormone alpha subunit gene with LIM homeobox transcription factor Lhx3. AB - The aim of this study was to characterize the promoter activity of the porcine pituitary glycoprotein hormone common alpha gene (Cga) promoter (-1059/+12) and the role of LIM homeodomain transcription factor Lhx3. A transfection assay using Chinese hamster ovary (CHO) cells showed that the -1059/-101 region of the Cga promoter definitely responds to Lhx3 and that the -1059/-240 region exhibits a high basal transcriptional level in a pituitary-derived cell line, LbetaT2. A DNA binding and DNase I footprinting assay demonstrated that Lhx3 has seven binding sites in the -1059/+12 region of Cga, including a pituitary glycoprotein hormone basal element (PGBE) known as a LIM homeodomain factor-binding site. A transfection assay of the sequence of Lhx3-binding sites fused with minimal promoter vector confirmed their Lhx3-dependent stimulations in LbetaT2 cells. RT PCR analysis of porcine pituitary ontogeny demonstrated that porcine Lhx3 showed striking changes of expression in both sexes during the fetal period but a stable high level of expression after birth. Thus, the porcine Cga promoter is regulated by Lhx3 through seven sites in the distal and proximal regions. PMID- 19444007 TI - Successful piglet production in a chemically defined system for in-vitro production of porcine embryos: dibutyryl cyclic amp and epidermal growth factor family peptides support in-vitro maturation of oocytes in the absence of gonadotropins. AB - To induce meiotic resumption of porcine oocytes, it is thought to be necessary to expose the cumulus-oocyte complexes (COCs) to gonadotropins during in-vitro maturation (IVM). However, the detailed mechanism of meiotic resumption by gonadotropins is still unknown, and successful piglet production has not been reported by using oocytes matured in gonadotropin-free media and fertilized in vitro. The present study was undertaken to examine the combinational effects of epidermal growth factor (EGF)-family members and dibutyryl cyclic AMP (cAMP) in a chemically defined medium on IVM of porcine oocytes and the developmental competence following in vitro fertilization (IVF). The basic IVM medium was a chemically defined medium, modified porcine oocyte medium (mPOM). Supplementation of the IVM medium with 10 or 1000 ng/ml EGF, amphiregulin and betacellulin during the whole IVM period, except for 10 ng/ml amphiregulin, increased the percentage of oocytes maturing to the metaphase-II stage. When COCs were exposed to both dibutyryl cAMP and EGF-family members during the first 20-h of IVM and then culture was continued in the absence of EGF-family members and dibutyryl cAMP, the incidence of metaphase-II oocytes was significantly increased and was not different from that of oocytes cultured in a standard IVM system with gonadotropins. The developmental competence of the oocytes to the blastocyst stage following IVF was no different from that of control oocytes matured with gonadotropins. When these blastocysts were transferred into the uterine horn of three recipients, all of gilts became pregnant and delivered a total of 11 piglets. These observations indicate that supplementation of a chemically defined maturation medium with EGF-family members and dibutyryl cAMP during the first 20 h of IVM can support well the meiotic progress and developmental competence of porcine oocytes. PMID- 19444008 TI - Optimal concentration of calcium and electric field levels improve tetraploid embryo production by electrofusion in mice. AB - Polyploid embryo production is an important technique in generating mice directly from embryonic stem (ES) cells. The present study was designed to assess the effect of different calcium concentrations and electric field intensities on the production of tetraploid embryos with higher developmental potential by electrofusion. Two-cell mouse embryos were electrofused in fusion solution containing different concentrations of calcium ion (0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2 and 1.4 mM). The rates of blastomere fusion, and subsequent cleavage and development of tetraploids to the blastocyst stage were highest when two-cell embryos were electrically stimulated in a fusion medium containing 1.0 mM calcium. Therefore, we tested electric field intensities (0.6, 0.8, 1.0, 1.2 and 1.4 kV/cm) for electrofusion of two-cell embryos and subsequent development to the blastocyst stage in 1.0 mM calcium. The highest rates of fusion and blastocyst formation were observed when the electric field strength was 0.8 kV/cm. The present results showed that mouse two-cell embryos stimulated with 0.8 kV/cm in a fusion medium containing 1.0 mM calcium had the highest rates of fusion and development to the blastocyst stage. PMID- 19444010 TI - Discovery of spontaneous deformation of Pd metal during hydrogen absorption/desorption cycles. AB - A drastic deformation was observed in Pd metal of various shapes after hydrogen absorption and desorption cycles at 150 degrees C at a gas pressure of 1-5 MPa. All of the phenomena observed indicate that some strong internal force is induced spontaneously during hydrogen absorption/desorption cycles to produce a collective deformation so as to minimize the surface. PMID- 19444009 TI - Theoretical studies of structure, function and reactivity of molecules--a personal account. AB - Last few decades theoretical/computational studies of structure, function and reactivity of molecules have been contributing significantly in chemistry by explanation of experimental results, better understanding of underlying principles and prediction of the unknown experimental outcome. Accuracy needed in chemistry has long been established, but due to high power dependency of such accurate methods on the molecular size, it has been a major challenge to apply theoretical methods to large molecular systems. In the present article we will review some examples of such applications. One is theoretical study of growth/formation of carbon nanostructures such as fullerenes and carbon nanotubes, using quantum mechanical molecular dynamics method. For growth of single walled carbon nanotube from transition metal cluster, we have demonstrated continued growth of attached nanotube, cap formation and growth from small carbon fragments. For homogeneous catalysis we presented results of studies on N(2) activation by Zr complexes. For biomolecular reactions we use active site and protein models and show that in some catalyses the protein environment is involved in reactions and changes the preferred pathway, and in some other case the effect is modest. The review is concluded with a perspective. PMID- 19444013 TI - HFE-associated hereditary hemochromatosis. AB - In populations of northern European descent, the p.C282Y mutation in the HFE gene is highly prevalent, and HFE-associated hereditary hemochromatosis is the most common type of inherited iron overload disorder. Inappropriate low secretion of hepcidin, which negatively regulates iron absorption, is postulated to be the mechanism for iron overload in this condition. The characteristic biochemical abnormalities are elevated serum transferrin-iron saturation and serum ferritin. Typical clinical manifestations include cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated serum aminotransferase levels, diabetes mellitus, restrictive cardiomyopathy and arthropathy of the second and third metacarpophalangeal joints. Most patients are now diagnosed before the development of these clinical features. Molecular genetic tests are currently available for genotypic diagnosis. In selected individuals, diagnosis might require liver biopsy or quantitative phlebotomy. Iron depletion by phlebotomy is the mainstay of treatment and is highly effective in preventing the complications of iron overload if instituted before the development of cirrhosis. Genetic testing is currently not recommended for population screening because of low yield as the majority of the healthy, asymptomatic p.C282Y homozygotes do not develop clinically significant iron overload. HFE gene testing remains an excellent tool for the screening of first-degree relatives of affected probands who are p.C282Y homozygotes. PMID- 19444015 TI - Celebrate being a nurse! PMID- 19444017 TI - American Recovery and Reinvestment Act of 2009 health information technology provisions: a "HIT" or miss? PMID- 19444018 TI - Standard 37: site selection. PMID- 19444019 TI - Is Europe falling behind the United States in the field of sharps safety? PMID- 19444020 TI - Transfusion-related acute lung injury: clinical features and diagnostic dilemmas. AB - Transfusion-related acute lung injury (TRALI) is recognized as the number-one cause of transfusion-associated death in the United States. Although TRALI was not designated as the number-one cause until 2004, respiratory-related symptoms associated with blood transfusion have been reported for decades. More recently, our understanding of the pathophysiology and clinical significance of TRALI has advanced significantly, and great efforts are being implemented for patient safety. This article reviews the background, history, definitions, clinical features, and pathophysiology of TRALI. It also discusses some of the difficulties in diagnosing TRALI, compares some of the important components in the differential diagnosis, and describes some of the efforts being implemented for patient safety. PMID- 19444021 TI - Drug therapies for the treatment of multiple sclerosis. AB - The name multiple sclerosis (MS) refers to 2 features of the disease: multiple describes the number of central nervous system lesions and sclerosis refers to the demyelinated nature of the lesions. Today, these lesions are usually called plaques rather than scleroses. Multiple sclerosis is a complex inflammatory disease of the central nervous system that is variable in terms of symptoms and presentation. The objectives of this article are to review briefly the epidemiology and pathophysiology of MS and to focus on the major categories of therapies currently in use to treat MS. Research is progressing at a rapid pace. The article also discusses some of the most promising new compounds in clinical trials. PMID- 19444022 TI - The use of ultrasound to improve practice and reduce complication rates in peripherally inserted central catheter insertions: final report of investigation. AB - The risk of thrombosis related to peripherally inserted central catheters (PICCs) is a well-known complication. A study was conducted to compare thrombosis rates associated with the old technique of inserting PICCs by visualizing veins in the antecubital fossa, using anatomical landmarks and palpation versus using ultrasound guidance to locate veins in the upper arm. The findings from data collected on 538 patients included a significant decline in the thrombosis rates, as thrombosis decreased from 9.3% with the palpation method to 1.9% with the ultrasound method, and successful PICC placements by registered nurses increased from 76.9% when using the old method to 98.9% when using ultrasound guidance. PMID- 19444023 TI - Chemotherapy and biotherapy-induced hypersensitivity reactions. AB - Nearly all chemotherapy and biotherapy drugs used in cancer treatment today can cause hypersensitivity reactions. Certain groups of drugs frequently associated with these reactions include the asparaginases, taxanes, platinum compounds, epipodophyllotoxins, and the monoclonal antibodies. Recognizing and managing hypersensitivity reactions are critical when caring for patients receiving these drugs because the reactions are potentially life-threatening. A thorough understanding of the drugs is necessary to assist the nurse in prevention, early recognition, and timely management. PMID- 19444030 TI - Hypertensive emergency successfully treated with metoprolol: a case report. AB - It has been estimated that up to 27% of all medical emergencies presenting to emergency departments are due to hypertension, predominantly in the adult population. Although this often is an insidious process, acutely, a hypertensive emergency occurs when a patient presents with severe hypertension and evidence of end organ damage. We discuss the case of a 12-year-old female with spastic cerebral palsy and global developmental delay secondary to neonatal asphyxia who presented to the emergency department after having a seizure at home. On arrival to the emergency department, she was found to have a heart rate (HR) of 170 and a left upper extremity blood pressure of 174/112. Initial electrocardiogram revealed a HR of 163, with significant ST segment elevations in leads I, II, and minimal elevations in V4, 5, and 6. Intravenous Metoprolol 2.5 mg was administered 3 times with 5 minutes interval between doses, which resulted in a decline in HR (106) and blood pressure (128/86), and subsequent resolution of the electrocardiogram changes. An extensive workup revealed the patient had gallstones, however, her hypertension did not resolve with pain control and, ultimately, cholecystectomy. The remainder of her evaluation confirmed the diagnosis of poststreptococcal glomerulonephritis, and her blood pressure was, eventually, controlled with 3 medications: clonidine, isradipine, and amlodipine. Over the ensuing 2 years, these were weaned with no recurrent hypertensive episodes. Although studies have shown extended release Metoprolol to be a safe and effective treatment in children with established hypertension, to the best of our knowledge, it has not been studied in a pediatric emergency setting. PMID- 19444031 TI - Moyamoya disease in an 8-year-old boy presenting with weakness. AB - Moyamoya disease is a progressive, unilateral, or bilateral carotid artery stenosis of unknown etiology. It often presents in children as a transient ischemic attack, with a focal neurological deficit. This case describes an 8-year old boy who presented with left-sided weakness secondary to moyamoya vasculopathy. PMID- 19444032 TI - Severe hypersensitivity reactions to corticosteroids in children. AB - OBJECTIVE: To present 3 children with hypersensitivity reaction to methylprednisolone sodium-succinate and review the literature regarding such reactions. METHODS: Data on the clinical features were obtained from the children's files. Skin prick tests were performed with a panel of corticosteroid preparations. RESULTS: Three patients (5, 7, and 8 years) with asthma who were treated with intravenous methylprednisolone succinate at the emergency department developed hypersensitivity reactions initially consider to be due to their primary disease. Two had a positive skin prick test to methylprednisolone sodium succinate but not to other corticosteroids or to the succinate ester. Skin prick tests to different corticosteroids, performed 4 years after the event in the third patient, were negative. CONCLUSIONS: Methylprednisolone sodium-succinate may cause anaphylactic/anaphylactoid reactions in children. Our patients' histories emphasize the importance of awareness to corticosteroid-induced reactions, especially in children with asthma in whom the symptoms may be considered as an exacerbation of their primary illness. PMID- 19444033 TI - Death from cardiac failure in a child with ruptured cerebral arteriovenous malformation. AB - We present the case of a 13-year-old boy with a ruptured cerebral arteriovenous malformation who had rapidly progressive cardiac failure leading to death. Serial electrocardiograms, cardiac enzymes, echocardiograms, and pulmonary artery catheter data confirmed severe ventricular dysfunction related to myocardial ischemia and infarction. Cardiac dysfunction after cerebral insult is commonly described in adults with aneurysmal subarachnoid hemorrhage and has been termed "neurogenic stunned myocardium" because of its transient nature in most of patients. In children, cardiovascular dysfunction has been described in a few reports and only after traumatic brain injury. No deaths have been reported. This case report illustrates the potentially lethal consequences of cardiovascular dysfunction in children after ruptured cerebral arteriovenous malformation with subarachnoid hemorrhage. Compromised cardiac function should be considered during the early evaluation and management of these patients and supportive care instituted to limit secondary brain injury from poor perfusion. PMID- 19444034 TI - Balloon extraction of a retained rectal foreign body under fluoroscopy, case report and review. AB - Rectal foreign body impaction in infancy is extremely rare, and the literature does not describe a standard treatment procedure. Extraction by fiberoptic rectosigmoidoscope is advocated as the treatment of choice but is not free of possible complications. It should be also taken into consideration that the type of foreign body has an impact on the timing of treatment. We report a 50-day-old male presenting with a retained broken tip of a mercury thermometer in the rectum. A novel method of diagnostic approach and treatment is discussed. PMID- 19444035 TI - Neonatal Meckel's diverticulum: spectrum of presentation. AB - Symptomatic neonatal Meckel's diverticulum is rare. We describe 2 interesting presentations of neonatal Meckel's diverticulum with review of the literature. Our first patient presented with massive bleeding per rectum in the first week of life, which is the only case reported so far. The second case presented with milk curd obstruction in the Meckel's diverticulum. We could find only one similar case in the literature. PMID- 19444036 TI - Septic arthritis of the pubic symphysis in an 11-year-old boy. AB - Septic arthritis of the pubic symphysis is a rare condition but one which has typical clinical characteristics and known risk factors. It should be considered in the differential diagnosis of all children presenting with groin or hip pain that is exacerbated when walking. Clinical suspicion should prompt magnetic resonance imaging. We report such a case in an 11-year-old boy, discuss current knowledge of its epidemiology and microbiology, and outline recommended practice for investigation and treatment. PMID- 19444037 TI - Review of new and newly discovered respiratory tract viruses in children. AB - Respiratory tract viral infection continues to be among the most common reasons for emergency department visits and hospitalization of children, particularly infants younger than 1 year, in the United States. Throughout the years, clinicians have considered respiratory syncytial virus followed by influenza as the most common pathogens responsible. Over the past decade, new viruses have been discovered through both more specific testing and the finding of new agents causing infection. This includes human metapneumovirus, which leads to similar but often epidemiologically more severe clinical symptoms than respiratory syncytial virus. Other agents responsible for lower respiratory tract infection include Coronavirus (severe acute respiratory syndrome), Bocavirus, and others. This review serves to focus on some of the recent literature on these agents and the clinical impact they have on pediatric lung infection. PMID- 19444039 TI - ECGs in the ED. PMID- 19444040 TI - Jumped off the trampoline: fell on knee: pain. PMID- 19444041 TI - What's new in Shock, June 2009? PMID- 19444042 TI - Do as we say, not as you do: using simulation to investigate clinical behavior in action. PMID- 19444043 TI - Anesthesiologist management of perioperative do-not-resuscitate orders: a simulation-based experiment. AB - INTRODUCTION: This study was performed to assess perioperative reevaluation of Do Not-Resuscitate (DNR) orders by practicing anesthesiologists. METHODS: As part of an Anesthesia Crisis Resource Management course, an anesthesiologist interviewed a patient-actor with prostate cancer and bone metastases scheduled for a central venous catheter placement. The chart included a properly documented DNR order and the patient-actor's scripted responses emphasized that he would accept resuscitative efforts only "if the adverse clinical events were believed to be both temporary and reversible." Later, the subject assumed responsibility for the anesthesia in which the patient subsequently developed an iatrogenically induced pneumothorax, became apneic, and had a cardiovascular arrest requiring a prolonged resuscitation. Responses to these events and a following survey were evaluated. RESULTS: Fifty-seven percent of the subjects (17/30) addressed resuscitation during the preoperative interview; 27% (8/30) decided to suspend the DNR order and 30% (9/30) instituted a goal-directed or procedure-directed DNR order. Ninety percent (27/30) of the groups chose to continue resuscitative efforts until the simulation ended. Of the surveyed participants, over 90% would place a chest tube, intubate the trachea, do chest compressions, and perform cardiac defibrillation. Common reasons for intervening were reversibility, iatrogenicity, and that intervention would be consistent with the patient's goals. CONCLUSIONS: Inadequacies in perioperative reevaluation of DNR orders existed at all stages. Simulation of perioperative DNR orders is a useful way to elicit anesthesiologist's actions in the heat of the moment, which may bring us closer to understanding the actions of anesthesiologists during clinical practice. PMID- 19444044 TI - Simulation-based crisis team training for multidisciplinary obstetric providers. AB - BACKGROUND: The use of team training programs is promising with regards to their ability to impact knowledge, attitudes, and behavior about team skills. The purpose of this study was to evaluate a simulation-based team training program called Obstetric Crisis Team Training Program (OBCTT) (based on the original training program of Crisis Team Training) framed within a multilevel team theoretical model. We hypothesized that participation in OBCTT would positively impact 10 variables: individual's knowledge (about team process and obstetric emergency care); confidence and competence in handling obstetric emergencies; and participant attitudes (toward the utility of a rapid response team, simulation technology as a teaching methodology, the utility of team skills in the workplace, comfort in assuming team roles; and individual and team performance). Improvement of objectively measured team performance in a simulated environment was also assessed. METHODS: Twenty-two perinatal health care professionals (attending physicians, nurses, resident, and nurse midwives) volunteered to participate in this pretest-posttest study design. All participants were given an online module to study before attending a 4-hour training session. Training consisted of participation in four standardized, simulated crisis scenarios with a female birthing simulator mannequin. Team simulations were video recorded. Debriefings were conducted after each simulation by having team members review the video and discuss team behaviors and member skills. Self-report measures of perinatal and team knowledge as well as several attitude surveys were given at the beginning and again at the end of the training session. A postsimulation attitude survey was administered immediately after the first and last simulation, and a course reaction survey was administered at the end of the training program. Objective task completion scores were computed after each simulation to assess performance. RESULTS: There were significant (P<0.004) improvements in three of the outcome variables, after controlling for type I error with Bonferroni's correction; attitudes toward competence in handling obstetric emergencies (t=1.6), as well as individual (t=4.2), and team performance (t=4.1). The remaining 6 variables, attitude toward simulation technology, attitude toward the rapid response team; confidence in handling obstetric emergencies; utility of team skills in the workplace; comfort in assuming various team roles; and knowledge, were not statistically significant. Overall task completion from the first to the last simulation (XF, df=3, n=3, 8.2, P=0.042) substantially improved (P<0.05). CONCLUSION: The crisis team training model is applicable to obstetric emergencies. Trainees exhibit a positive change in attitude; perception of individual and team performance, and overall team performance in a simulated environment. The ability of individuals to accurately assess their performance improved as a result of training. PMID- 19444045 TI - Teaching residents the two-challenge rule: a simulation-based approach to improve education and patient safety. AB - INTRODUCTION: Residents train in a historically hierarchical system. They may be compelled to question their teachers if they do not understand or disagree with a clinical decision, have a patient safety concern, or when treatment plans are unclear. We sought to determine whether a debriefing intervention that emphasizes (1) joint responsibility for safety and (2) the "two-challenge rule" (a rubric for challenging others) using a conversational technique that is assertive and collaborative (advocacy-inquiry) can improve the frequency and effectiveness with which residents "speak up" to superiors. METHODS: In a simulated operating room, anesthesiology trainees were presented with opportunities to challenge coworkers (eg, orders to administer a relatively contraindicated medication). Opportunities to challenge the attending faculty anesthesiologist, attending faculty surgeon, and nurse (all confederates) were presented. When debriefed, subjects were taught the two-challenge rule and a communication technique that paired advocacy (stating trainee's observation) and inquiry (request for the other's reasoning). A second scenario offered new opportunities to challenge. Video recorded scenarios were evaluated by two investigators and trainee use of the prescribed advocacy-inquiry language was rated on a 5-point scale. RESULTS: Forty subjects participated. Overall use of the two-challenge rule and advocacy-inquiry increased after debriefing. The debriefing and instruction specifically improved the frequency and quality of challenges directed toward superordinate physicians, without improving resident challenges toward nurses. CONCLUSIONS: This instructional intervention improves "speaking up" by residents to other physicians during simulated obstetric cases. Providing increased opportunities for resident learning, sharing responsibility for patient safety, and overcoming communication barriers within the medical hierarchy may improve teamwork and patient safety. PMID- 19444046 TI - Development of a standardized curriculum for teaching cystoscopic skills using a computer-based endourologic simulator. AB - INTRODUCTION: Educational opportunities with simulation are now available to teach endoscopic skills outside the clinical setting. The goal of this study is to assess the learning curve and subjective impressions of cystoscopic tasks performed by untrained subjects on a computer-based simulator using a standardized curriculum. METHODS: We evaluated ten novice subjects on a computer based cystoscopic simulator (URO Mentor, Simbionix, Lod, Israel) during a standardized cystoscopy skills course developed for the study. All trainees performed three basic cystoscopic tasks as part of the curriculum. Subjects were evaluated until a steady state of performance was observed. Subjectively, participants assessed their performance and opinions regarding the computer-based simulator. RESULTS: Among the ten novice subjects (five men, five women), a median of six training sessions were required to achieve a steady state of performance. Significant performance improvements were noted with additional simulator time (P<0.001), however, the rate of improvement declined with time. Regression analysis of completion times revealed significant gender effects for one cystoscopic task. At study end, gender performance differences for any task were not significant. Uniformly, novices felt that URO Mentor was easy to use and provided an overall realistic training experience. CONCLUSION: In this study a computer-based simulator was successfully incorporated into a training curriculum for cystoscopy education. For simulated tasks performed with rigid and flexible cystoscopes, a median of six training sessions was necessary. Objectively, performance on the testing scenarios significantly increased with experience. Subjectively based on nonvalidated criteria, comfort level, and perceived competency increased significantly from the pre- to postcourse evaluations. PMID- 19444047 TI - Virtual reality simulation in acquiring and differentiating basic ophthalmic microsurgical skills. AB - OBJECTIVE: A virtual reality (VR) surgical simulator (EyeSi ophthalmosurgical simulator: VRMagic, Mannheim, Germany) was evaluated as a part-task training platform for differentiating and developing basic ophthalmic microsurgical skills. METHODS: Surgical novice performance (residents, interns, and nonmicrosurgical ophthalmic staff) was compared with surgical expert performance (practicing ophthalmic microsurgeons) on a basic navigational microdexterity module provided with the EyeSi simulator. RESULTS: Expert surgeons showed a greater initial facility with all microsurgical tasks. With repeated practice, novice surgeons showed sequential improvement in all performance scores, approaching but not equaling expert performance. CONCLUSION: VR simulator performance can be used as a gated, quantifiable performance goal to expert-level benchmarks. The EyeSi is a valid part-task training platform that may help develop novice surgeon dexterity to expert surgeon levels. PMID- 19444048 TI - Do metrics matter? Time versus motion tracking for performance assessment of proficiency-based laparoscopic skills training. AB - INTRODUCTION: The purpose of this study was to compare the added value of motion metrics in determining training completion during a proficiency-based simulator curriculum compared with traditional metrics (time). METHODS: Novices (n=16) practiced on a basic laparoscopic task of a hybrid simulator until expert-derived proficiency levels for time, path length, and smoothness were achieved on two consecutive attempts. The order by which proficiency in each metric was achieved was recorded and correlated to baseline characteristics. Motion metrics were considered valuable if their incorporation led to extension of training duration. RESULTS: Compared with baseline participant performance improved at training completion according to all metrics (time 67+/-17 to 20+/-6 seconds; P<0.001, pathlength 5326+/-1444 to 2339+/-545 cm; P<0.001, and smoothness from 529+/-185 to 133+/-59; P<0.001). Pathlength was the easiest metric to reach the proficiency level and time the most difficult. Four (33%) participants benefited from the motion metrics as their training was prolonged by an average of 50% compared with using time alone. Baseline characteristics did not correlate to the order of achievement of these metrics. CONCLUSIONS: Time may be superior to motion tracking metrics for performance assessment during proficiency-based simulator training. Nevertheless, in this study one third of trainees benefited from motion analysis metrics by having their training duration extended. Further study is needed to establish the value of motion metrics during simulator training and their impact on operating room performance improvement. PMID- 19444049 TI - Regional anesthesia emergencies. PMID- 19444050 TI - Three scenarios to teach difficult discussions in pediatric emergency medicine: sudden infant death, child abuse with domestic violence, and medication error. PMID- 19444051 TI - An anatomic and radiographic study of lumbar facets relevant to percutaneous transfacet fixation. AB - STUDY DESIGN: An anatomic study of lumbar facet anatomy for transfacet fixation. OBJECTIVE: Describe the ideal starting point and trajectory for percutaneous transfacet fixation. SUMMARY OF BACKGROUND DATA: Percutaneous transfacet fixation is gaining popularity for posterior stabilization after anterior lumbar interbody fusion. Despite biomechanical and clinical studies, there are no anatomic guidelines for safe placement of percuatenous transfacet screws. METHODS: Eighty L3-S1 facet joints from embalmed cadaveric spines were analyzed. Linear and angular measurements of the facets were recorded. Under direct visualization, the segments were pinned with an ipsilateral transfacet technique. The degrees of angulation in the sagittal and axial plane were recorded. The distances of the starting point relative to landmarks of the superior body were measured. Under fluoroscopy, radiographic parameters for ideal visualization of the pin and pin ending points were determined. RESULTS: Inferior and superior facet heights ranged from 15.7 to 17.5 mm at all levels. The percentage of inferior facet extending below the L3 and L4 end plates was 84% and 86% respectively and decreased at L5 to 72%. The percentage of superior facet extending above the end plate ranged from 36% to 44% at all levels. The transverse facet angle progressively increased from L3 to S1. The L2-L3 segments could not be instrumented from the ipsilateral side due to the vertical facet orientation. For L3-S1 segments, the starting point in the coronal plane is based on the superior body of the instrumented segment and should be in line with the medial border of the pedicle in the medial-lateral direction and in line with the inferior end plate in the cranial-caudal direction. The screw should be laterally angulated approximately 15 degrees in the axial plane approximately 30 degrees caudally in the sagittal plane. The screw should end in the inferolateral quadrant of the pedicle on the AP radiograph and at the pedicle-vertebral body junction on the lateral radiograph. 35 degrees of axial rotation is the optimal fluoroscopic view for confirming screw placement. CONCLUSION: Ipsilateral transfacet fixation can be successfully performed in the L3-S1 segments by using the inferior end plate and medial pedicle wall of the superiorly instrumented level as anatomic landmarks in conjunction with axial and sagittal angles of insertion. PMID- 19444052 TI - Recording diffusion responses from contralateral intercostal muscles after stimulus-triggered electromyography: refining a tool for the assessment of thoracic pedicle screw placement in an experimental porcine model. AB - STUDY DESIGN: A new stimulus-triggered electromyography (EMG) test for detecting stimulus diffusion to contralateral intercostal muscles during thoracic pedicle screw placement was assessed in a porcine model. OBJECTIVE: To determine if electromyographic thresholds in the intercostal muscles of both sides of the thorax could discriminate thoracic pedicle screw malpositions with and without neural contact at different aspects of the spinal cord and nerve roots. SUMMARY OF BACKGROUND DATA: There is controversy about the value of triggered EMG stimulation for aiding precise insertion of thoracic pedicle screws. A universally validated threshold that confirms screw malposition has not been established. Diffusion of EMG responses to the contralateral intercostal muscles has not previously been investigated. METHODS: Nine domestic pigs weighing 60 to 75 kg had 108 pedicle screws placed bilaterally in the thoracic spine from T8 T13. Before spine instrumentation, neural structures were stimulated in 4 animals under direct vision at different anatomic locations from T9-T12. Recording electrodes were placed over the right and left intercostal muscles. Increasing stimulus intensity was applied until muscle response was detected at the contralateral side (EMG diffusion phenomenon). After this first experiment, the thoracic spine was instrumented in all 9 animals. Screws were placed in the pedicle in different positions, the anatomic intrapedicular location and within the spinal canal, with and without contact with the neural elements. RESULTS: Response thresholds to direct nerve root stimulation were significantly lower than those obtained by stimulation of the dorsal aspect of the spinal cord (0.44 +/- 0.22 mA vs. 1.38 +/- 0.71 mA, P < 0.01). However, a 14-fold stimulation intensity (6.50 +/- 0.29 mA) was necessary to obtain diffusion of the EMG response to the opposite (left) side if the right nerve root was stimulated. A 2 fold increment (3.17 +/- 0.93 mA) elicited diffusion of the EMG responses to the contralateral side when stimulation was applied to the dorsal aspect of the spinal cord. EMG recordings of the 108 stimulated screws showed a significant decrease in the EMG response when the screw was in contact with the spinal cord (2.72 +/- 1.48 mA; P < 0.01) compared with that found when the pedicle track was intact (mean: 5.01 +/- 1.89 mA). Screws violating the medial wall of the pedicle, but not touching neural tissues, responded to slightly lower intensities than well-positioned screws, but this was not statistically significant (3.91 +/- 1.39 mA vs. 4.89 +/- 1.30 mA, P > 0.05). CONCLUSION: Stimulus-triggered EMG can identify screws that violate the medial pedicle wall if they are in contact with neural tissues. EMG thresholds could not discriminate screws that violated the medial pedicle wall without neural contact from screws with accurate intraosseous placement. However, recording EMG potentials at the contralateral intercostal muscles (stimulus diffusion phenomenon) proved to be a reliable method for identifying the neural structures at risk. PMID- 19444053 TI - A porcine model for progressive thoracic scoliosis. AB - STUDY DESIGN: An IACUC-approved study to create a scoliotic deformity representative of adolescent idiopathic scoliosis. OBJECTIVE: The goal of this study was to develop a reliable porcine scoliosis model and to evaluate the three dimensional progression of the deformity. SUMMARY OF BACKGROUND DATA: Optimal development of nonfusion techniques for treatment of adolescent idiopathic scoliosis requires a reliable large animal model that achieves a progressive three-dimensional (frontal, sagittal, axial) deformity. Limitations in previous work have led our team to the development of a porcine model. METHODS: This IACUC approved study included 18 Yorkshire pigs, obtained at 11 weeks old. Scoliosis was induced through unilateral posterior ligament tethering of the spine via pedicle screw fixation, and ipsilateral ribcage tethering. Progressive deformity was documented with biweekly radiographs. Frontal, sagittal, and axial modifications were assessed using the Cobb method. Animals were observed until severe deformity (>50 degrees) developed, then killed. RESULTS: Animals were observed for a mean 11 weeks. The mean coronal Cobb angle was 25 degrees immediately postoperatively and 55 degrees at 11 weeks. The mean lordosis increased from 4 degrees postoperative to 24 degrees at final follow-up. Apical axial rotation (posterior elements into concavity) increased from 4% postoperative to 27% at 11 weeks. Rate of coronal curve progression was significantly correlated with the initial Cobb index. CONCLUSION: This study establishes a porcine scoliosis model. With placement of a unilateral ligamentous spinal tether combined with concave ribcage ligament tethering a three dimensional (frontal, sagittal, and axial) spinal deformity can be obtained. The speed of the progressive deformity leaves significant remaining skeletal growth to assess growth modulating therapies for correction. This work forms the basis for a number of investigative efforts at developing new fusionless therapies for patients suffering from adolescent scoliosis. PMID- 19444054 TI - Safety of chiropractic interventions: a systematic review. AB - STUDY DESIGN: Systematic review of reported adverse events. OBJECTIVE: To evaluate the tolerability and safety of chiropractic procedures. SUMMARY OF BACKGROUND DATA: Despite the increasing popularity of chiropractic, there are few properly designed prospective controlled trials, and there is a disproportionate lack of evaluation of its safety profile. The literature reports multiple neurologic complications of spinal manipulation, some of which are clinically relevant and even life threatening. METHODS: We performed an electronic search in 2 databases: Pubmed and the Cochrane Library for the years 1966 to 2007. All articles that reported adverse reactions associated with chiropractic were included irrespective of type of design. The outcome measures were the type of adverse events associated or attributed to chiropractic interventions and their frequency. RESULTS: A total of 376 potential relevant articles were identified, 330 of which were discarded after abstract or complete article analysis. The search identified 46 articles that included data concerning adverse events: 1 randomized controlled trial, 2 case-control studies, 7 prospective studies, 12 surveys, 3 retrospective studies, and 115 case reports. Most of the adverse events reported were benign and transitory, however, there are reports of complications that were life threatening, such as arterial dissection, myelopathy, vertebral disc extrusion, and epidural hematoma. The frequency of adverse events varied between 33% and 60.9%, and the frequency of serious adverse events varied between 5 strokes/100,000 manipulations to 1.46 serious adverse events/10,000,000 manipulations and 2.68 deaths/10,000,000 manipulations. CONCLUSION: There is no robust data concerning the incidence or prevalence of adverse reactions after chiropractic. Further investigations are urgently needed to assess definite conclusions regarding this issue. PMID- 19444055 TI - Synovial chondromatosis presenting with lumbar radiculopathy. AB - STUDY DESIGN: A case report of lumbar synovial chondromatosis with radiculopathy. OBJECTIVE: To report a case of synovial chondromatosis of a lumbar facet joint that extended into the spinal canal and compromised the lumbar nerve root and raised spinal surgeons' awareness of the possibility of this unusual clinical problem. SUMMARY OF BACKGROUND DATA: Synovial chondromatosis is an uncommon disorder characterized by the formation of multiple cartilaginous nodules in the synovium of a facet joint. It most commonly affects large joints. Synovial chondromatosis in the spine is rare and there is no previous report of associated lumbar radiculopathy. METHODS: A 24-year-old woman presented with low back pain and right sciatica lasting 5 months. There was no objective weakness. Computed tomography scans showed multiple calcified nodules anterior and medial to the right apophyseal joint of L5-S1 and extending into the spinal canal. Magnetic resonance imaging showed a lobulated, heterogeneous enhancing extradural mass arising from the anteromedial aspect of the right L5-S1 facet joint. The lesion was removed in multiple pieces with curette after exposure of the corresponding intervertebral space through a conventional interlaminar approach. The histologic examination showed nodules of hyaline cartilage beneath the synovial cell lining. RESULTS: The patient was completely free of low back pain and right sciatica 5 days after the surgery. All neurologic tests were normal from that point onwards. CONCLUSION: Synovial chondromatosis may compromise lumbar nerve roots when it extends into the spinal canal from the facet joint. Although synovial chondromatosis of the lumbar spine is rare, it should be included in the differential diagnosis of radiculopathy. PMID- 19444056 TI - Transoral osteosynthesis C1 as a function-preserving option in the treatment of bipartite atlas deformity: a case report. AB - STUDY DESIGN: A case report about transoral osteosynthesis C1 as a function preserving option in the treatment of bipartite atlas deformity. OBJECTIVE: To illustrate a new method, which preserves the function of the C1-C2 joint in young patients. SUMMARY OF BACKGROUND DATA: To the authors' knowledge, bipartite atlas deformity are usually treated conservatively by immobilization or traction or surgically by posterior fusion C1-C2. METHODS: A 20-year-old man, who complained about occipitocervical pain and cervical activities limitation, and presented with a 3-month history of weakness and numbness of all 4 limbs after sustaining a minor head trauma. Computed tomography scan showed anterior arch midline defect, posterior arch midline aplasia. Steel plate fixation by transoral approach was performed to repair bipartite atlas deformity. RESULTS: In 1-month follow-up, occipitocervical pain disappeared. The patient had significant improvement over next 3 months. In 6-month follow-up, we observed bony union of anterior arch of atlas without abnormal manifestations. The postoperative rotation in the atlantoaxial joint was returned to normal. The patient had no symptoms of postoperative instability of C1-C2. CONCLUSION: We described a rare association of an anterior arch midline defect, posterior arch midline aplasia. The natural history of patients with bipartite atlas deformity suggests that these people have a potentially precarious existence. Transoral osteosynthesis of the anterior ring and the lateral masses of C1 is a new technique that allows maintenance of rotatory mobility in the C1-C2 joint and restoration of congruency in the atlanto occipital and atlantoaxial joints. PMID- 19444058 TI - A prospective randomized study of clinical outcomes in patients with cervical compressive myelopathy treated with open-door or French-door laminoplasty. AB - STUDY DESIGN: A prospective randomized clinical study. OBJECTIVE: To compare the clinical outcomes of open-door and French-door laminoplasties. SUMMARY OF BACKGROUND DATA: Expansive laminoplasty for cervical compressive myelopathy is well established and a variety of modifications procedures have been developed. The procedures are mainly classified into open-door and French-door. It has never been prospectively investigated as to which surgical procedure, open-door or French-door laminoplasty, results in a more favorable outcome. METHODS: After informed consent was obtained from 40 patients, they were randomized into 2 surgical groups A and B. Patients in group A had open-door laminoplasty, and patients in group B underwent French-door laminoplasty with reattachment of the spinous process and extensor musculatures. The following criteria were evaluated: operation time, blood loss, perioperative complications, Japanese Orthopedic Association (JOA) scores, recovery rates, axial pain, and short-form 36 (SF-36). For radiographic evaluation, cervical lordosis was reviewed as lordotic angles, which were measured at C2-C7. RESULTS: Although the operation time was significantly less in group A as compared with group B, the mean blood loss in group A was significantly more than group B. Perioperative complications occurred more frequently in group A than in group B. Although there were no significant differences in postoperative JOA scores and recovery rates between the 2 groups, axial pain was significantly decreased in group B at final follow-up. The scores of every subscale of the SF-36 were higher in group B than group A. CONCLUSION: Perioperative complications occurred more frequently in open-door laminoplasty than in French-door laminoplasty. JOA scores and recovery rates suggested that both open-door and French-door laminoplasties could be similarly effective in decompressing the spinal cord. Axial pain was improved in French-door laminoplasty but became worse in open-door laminoplasty. SF-36 suggested that French-door laminoplasty could be more beneficial than open-door laminoplasty for patients with cervical compressive myelopathy. PMID- 19444059 TI - The time course of range of motion loss after cervical laminoplasty: a prospective study with minimum two-year follow-up. AB - STUDY DESIGN: A prospective study. OBJECTIVE: To identify the time-dependent change in range of motion (ROM) after cervical laminoplasty. SUMMARY OF BACKGROUND DATA: Although numerous studies have reported on the loss of flexion/extension ROM associated with laminoplasty, few have reported on the time course of this loss of motion. METHODS: Twenty-three patients who received unilateral open-door laminoplasties, including miniplate fixation over 2 levels, were serially evaluated at regular set intervals after surgery. The mean follow up period was 26.78 months (range: 24-41 months). Twelve patients had OPLL and 11 patients had cervical spondylotic myelopathy. Enrolled patients were divided into 2 groups (ossification of posterior longitudinal ligament [OPLL] and cervical spondylotic myelopathy) to compare the ROM between the OPLL and the spondylosis patients. We evaluated the time-dependent neck ROM changes by taking neutral, flexion, and extension radiographs before surgery and at 1, 3, 6, 9, 12, 18, and 24 months after surgery. Postoperative neck and arm pain was evaluated using a numerical rating scale. RESULTS: The preoperative, and 1-, 3-, 6-, 9-, 12-, 18-, and 24-month postoperative ROM figures were 37.8 degrees +/- 14.6 degrees, 34.1 degrees +/- 12.9 degrees, 35.0 degrees +/- 12.3 degrees, 30.3 degrees +/- 13.0 degrees, 28.6 degrees +/- 15.1 degrees, 27.3 degrees +/- 12.4 degrees, 26.1 degrees +/- 14.8 degrees, and 25.9 degrees +/- 13.2 degrees, respectively, and at the most recent follow-up, ROM was 25.8 +/- 15.2 degrees. Thus, the mean ROM decreased by 10.1 degrees +/- 9.5 degrees (31.66%) after surgery (P = 0.002). In OPLL group, we observed a more limited cervical ROM than in cervical spondylotic myelopathy group (35.3% vs. 29.2%). However, the rate of ROM reduction slowed with time in both groups (P = 0.000). Postoperative axial pain did not correlate with the degree of serial cervical ROM. CONCLUSION: The results suggest that the loss of cervical ROM is time-dependent and plateaus by 18 months after surgery, with no further decreases thereafter. PMID- 19444060 TI - Three-dimensional finite element model of the cervical spinal cord: preliminary results of injury mechanism analysis. AB - STUDY DESIGN: A three-dimensional finite element investigation. OBJECTIVES: To create a three-dimensional finite element model of the cervical spinal cord enlargement and to simulate a hyperextension injury of the cervical cord. SUMMARY OF BACKGROUND DATA: Experimental studies are difficult to simulate the complex mechanism of spinal cord injuries. The introduction of three-dimensional modeling technique into neurotrauma studies is essential to further understand mechanical behavior of the nerve tissue during traumatic injuries. METHODS: Geometrical reconstruction of cervical spinal cord enlargement was developed based on the morphologic features of each segment of the fresh human cervical cord. After the validation of the model, the pinching condition in the hyperextension injuries was simulated with compressive and extension forces applied on the cervical enlargement model. The average von Mises stress of the 9 anatomic regions, such as anterior funiculus, lateral part of the lateral funiculus, medial part of the lateral funiculus, lateral part of the posterior funiculus, medial part of the posterior funiculus, anterior horn, the bottom of anterior horn, the apex of posterior horn, the cervix cornu posterioris, and caput cornu posterioris was recorded. RESULTS: The force-displacement response of the spinal cord under compression and axial tension loading was close to the experimental results reported in the literature. The stress distribution of the spinal cord according to the numerical simulation and the morphologic features of the in vivo experiment were also in close agreement. Hyperextension injury simulation showed high localized stress at the anterior and posterior horn in the gray matter. CONCLUSION: The finite element method as a three-dimensional modeling technique can improve the understanding of the biomechanical behavior of the spinal cord. The results of hyperextension injury simulation of the cervical spinal cord probably account for the predominance of the hand weakness in patients with central cord injury. PMID- 19444061 TI - Does ossification of the posterior longitudinal ligament affect the neurological outcome after traumatic cervical cord injury? AB - STUDY DESIGN: Retrospective outcome measurement study. OBJECTIVES: The purpose of this study is to assess whether ossification of the posterior longitudinal ligament (OPLL) affects neurologic outcomes in patients with acute cervical spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: There have so far been few reports examining the relationship between OPLL and SCI and there is controversy regarding the deteriorating effects of OPLL-induced canal stenosis on neurologic outcomes. METHODS: To obtain a relatively uniform background, patients nonsurgically treated for an acute C3-C4 level SCI without any fractures or dislocations of the spinal column were selected, resulting in 129 patients. There were 110 men and 19 women (mean age was 61.1 years), having various neurologic conditions on admission (American Spinal Injury Association [ASIA] impairment scale A, 43; B, 16; C, 58; D, 12). The follow-up period was the duration of their hospital stay and ranged from 50 to 603 days (mean, 233 days). The presence of OPLL, the cause of injury, the degree of canal stenosis (both static and dynamic), and the neurologic outcomes in motor function, including improvement rate, were assessed. RESULTS: Of the 129 patients investigated in this study, OPLL was identified at the site of the injury in 13 patients (10.1%). In this OPLL+ group, the static and dynamic canal diameters at C3 and C4 were significantly smaller than those of the remaining 116 patients (OPLL- group). However, no significant difference was observed between the 2 groups in terms of ASIA motor score both at the time of administration and discharge, and the mean improvement rate in ASIA motor score was 55.5 +/- 9.0% in OPLL+ group, while it was 43.1 +/- 2.8% in the OPLL-group. Furthermore, no significant correlation was observed between the static/dynamic canal diameters and neurologic outcome in all 129 patients. CONCLUSION: No evidence was found for OPLL to have any effect on the initial neurologic status or recovery in motor function after traumatic cervical cord injury, suggesting that the neurologic outcome is not significantly dependent on canal space. PMID- 19444062 TI - Artificial disc replacement combined with fusion versus two-level fusion in cervical two-level disc disease. AB - STUDY DESIGN: A prospective analysis. OBJECTIVE: The purpose of this study was to compare the clinical and radiologic outcomes of cervical artificial disc replacement (C-ADR) combined with anterior cervical discectomy and fusion (ACDF) and 2-level ACDF in patients with 2-level cervical disc disease. SUMMARY OF BACKGROUND DATA: Adjacent segment degeneration is a long-term complication of ACDF, and estimated to affect 25% of patients within 10 years of the initial surgery. Two-level fusion leads to a substantially greater increase in intradiscal pressure than one-level fusion. It has been demonstrated that C-ADR maintains motion at the level of the surgical procedure and decreases strain on the adjacent segments for prevention of adjacent segment degeneration. In the case of 2-level cervical disc disease, hybrid surgery (HS), consisting of C-ADR combined with ACDF, may be a reasonable alternative to 2-level ACDF (2-ACDF). METHODS: Between 2004 and 2006, 40 patients undergoing 2-level cervical disc surgery at our hospital were identified who met the following surgical indications: 2 consecutive level degenerative disc disease between C3/4 and C6/7; either a radiculopathy or myelopathy; and no response to conservative treatment for >6 weeks. Twenty patients of the HS group were matched to 20 patients of the 2-ACDF group based on age and gender. Patients were asked to check the neck disability index (NDI) and grade their pain intensity before surgery and at routine postoperative intervals of 1, 3, 6, 12, and 24 months. Dynamic flexion and extension lateral cervical radiographs were obtained in the standing position before surgery and at routine postoperative intervals of 1, 3, 6, 12, and 24 months. The angular range of motion (ROM) for C2-C7 and adjacent segments were measured using the Cobb method with PACS software. RESULTS: The HS group had better NDI recovery 1 and 2 years after surgery (P < 0.05). Postoperative neck pain was less in the HS group 1 month and 1 year after surgery (P < 0.05). There was no difference in arm pain relief between the groups. The HS group showed faster C2-C7 ROM recovery. The mean C2-C7 ROM of the HS group recovered to that of the preoperative value, but that of the 2-ACDF group did not (P < 0.05). The inferior adjacent segment ROM showed significant differences between the groups 6 and 9 months, and 1 and 2 years after surgery (P < 0.05, P < 0.01, P < 0.05, and P < 0.05, respectively). CONCLUSION: HS is superior to 2-ACDF in terms of better NDI recovery, less postoperative neck pain, faster C2-C7 ROM recovery, and less adjacent ROM increase. PMID- 19444064 TI - Comparison of selective anterior versus posterior screw instrumentation in Lenke5C adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective review of anterior and posterior fusions for treatment of Lenke5C adolescent idiopathic scoliosis (AIS). OBJECTIVE: To compare the clinical and radiographic results of anterior versus posterior pedicle screw instrumentation in Lenke5C AIS. SUMMARY OF BACKGROUND DATA: Anterior and posterior pedicle screw instrumentations are 2 established methods of correcting Lenke5C AIS. However, there are few reports that compare the 2 methods. METHODS: Forty-six consecutive patients with Lenke5C AIS curves underwent selective lumbar or thoracolumbar fusion (1999-2005). Twenty-two patients had anterior surgery, and 24 patients had posterior surgery. Patients were evaluated at a minimum 2 year follow-up. RESULTS: No complications occurred in either group. The number of levels involved in the major curve was similar for the anterior and posterior groups (5.5 vs. 5.7). Preoperative thoracic (24.13 degrees +/- 4.9 degrees vs. 22.88 degrees +/- 5.14 degrees) and lumbar/thoracolumbar (50.2 degrees +/- 7.52 degrees vs. 52.2 degrees +/- 6.40 degrees). Cobb values for the 2 groups were also similar. The percent correction of the lumbar curve was similar between the 2 groups at all stages of follow-up (56% vs. 57.7%), as was the percent of spontaneous correction of the unfused thoracic curve (25% vs. 27.2%). However, fusion levels were significantly shorter in the anterior group (mean, 5.09 vs. 6.13), and there were 8 patients (4 in the anterior group and 4 in the posterior group) whose thoracic curve became greater at the latest follow-up. The thoracolumbar/lumbar-thoracic Cobb ratio for these 8 patients was less than that for the other patients (1.34 vs. 2.43), and their curve flexibility was worse. CONCLUSION: Selective anterior and posterior screw instrumentation both achieved good surgical lumbar and subsequent spontaneous thoracic correction. There was no statistically significant difference between the 2 groups in lumbar correction or thoracic correction, but fusion levels were shorter in the anterior group. Patients with late thoracic curve decompensation had smaller thoracolumbar/lumbar thoracic Cobb ratios and less preoperative flexibility than those who did not decompensate. PMID- 19444065 TI - Surgical correction and fusion using posterior-only pedicle screw construct for neuropathic scoliosis in patients with cerebral palsy: a three-year follow-up study. AB - STUDY DESIGN: It is a retrospective study of 52 neuromuscular scoliosis patients with cerebral palsy (CP). OBJECTIVE: To determine the effectiveness and amount of correction using posterior-only pedicle screw construct. SUMMARY OF BACKGROUND DATA: Although there have been many reports in literature supporting the use of pedicle screw-only constructs for the correction of adolescent idiopathic scoliosis, similar studies have not been reported in patients with CP. METHODS: We retrospectively evaluated outcomes of 52 neuropathic scoliosis patients (28 males and 24 females) with CP over minimum 2 years of follow-up. All patients underwent pedicle screw fixation without any anterior procedure for the correction. Pelvic fixation was done in 10 patients who had pelvis obliquity more than 15 degrees . All coronal and sagittal parameters were noted after surgery and at final follow-up. Patient's functional outcome was measured using modified Rancho Los Amigos Hospital system criteria. Complications were recorded from record sheets and any change in the ambulatory status was also recorded. RESULTS: Mean age was 22 years at the time of operation and average follow-up was 36.1 month. Cobb's angle was improved to 62.9% (P < 0.0001) from 76.8 degrees to 30.1 degrees after surgery and 31.5 degrees at final follow-up. This correction of scoliosis (41% approximately 92%) was found to be statistically significant (P < 0.0001). Overall correction in pelvic obliquity was 56.2% from 9.2 degrees before surgery to 4.0 degrees after surgery which was 43.1% at final follow-up to 5.2 degrees. Twenty-one patients (42%) improved their functional ability by grade 1 with 2 patients by grade 2. After the operation parent or caretakers of patients exhibited better sitting balance and nursing care. There were 32% complications in the series major being pulmonary. There were 2 perioperative deaths and 1 patient developed neurologic deficit due to screw impingement in canal, which was resolved after removal. CONCLUSION: We reported satisfactory coronal and sagittal correction with posterior-only pedicle screw fixation without higher complication rate in CP patients. Further long-term study is recommended to evaluate the success of pedicle screw in this population. PMID- 19444066 TI - Radiographic outcomes over time after endoscopic anterior scoliosis correction: a prospective series of 106 patients. AB - STUDY DESIGN: A prospective, consecutive series of 106 patients receiving endoscopic anterior scoliosis correction. OBJECTIVE: To analyze changes in radiographic parameters and rib hump in the 2 years after surgery. SUMMARY OF BACKGROUND DATA: Endoscopic anterior scoliosis correction is a level sparing approach and therefore, it is important to assess the amount of decompensation which occurs after surgery. METHODS: All patients received a single anterior rod and vertebral body screws using a standard compression technique. Cleared disc spaces were packed with either mulched femoral head allograft or rib head/iliac crest autograft. Radiographic parameters (major, instrumented, minor Cobb, T5-T12 kyphosis) and rib hump were measured at 2, 6, 12, and 24 months after surgery. Paired t tests and Wilcoxon signed ranks tests were used to assess the statistical significant of changes between adjacent time intervals. RESULTS: Mean loss of major curve correction from 2 to 24 months after surgery was 4 degrees. Mean loss of rib hump correction was 1.4 degrees. Mean sagittal kyphosis increased from 27 degrees at 2 months to 30.6 degrees at 24 months. Rod fractures and screw-related complications resulted in several degrees less correction than patients without complications, but overall there was no clinically significant decompensation after complications. CONCLUSION: There are small changes in deformity measures after endoscopic anterior scoliosis surgery, which are statistically significant but not clinically significant. PMID- 19444067 TI - Musculoskeletal pain combinations in adolescents. AB - STUDY DESIGN: A 2-year follow-up in a birth cohort of adolescents aged 15 to 19 years. OBJECTIVE: To evaluate the prevalence of neck, shoulder, low back, peripheral (limb) pain, and combinations of pain at these anatomic locations. SUMMARY OF BACKGROUND DATA: Few previous studies have evaluated combinations of musculoskeletal pain among adolescents. METHODS: Prevalence of neck, shoulder, low back, and peripheral pain (elbow, wrist, knee, and ankle-foot pain) during the previous 6 months were obtained by questionnaire in a follow-up study of the Northern Finland Birth Cohort 1986 at 16 and 18 years of age (n = 1773). Latent class analysis was used in clustering of pain combinations at both time points. RESULTS: No pain at all in the past 6 months at 16 and 18 years was reported by 17% and 8% of girls, and 33% and 24% of boys, respectively. Only 1 pain location (neck, shoulder, low back, or peripheral pain) was reported by 21% of girls and 25% of boys at 16, and 11% of girls and 20% of boys at 18 years, while all 4 pain locations were reported by 15% of girls and 9% of boys at 16, and 27% and 15%, respectively, at 18 years. Latent class analysis resulted in 2 to 3 pain clusters in both genders at both time points. Probability of pain increased during the 2 year follow-up, with subjects more likely to belong to a cluster with a higher likelihood of pain. CONCLUSION: As very few adolescents did not report any pain, the relevance of self-reported pain is questionable without assessment of pain related disability. The clinical relevance of these pain combinations must be evaluated in further studies. PMID- 19444068 TI - Predictive factors for the outcome of fusion in adult isthmic spondylolisthesis. AB - STUDY DESIGN: A prospective study on predictive factors for the outcome of 164 patients with adult isthmic spondylolisthesis operated on with fusion. OBJECTIVE: In view of the need to better select patients for fusion, we investigated the use of the pain drawing (PD) and other potential factors for predicting the outcome of fusion. SUMMARY OF BACKGROUND DATA: Results on predictive factors of outcome after spinal fusion have been contradictory and large, well-defined, patient samples with adequate observation times are lacking. METHODS: Questionnaires including possible predictive factors and PDs were obtained before surgery. Degree and level of slip were documented. Outcome was quantified by measurement of pain (VAS), Disability Rating Index, the Oswestry Disability Index, and global assessment by the patient into "much better," "better," "unchanged," or "worse." The 2-year follow-up rate was 160 of 164 (98%). RESULTS: In the total sample 49% of patients were much better, 25% better, 14% unchanged, and 12% worse. The following preoperative factors correlated to a worse outcome in the univariate analysis: not working, no regular exercise, female gender, shortness in stature, and a nonorganic PD. The multivariate regression analysis showed that work status was the main determinant of outcome. Gender and exercise had less but significant impact (P = 0.004 and 0.02, respectively). In the multivariate regression analysis the PD was not a significant predictor (P = 0.06). CONCLUSION: The present study shows that patients working before surgery have a more favorable outcome. Also male gender and regular exercise are indicators of a better outcome after fusion. Female patients not working, not exercising or, if these factors are not known, with nonorganic PDs, should be informed about their suboptimal chances of an excellent outcome after fusion. PMID- 19444069 TI - Validation of the simplified Chinese version of the Oswestry Disability Index. AB - STUDY DESIGN: Translation, cross-cultural adaptation, and validation were performed on the Chinese version of the Oswestry Disability Index (ODI). OBJECTIVE: The objective of this study was to translate and adapt the ODI into simplified Chinese and to then validate its use in Chinese patients with low back pain. SUMMARY OF BACKGROUND DATA: A traditional Chinese version of the ODI (TCODI) has been developed and used in Hong Kong. However, there is no simplified Chinese version of the ODI (SCODI). METHODS: Translation and cross-cultural adaptation of the latest version of the ODI (2.1a) were performed following instructions from the published international guidelines. The translation procedure included forward translation, back translation, and a discussion among experts. The prefinal version was tested in 40 outpatients with LBP. Then, 179 patients with LBP, including 140 outpatients and 39 inpatients, participated in the final test. They finished the SCODI, the Short-Form 36, and the Visual Analog Scale. Those 39 inpatients also finished a second ODI questionnaire within 24 hours. Last, the SCODI and TCODI were tested in another 25 inpatients for comparison. RESULTS: All of the patients in the prefinal test understood the simplified Chinese version correctly. In the final test, Cronbach's alpha for internal consistency was 0.93. A very high intraclass correlation coefficient was observed (ICC = 0.99) in the test-retest group. The SCODI showed a significant correlation with the 8 subscales of the Short-Form 36, especially in physical functioning (r = 0.78, P < 0.001). There was a moderate correlation between the ODI scores and the Visual Analog Scale (r = 0.69, P < 0.001). A significant difference in the mean score was demonstrated between the SCODI and the TCODI. Patients who participated in the comparison test all agreed that the SCODI was easier to understand than the TCODI. CONCLUSION: The results showed that the translation and adaptation were successful. The SCODI has proven to be valid and reliable when used in the simplified Chinese speaking population. PMID- 19444071 TI - Percutaneous treatment of vertebral compression fractures: a meta-analysis of complications. AB - STUDY DESIGN AND OBJECTIVE: This study performs a meta-analysis to compare complication rates from vertebroplasty (VP) and kyphoplasty (KP). SUMMARY OF BACKGROUND DATA: Recently, the development of VP and balloon KP has been shown to provide symptomatic relief and restoration of sagittal alignment of vertebral compression fractures refractory to medical therapy. Complications in treatment of vertebral compression fractures are rare, however can be potentially devastating. Fortunately, clinical sequelae are rare; however, severe clinical complications from cement extravasation have been reported. METHODS: Using PubMed and Ovid, we performed a literature search for "kyphoplasty," "vertebroplasty," and "vertebral augmentation." This search was performed in December 2006. Case reports and reports not available in English were excluded. We categorized complications in 3 categories: (1) procedure-related complications, (2) medical complications, and (3) new vertebral fracture. Cement leakage, asymptomatic and symptomatic, and its locations were recorded. We performed a meta-analysis of complications of all studies. We then repeated the meta-analysis examining only prospective studies. We then used proportion analysis to determine statistical significance. We defined statistical significance as a P value less than 0.05. RESULTS: We identified 121 reports of KP and/or VP that specifically addressed complications. Of these studies, 33 addressed KP and 82 addressed VP (6 reports addressed complications of both). There were 29 reports in which the data appeared to be collected prospectively. Of these, 9 addressed KP and 21 addressed VP.VP was found to have a significantly increased rate of procedure-related complications than KP in the analysis of all studies and only prospective studies. VP also appears to have a significantly higher rate of symptomatic and asymptomatic cement leakage than KP (P < 0.05). The incidence of medical complications was significantly higher in the KP procedure; however, this difference was not observed when analyzing only prospective studies. The incidence of new fracture was significantly higher in the VP procedure; however, this was not observed when analyzing only prospective studies. CONCLUSION: VP and KP are 2 minimally invasive procedures that have been shown to be effective in the treatment of symptomatic vertebral compression fractures. Although the incidence of adverse events for both VP and KP are low, it appears that VP is associated with a statistically significant increased rate of procedure-related complications and cement extravasation (symptomatic and asymptomatic). Future prospective studies with large patient enrollment will be needed to further validate the finding of this meta-analysis. PMID- 19444072 TI - Differences in balance strategies between nonspecific chronic low back pain patients and healthy control subjects during unstable sitting. AB - STUDY DESIGN: A 2-group experimental design. OBJECTIVE: To investigate differences in postural control strategies of pelvis and trunk movement between nonspecific chronic low back pain (CLBP) patients and healthy control subjects using 3-dimensional motion analysis. SUMMARY OF BACKGROUND DATA: Increased postural sway assessed by center of pressure displacements have been documented in patients with low back pain (LBP). The 3-dimensional movement strategies used by patients with LBP to keep their balance are not well documented. METHODS: Nineteen CLBP patients and 20 control subjects were included based on detailed clinical criteria. Every subject was submitted to a postural control test in an unstable sitting position. A 3-dimensional motion analysis system, equipped with 7 infrared M1 cameras, was used to track 9 markers attached to the pelvis and trunk to estimate their angular displacement in the 3 cardinal planes. RESULTS: The total angular deviation in all 3 directions of pelvis and trunk was higher in the CLBP group compared with the control group. In 4 of the 6 calculated differences, a significant higher deviation was found in the CLBP group (significant P-values between 0.013 and 0.047). Subjects of both groups mostly used rotation compared with lateral flexion and flexion/extension displacements of pelvis and trunk to adjust balance disturbance. The CLBP group showed a high correlation (Pearson: 0.912-0.981) between movement of pelvis and trunk, compared with the control group. CONCLUSION: A higher postural sway and high correlation between pelvis and trunk displacements was found in the LBP group compared with healthy controls. PMID- 19444073 TI - Nerve injury to the posterior rami medial branch during the insertion of pedicle screws: comparison of mini-open versus percutaneous pedicle screw insertion techniques. AB - STUDY DESIGN: The risk for transection of the medial branch nerve (MBN) after minimally invasive insertion of pedicle screws was evaluated in a human cadaver model. OBJECTIVE: The purpose of this study is to compare the risk of MBN transection after pedicle screw insertion using mini-open versus percutaneous minimally invasive techniques. SUMMARY OF BACKGROUND DATA: The multifidus muscle is innervated by the MBN that originates from the posterior rami. Since the anatomic course of the MBN passes near the mamillary process it is vulnerable to injury during pedicle screw insertion, even if minimally invasive spine techniques are implemented. METHODS: Five cadaveric specimens were used for the study. Pedicle screws were inserted into the lumbar spine using either percutaneous or mini-open techniques. The integrity of the MBN was examined directly through anatomic dissection of the posterior spine. RESULTS: The soft tissue damage area around the screw insertion site was significantly greater in the mini-open compared with the percutaneous technique. MBN transection was observed in 84% (21/25) of the pedicles when using the mini-open technique and in 20% (5/25) when the percutaneous insertion technique was used (P < 0.01%). CONCLUSION: Using a percutaneous technique for pedicle screw insertion significantly reduces the risk of injury to the MBN. We therefore recommend using this technique especially at the most cephalic levels to minimize the risk of denervating the multifidus muscle fascicles that originate from the adjacent mobile level. PMID- 19444074 TI - HIV infection and the risk of diabetes mellitus. AB - BACKGROUND: The influence of HIV infection on the risk of diabetes is unclear. We determined the association and predictors of prevalent diabetes mellitus in HIV infected and uninfected veterans. METHODS: We determined baseline prevalence and risk factors for diabetes between HIV infected and uninfected veterans in the Veterans Aging Cohort Study. Logistic regression was used to determine the odds of diabetes in HIV infected and uninfected persons. RESULTS: We studied 3227 HIV infected and 3240 HIV-uninfected individuals. HIV-infected individuals were younger, more likely to be black males, have HCV coinfection and a lower BMI. HIV infected individuals had a lower prevalence of diabetes at baseline (14.9 vs. 21.4%, P < 0.0001). After adjustment for known risk factors, HIV-infected individuals had a lower risk of diabetes (odds ratio = 0.84, 95% confidence interval = 0.72-0.97). Increasing age, male sex, minority race, and BMI were associated with an increased risk. The odds ratio for diabetes associated with increasing age, minority race and BMI were greater among HIV-infected veterans. HCV coinfection and nucleoside and nonnucleoside reverse transcriptase inhibitor therapy were associated with a higher risk of diabetes in HIV-infected veterans. CONCLUSION: Although HIV infection itself is not associated with increased risk of diabetes, increasing age; HCV coinfection and BMI have a more profound effect upon the risk of diabetes among HIV-infected persons. Further, long-term ARV treatment also increases risk. Future studies will need to determine whether incidence of diabetes mellitus differs by HIV status. PMID- 19444075 TI - Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV. AB - OBJECTIVE: To estimate the prevalence and characteristics of long-term nonprogressor (LTNP) and HIV controller patients in a very large French cohort of HIV1-infected patients. METHODS: In the French Hospital Database on HIV [FHDH, Agence Nationale de Recherches sur le SIDA et les hepatites virales (ANRS) CO4], we selected patients who had been seen in 2005, who had been infected for more than 8 years, who were treatment-naive, and who remained asymptomatic. Patients with these characteristics then categorized as follows: LTNP (> or =8 years of HIV infection and CD4 cell nadir > or =500/microl), elite LTNP (> or =8 years of HIV infection, CD4 cell nadir > or =600/microl, and a positive CD4 slope), HIV controllers (>10 years of HIV infection with 90% of plasma viral load values < or =500 copies/ml), and elite controllers (same as HIV controllers, but with last plasma viral load value < or =50 copies/ml in 2005). RESULTS: Among the 46 880 HIV1-infected patients followed in 2005 in the French Hospital Database on HIV, 0.4% (N = 202) were LTNP, 0.05% (N = 25) were elite LTNP, 0.22% (N = 101) were HIV controllers, and 0.15% (N = 69) were elite controllers. Ten elite LTNP patients (40%) were also HIV controllers, eight (32%) were elite controllers, and 60% had detectable plasma viral load (>50 copies/ml). Among the elite controllers, 32 (46%) were LTNP, eight (12%) were elite LTNP, and one-quarter had a last CD4 cell count less than 500/microl. CONCLUSION: LTNP, elite LTNP, HIV controller, and elite controller patients are rare phenotypes. Elite LTNP patients are less frequent than HIV controllers. There is little overlap among the four subgroups of patients. PMID- 19444076 TI - Trefoil peptides, E-cadherin, and beta-catenin expression in sporadic fundic gland polyps: further evidence toward the benign nature of these lesions. AB - Sporadic fundic gland polyps (FGP) are the most common type of gastric polyps and their pathogenesis is still unclear, although a beta-catenin gene mutation has been described. They are regarded as benign lesions but low-grade dysplasia has been observed, arising more debate on their potential progression to a malignant phenotype. We investigated in FGP the role of factors involved in cell integrity, proliferation, and intercellular adhesion: trefoil peptides (TFF1, TFF2), MIB1, E cadherin, and beta-catenin. We selected randomly 24 patients with FGP, 24 with normal gastric mucosa and 12 with atrophic gastritis with diffuse intestinal metaplasia (IM-gastritis), all Helicobacter pylori negative. The expression of all factors was examined by immunohistochemistry. In polyps and normal mucosa, TFF1 is expressed only in foveolar compartment whereas in IM-gastritis the signal is reduced in all the compartments. TFF2 is expressed in polyps and normal mucosa, in proliferative and basal compartment, whereas in IM-gastritis the expression is reduced or absent. E-cadherin is expressed in the entire zone: with a medium signal in normal mucosa and polyps, and weaker in IM-gastritis. The beta catenin's signal in normal mucosa and polyps is moderate-to-intense in proliferative and basal compartments, whereas in IM-gastritis signal is significantly reduced in all the compartments. MIB1 in normal mucosa and polyps is expressed only in proliferative compartment, whereas its expression is stronger in IM-gastritis and involves also basal compartment. In conclusion all the factors considered were normally expressed in FGP and this, especially considered against the findings in IM-gastritis, supports the benign nature of FGP. PMID- 19444077 TI - Large cell carcinoma of the lung: an endangered species? AB - This study aims to evaluate large cell carcinomas (LCC) of the lung with a panel of immunohistochemical markers in an attempt to identify tumors belonging to other categories. We analyzed a tissue microarray platform of 101 LCC with a panel of 31 monoclonal antibodies. The tumors were 82 (81.3%) classic LCC, 7 (6.9%) neuroendocrine LCC, 6 (5.9%) lymphoepithelioma-like LCC, 3 (2.9%) basaloid LCC, 2 (2%) clear cell LCC, and 1 (1%) LCC with rhabdoid phenotype. Characteristic classic LCC immunophenotype was loss of staining with CK5/6, CK14 positive in most squamous cell carcinoma (SCC), lack of MOC 31 positive in most adenocarcinomas, and positive immunoreactivity to EGFR, PDGFR-alpha and c-kit. 27 of 82 classic LCC (32.9%) were re-classified as adenocarcinomas, because they coexpressed TTF-1, CK7, and CK19, and were negative for p63. 31 (37.8%) of 82 classic LCC were reclassified as poorly differentiated SCC, based on their immunoreactivity with 34betaE12, p63, thrombomodulin, and CD44v6. 16 (19.5%) of 82 classic LCC correspond to undifferentiated adenosquamous carcinomas, since they displayed conflicting immunostaining for markers of both SCC and adenocarcinomas. The use of 7 immunohistochemical markers, consisting of TTF-1, CK7, CK19, p63, 34betaE12, thrombomodulin, and CD44v6, markedly reduces dramatically to less than 10%, the number of classic LCC by readily identifying cases of poorly differentiated SCCs, adenosquamous carcinoma and adenocarcinomas. PMID- 19444078 TI - Advance directive use and psychosocial characteristics: an analysis of patients enrolled in a psychosocial cancer registry. AB - Advance directives (ADs) refer to a category of documents that enable individuals to state their preferences for future healthcare decisions in the event of incapacitation. The purpose of the study was to examine differences in psychosocial characteristics and AD completion rates in persons newly diagnosed with cancer. This sample comes from data collected for a psychosocial registry for patients with cancer. The following psychosocial data were collected: Functional Assessment of Cancer Therapy-General, Profile of Mood States-short form, and the Functional Assessment of Chronic Illness Therapy-Spiritual Well being Scale. The sample included 312 persons who had been diagnosed with cancer within the previous 5 months. There were no statistically significant differences between completion of an AD and the measured psychosocial characteristics at baseline (mean, 4.2 months); however, at 3 months, patients who reported higher quality of life (Functional Assessment of Cancer Therapy-General) were associated with lower AD completion rates and persons with greater mood disturbances had higher rates of AD completion. Our data suggest the need to develop strategies that would facilitate discussion of ADs for patients entering the cancer care continuum. PMID- 19444079 TI - The experience of a sore mouth and associated symptoms in patients with cancer receiving outpatient chemotherapy. AB - This study aimed to describe sore mouth (SM) severity and distress, associated symptoms, and consequences in cancer chemotherapy outpatients. Secondary analysis was used in this study. A total of 223 patients in 4 treatment centers participated in the study. Data from an intervention study using a computer-based telephone communication system to assess patients' daily symptom experience were analyzed to obtain highest, average, and lowest ratings of severity and distress for SM, fatigue, trouble sleeping, feeling down/blue, and feeling anxious. Consequence data included oral intake, time spent lying down, ability to work, and daily activity. Approximately 51% reported SM, with a mean highest, average, and lowest severity score of 3.1 in cycle 2 and 3.09 in cycle 3. Sore mouth severity was correlated with severity of fatigue, feeling down/blue, feeling anxious, and trouble sleeping. Sore mouth distress was correlated with the same symptoms. Sore mouth severity was correlated with the number of 8-oz glasses of liquid consumed, effect on daily activity, time spent lying down, but not with ability to work. Half of patients experienced SM, which was associated with several other symptoms and led to specific consequences. Understanding the complex symptom experience of patients with SM, including consequences, will assist nurses in developing more comprehensive clinical assessments and interventions. In addition, the association of multiple symptoms with SM will provide a foundation for further research investigation in oral mucositis. PMID- 19444081 TI - Healthcare needs of noninstitutionalized Jordanian cancer patients: an exploratory descriptive study. AB - Despite all advances in healthcare, provision of healthcare for cancer patients remains one of major continuing challenges for healthcare professionals. One of these challenges is shorter hospital stay. In this fast-paced environment, identification of cancer patients' needs is limited yet necessary to initiate an appropriate treatment plan for this group of patients. The major purpose of this study was to identify healthcare needs of noninstitutionalized patients with cancer from Arab Jordanians' perspective. The study was conducted at a chemotherapy clinic of a major university hospital in Jordan. An exploratory descriptive design using a structured interview was used to collect the data. The questions of the interview composed of items of several scales including the Patient Need Scale. Sixty-two participants met the inclusion criteria and agreed to participate. The participants were patients with cancer, were receiving chemotherapy, and were (a) Jordanian male or female patients, (b) able to communicate in Arabic, (c) 19 years of age or older, and (d) free from psychiatric or mental illnesses. Participants reported 70 existing needs (68.6%). However, 50% of these identified needs were perceived as being not met. Jordanian patients with cancer reported more healthcare needs than patients in Western cultures. Individualized comprehensive assessment of patients' needs from their perspective is essential to initiate an effective treatment plan. PMID- 19444080 TI - The Self-regulation Model of Illness applied to smoking behavior in lung cancer. AB - Thirteen to 20% of lung cancer patients continue to smoke after diagnosis. Guided by Self-regulation Theory, the purpose of this study was to examine illness perceptions over time in a sample of lung cancer patients. This prospective 1 group descriptive longitudinal design study included participants 18 years or older, with a lung cancer diagnosis within the past 60 days who self-reported smoking within the past 7 days. At baseline, patients completed a sociodemographics and tobacco use history questionnaire. The Illness Perception Questionnaire-Revised (IPQ-R) was repeated at 3 time points (baseline, 2-4 weeks, and 6 months). Fifty-two participants provided data for the IPQ-R at baseline, 47 at 2 to 4 weeks, and 29 at 6 months. Differences between mean scores for each illness representation attribute of the IPQ-R at repeated time points were calculated by within-subjects repeated-measures analysis of variance and Wilcoxon Signed-Rank Tests. Identity (baseline vs 2-4 weeks: P = .026; baseline vs 6 months: P = .005) and acute/chronic timeline (P = .018) mean scores significantly increased over time; personal and treatment control mean scores significantly decreased over time (P = .007 and P = .047, respectively). Understanding the context in which a patient perceives disease and smoking behavior may contribute to developing interventions that influence behavior change. PMID- 19444082 TI - Uncertainty during the transition from cancer patient to survivor. AB - This prospective study evaluated the impact that uncertainty has on quality of life as cancer patients end the active phase of their treatment. The transition from patient status to survivor may be a particularly important point in recovery because it may affect how much stress cancer survivors experience. Guided by a within-subjects design framework, 53 cancer patients (predominantly breast cancer) participated in the present study as they approached the end of adjuvant treatment and were followed for 4 months. Distress levels increased the further patients moved away from the end-of-active treatment; however, preceding these ascending scores of distress was a period characterized by little unrest-best described as a "honeymoon" phase. Using hierarchical linear modeling, greater uncertainty 1 month after treatment ended predicted more functional and physical impairment 4 months after the completion of adjuvant treatment. In both cases, uncertainty accounted for nearly 70% of the variance of these changes over time. A period of rest may emerge as active treatment ends, but that it is short-lived, particularly if uncertainty regarding health emerges. Furthermore, uncertainty may a represent a key mechanism (and target for intervention) during the transition from cancer patient to survivor. PMID- 19444083 TI - Effect of perceived barriers to symptom management on quality of life in older breast cancer survivors. AB - Negative attitudes of both older adults and healthcare providers about aging can be barriers to self-care in old age. The aims of this study were to (1) examine the extent to which older breast cancer survivors experience barriers to symptom management and (2) explore whether barriers influence quality of life. Three possible barriers to symptom management were examined: negative beliefs about managing symptoms, perceived negative attitudes of healthcare providers, and difficulties in communicating about symptoms. This study was a secondary analysis of pooled baseline data from 61 older (age >64 years) women who participated in 2 pilot studies that tested a symptom management intervention for older breast cancer survivors. The most frequent barrier reported was difficulties in communicating about symptoms with healthcare providers. Each of the barriers affected psychosocial, but not physical, quality of life. Barriers to symptom management may lead to poorer self-care of symptoms that can result in lower levels of psychosocial quality of life. Healthcare providers need to encourage older cancer survivors to report symptoms and worries related to their cancer diagnosis and should be cautious in expressing attitudes that could reinforce older adults' negative perceptions about aging. PMID- 19444084 TI - Breast cancer risk perception and lifestyle behaviors among White and Black women with a family history of the disease. AB - Although researchers have investigated the relationships between perceived risk and behavioral risk factors for breast cancer, few qualitative studies have addressed the meaning of risk and its impact on decision making regarding lifestyle behaviors. This qualitative study explored factors involved in the formulation of perceived breast cancer risk and associations between risk perception and lifestyle behaviors in white and black women with a family history of breast cancer. Eligible participants were North Carolina residents in the Sister Study, a nationwide study of risk factors for breast cancer among women who have at least 1 sister diagnosed with breast cancer. Personal interviews were conducted with 32 women. Although most had heightened perceived risk, almost 20% considered themselves below-to-average risk. Participants with moderate-to-high perceived risk were more likely to report an affected sister and mother, a first degree relative's diagnosis within 4 years, and death of a first-degree relative from breast cancer. Many women were unaware of associations between lifestyle behaviors and breast cancer risk. Only one-third of the women reported healthy lifestyle changes because of family history; dietary change was most frequently reported. Findings may be important for cancer nurses involved in developing breast cancer education programs for women with a family history of breast cancer. PMID- 19444086 TI - Secondary traumatic stress in oncology staff. AB - As empathetic caregivers, oncology staff may be prone to secondary traumatic stress (STS). Secondary traumatic stress results from exposure to persons who have experienced trauma and from giving care to such persons. The presence of STS among oncology staff has not been documented. This correlational descriptive study examined STS among oncology staff at a 500-bed Magnet-designated community hospital by determining the presence of individual symptoms and frequency with which diagnostic criteria for STS are met. Also determined were associations between STS demographic characteristics and specific stress-reduction activities.In this study, 43 staff members from an inpatient oncology unit completed mailed surveys. The Secondary Traumatic Stress Scale assessed the frequency of intrusion, avoidance, and arousal symptoms associated with STS; also assessed were use/helpfulness of stress-reduction activities. In this first study to document the prevalence of STS among oncology staff, prevalence ranged from 16% (Bride's method) to 37% (cutoff-score method). Most common symptoms were difficulty sleeping, intrusive thoughts about patients, and irritability. Least common were avoidance of people, places, and things and disturbing dreams about patients. Current use of massage was significantly predictive of not having STS. Ethnicity of staff member was related to having STS. Further research is warranted evaluating STS prevalence in different groups of oncology staff along with the effect of STS on burnout and job retention. PMID- 19444085 TI - Epidemiological and genetic factors associated with ovarian cancer. AB - The purpose of this article was to provide a comprehensive review of the epidemiological and genetic factors associated with ovarian cancer. A more complete understanding of the determinants of ovarian cancer may lead to the development of better screening and detection methods for this disease. The first section of this article reviews current literature on screening and early detection of ovarian cancer. The second section reviews the epidemiology of ovarian cancer, specifically highlighting the risk factors associated with the development of this disease. The article concludes with a discussion of how oncology nurses can apply this information to improve patient care. PMID- 19444087 TI - Health-related quality of life in patients undergoing allogeneic stem cell transplantation after reduced intensity conditioning versus myeloablative conditioning. AB - The aim of this prospective study was to describe health-related quality of life (HRQOL) in patients during the first year after stem cell transplantation (SCT) who were undergoing reduced intensive conditioning (RIC) compared with patients undergoing myeloablative conditioning (MAC). Fifty-seven patients (25 for MAC and 32 for RIC) were enrolled in the study. HRQOL was assessed at 6 occasions during the first year after SCT using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the 19-item treatment-specific module High-Dose Chemotherapy. Both groups reported most symptoms and worst functioning 1 month after SCT, but there were substantial differences. The MAC group deteriorated considerably in 20 symptom scales compared with 8 in the RIC group (score differences <10; P values ranged from .001 to .05). Dry mouth, sore mouth, appetite loss, and change of taste were among the most frequent symptoms in both groups. Thereafter, the functioning improved and the symptom scores decreased and returned to baseline in both groups, except dry mouth, which remained a worse problem for the MAC group. Overall, the RIC group regained health and QOL faster than the MAC group did. However, there were no significant differences in global QOL between the groups 1 year after SCT. PMID- 19444088 TI - Changes in sexuality and intimacy after the diagnosis and treatment of cancer: the experience of partners in a sexual relationship with a person with cancer. AB - Changes in sexuality and intimacy after cancer were examined using open-ended questionnaire responses with 156 informal carers who were partners of a person with cancer. Interviews were conducted with 20 participants to examine changes in depth. Seventy-six percent of partners of a person with "nonreproductive" cancer types and 84% of partners caring for a person with cancer involving "reproductive" sites reported an impact on their sexual relationship. Cessation or decreased frequency of sex and intimacy was reported by 59% of the women and 79% of the men. Renegotiation of sexuality and intimacy after cancer was reported by only 19% of the women and 14% of the men. Reasons for changes to sexuality after cancer were the impact of cancer treatments, exhaustion due to caring, and repositioning of the person with cancer as a patient, not a sexual partner. Changes to sexuality were associated with reports of self-blame, rejection, sadness, anger, and lack of sexual fulfillment. Positive consequences of changes included accepting the changed sexual relationship and having increased closeness and intimacy. These findings reinforce the need to acknowledge the sexual needs of partners as well as people with cancer, by healthcare professionals working in cancer and palliative care. PMID- 19444089 TI - The impact of culture and sociological and psychological issues on Muslim patients with breast cancer in Pakistan. AB - Breast cancer is the most common form of cancer in Muslim women in Pakistan. The impact of the initial diagnosis, culture, religion, and psychosocial and psychological aspects of the disease is not well established. This qualitative study examined the experience and coping strategies used by patients with breast cancer in relation to its impact on their physical, mental health, religious, and family issues. Thirty patients with breast cancer were interviewed. Data were analyzed using thematic analysis. The patient's experience of breast cancer focused on the range of emotions felt throughout the illness trajectory, the importance of religion and family support on coping strategies used to manage the adverse effects of chemotherapy, and also the financial concerns. This is the first study to examine Pakistani Muslim women's views on the lived experience of breast cancer. This article provides clarification of the voiced experiences of women with breast cancer. The data not only highlight the role of religion and family support as essential coping strategies but also emphasize the issues of isolation, aggression, and anger as common responses to chemotherapy. Unique features of this study are women's need to seek spiritual support for their illness and the overriding innate characteristic of maternal responsibility. These cultural features require further analysis and research. PMID- 19444090 TI - X-linked alpha thalassaemia/mental retardation syndrome: a case with gonadal dysgenesis, caused by a novel mutation in ATRX gene. PMID- 19444091 TI - The reliability of fractional flow reserve measurement in patients with diabetes mellitus. AB - BACKGROUND: Fractional flow reserve (FFR) is an invasive method to assess the functional significance of coronary stenoses. The value of FFR in diabetic patients is controversial because of microvascular dysfunction. The aim of this study is to investigate the effect of diabetes mellitus (DM) on FFR measurements. METHODS: One hundred and twenty-one patients with an intermediate lesion who had undergone FFR measurement were included in the study. Lesion severity was determined by quantitative coronary angiography. The patients were divided into groups according to the presence (group 1) or absence (group 2) of DM. The patients were further categorized according to the degree of luminal narrowing caused by the lesion (40-50, 51-60, and >60%) and reference vessel diameter (> or = 2.8 and <2.8 mm). FFR measurements were compared in each category. RESULTS: There was no difference between the FFR values of diabetic and nondiabetic patients who had coronary lesions with similar degree of luminal narrowing (0.87+/-0.08 vs. 0. 0.85+/-0.07; 0.81+/-0.08 vs. 0.82+/-0.10; 0.81+/-0.10 vs. 0.83+/-0.09, P = 0.957). In the analysis comparing FFR measurements in the categories set according to reference vessel diameter, we did not find a difference either (0.82+/-0.09 vs. 0.83+/-0.09; 0.84+/-0.09 vs. 0.82+/-0.09, P = 0.878). The DeltaFFR value, which is the difference between FFR values before and after adenosine administration, was also similar in diabetic and nondiabetic patients (8.4+/-6.0 vs. 8.4+/-5.5, P = 0.997). CONCLUSION: The presence of DM does not have a significant impact on FFR values in coronary stenoses of intermediate severity. PMID- 19444092 TI - Ranolazine improves endothelial function in patients with stable coronary artery disease. AB - OBJECTIVES: We investigated the effect of ranolazine on endothelial-dependent vasodilatation (EDV), serum markers of endothelial dysfunction, and inflammation. BACKGROUND: Endothelial dysfunction has been shown to be independently associated with the occurrence of cardiovascular events. We sought to investigate whether ranolazine, a novel antianginal medication with no effect on heart rate or blood pressure, improves endothelial function in patients with stable coronary artery disease (CAD). METHODS: Twenty-seven patients with stable CAD were randomly assigned to either 1000 mg twice daily of ranolazine or to matching placebo for 6 weeks and then crossed over for an additional 6 weeks in a double-blind design. EDV was assessed using reactive hyperemia peripheral arterial tonometry (RH-PAT) at baseline, 6, and 12 weeks. Markers of endothelial dysfunction and inflammation were also evaluated. RESULTS: After 6 weeks, treatment with ranolazine significantly increased the EDV RH-PAT index as compared with baseline (1.85+/ 0.42 vs. 2.08+/-0.57, P = 0.037). EDV RH-PAT did not change while on placebo (1.69+/-0.35 vs. 1.78+/-0.41, P = 0.29). In addition, there was a significant drop in asymmetric dimethylarginine levels with ranolazine treatment (0.66+/-0.12 vs. 0.60+/-0.11 micromol/l, P = 0.02) and a near significant decrease in C reactive protein levels (0.40+/-0.80 vs. 0.30+/-0.61 mg/dl, P = 0.05). CONCLUSION: Ranolazine improves endothelial function, asymmetric dimethylarginine, and C-reactive protein levels in a group of patients with stable CAD. Our results suggest a novel mechanism of action of ranolazine. PMID- 19444093 TI - Rare, medium, or well done? The effect of heating and food matrix on food protein allergenicity. AB - PURPOSE OF REVIEW: To review recent advances in the area of food allergen processing and the effect on protein allergenicity. RECENT FINDINGS: Heating generally decreases protein allergenicity by destroying conformational epitopes. In peanut and shrimp, heat-induced Maillard reaction (glycation) may increase allergenicity. The majority of milk and egg-allergic children tolerate extensively heated (baked with wheat matrix) milk and egg. Introduction of extensively heated milk and egg proteins is associated with decreasing sizes of skin prick test wheals and increasing serum food-specific IgG4 levels. SUMMARY: Heating and other methods of food processing have different effects on food allergens, even those contained in the same complex food. Structural homology does not reliably predict the effect of processing on allergenicity, and individual food allergens have to be tested. Interactions with other proteins, fat, and carbohydrates in the food matrix are complex and poorly understood. Introduction of extensively heated milk and egg proteins into the diet of allergic children may represent an alternative approach to oral tolerance induction. Better characterization of these aspects of food allergy is critical for elucidation of food protein interactions with the gut-associated lymphoid tissue, the ability to induce IgE sensitization, the potential to trigger hypersensitivity reactions, and different clinical phenotypes of food allergy with regard to severity and persistence. PMID- 19444094 TI - Three-dimensional stress echocardiography: the promise and limitations of volumetric imaging. AB - PURPOSE OF REVIEW: Three-dimensional (3D) volumetric imaging has potential advantages in stress echocardiography, including the ability to provide an unlimited number of planes for analysis and more rapid acquisition than conventional two-dimensional (2D) imaging. This review focuses on the advantages and disadvantages of 3D volumetric imaging and the current and future role of the technique in stress echocardiography. RECENT FINDINGS: Three-dimensional volumetric imaging uniformly shortens the time required for acquisition of stress images. The success of imaging is high with pharmacologic stress but the feasibility is not established with exercise stress. The lower spatial and temporal resolution of 3D imaging and artifacts introduced by suboptimal subvolume integration are limitations of the current 3D technique. The ability to provide more planes for analysis has not been clearly shown to improve the accuracy of stress echocardiography. However, 3D imaging eliminates apical foreshortening, which is common with 2D imaging, and may improve detection of apical wall motion abnormalities. SUMMARY: In general, 3D imaging has shown rates of success and accuracy comparable to those of 2D imaging in pharmacologic stress echocardiography. Further studies are needed in larger and more heterogeneous patient populations. As improvements in 3D technology continue, successful application of the technique to exercise echocardiography is likely. Development of automated image registration, quantitative analysis techniques, and single beat acquisition is needed to fully exploit the potential of 3D imaging in the stress laboratory. PMID- 19444095 TI - Conduct of clinical trials in developing countries: a perspective. AB - PURPOSE OF REVIEW: To provide a broad perspective of contextual factors involved in the conduct of clinical trials in developing countries. RECENT FINDINGS: The quantity of research in developing countries continues to be inadequate, with clinical trials comprising a small fraction of the total research output. Most trials done in developing countries tend to be designed in developed countries and led by investigators in those nations. The main challenges in the conduct of trials in developing countries stem from the vulnerability of the populations due to illiteracy, poverty, limited research infrastructure, lack of sufficient numbers of experienced investigators and trained support personnel, and fragmented healthcare system. SUMMARY: There is a need to formulate and conduct trials to test treatments that are context-specific and socially relevant. With careful planning in advance and shared partnership among sponsors, host-country research practitioners, government agencies and the community, many of the challenges facing clinical trial research can be overcome over the medium to long term. This would enable conformity to contemporary guidelines in both letter and spirit and hopefully develop research questions addressing the needs of developing countries. PMID- 19444096 TI - Antibiotics and probiotics in inflammatory bowel disease: why, when, and how. AB - PURPOSE OF REVIEW: To summarize recent evidence on the role of intestinal bacteria in inflammatory bowel diseases, and of antibiotics and probiotics in their treatment. The implications connected with the use of antibiotics are also examined. RECENT FINDINGS: The hypothesis that Mycobacterium paratuberculosis could be a causative agent of Crohn's disease has not been confirmed by a large trial on symptomatic patients treated by a combination of antibiotics active against this bacterium. An increased number of adherent-invasive Escherichia coli have been found in the intestinal tissue of patients with Crohn's disease, but their role in the pathogenesis of this condition remains to be defined. The combination of metronidazole and azathioprine, associating the effects of a reduced bacterial load with immunosuppression, appears to be a therapeutic option to decrease the recurrence of postoperative Crohn's disease in high-risk patients. However, concerns are raised by the possibility that antibiotics may induce disease relapse due to Clostridium difficile infection. SUMMARY: Recent literature provides increasing support for the use of antibiotics in Crohn's disease, although the side effects limit their long-term use. The efficacy of antibiotics in ulcerative colitis is not confirmed by the available literature, except in severe colitis. More trials are needed to support the use of probiotics as therapy in inflammatory bowel disease. PMID- 19444097 TI - What's new in the diagnosis and therapy of eosinophilic esophagitis? AB - PURPOSE OF REVIEW: Eosinophilic esophagitis (EoE) is a relatively new chronic inflammatory disease of the esophagus. Novel aspects in the diagnosis and treatment of EoE are discussed in this review. RECENT FINDINGS: Development of diagnostic guidelines consisting of symptoms as well as endoscopic and histopathologic criteria has improved the awareness of clinicians and the diagnosing of EoE. The clinically challenging discrimination of EoE from gastroesophageal reflux disease has become more obvious and has evoked the need for more individualized therapy options. Today, most patients with EoE can be treated successfully with topical corticosteroids. However, no convincing alternative treatment strategies exist for corticosteroid-refractory or corticosteroid-dependent patients. Interestingly, a single-nucleotide polymorphism in the eotaxin-3 gene has been linked to increased disease susceptibility for EoE. SUMMARY: EoE is an emerging esophageal disease. A better understanding of the pathogenesis of this disorder would improve the clinical recognition and diagnostic ability and ultimately provide patients with more optimal treatment options. PMID- 19444098 TI - mAbs in nonlupus autoimmune rheumatic disease. AB - PURPOSE OF REVIEW: mAb therapies are being used more frequently in all medical conditions, including the autoimmune rheumatic diseases. Autoimmune myositis, vasculitis and primary Sjogren's syndrome are rare diseases in which these therapies are being used without the support of large-scale randomized controlled trials. We have summarized the evidence that does exist to support the use of mAb therapies in these diseases. RECENT FINDINGS: There have been a number of open label trials and case reports using mainly rituximab and antitumour necrosis factor-alpha agents to treat these diseases. The results have in general shown efficacy, the main exception being the use of antitumour necrosis factor-alpha agents with cyclophosphamide for the treatment of vasculitis. SUMMARY: mAb therapies have shown efficacy in the treatment of patients with autoimmune rheumatic diseases who have failed conventional therapy. Their use ahead of conventional immunosuppressive strategies cannot be supported on the basis of current evidence. PMID- 19444099 TI - Erythroid cells in vitro: from developmental biology to blood transfusion products. AB - PURPOSE OF REVIEW: Red blood cells (RBCs) transfusion plays a critical role in numerous therapies. Disruption of blood collection by political unrest, natural disasters and emerging infections and implementation of restrictions on the use of erythropoiesis-stimulating agents in cancer may impact blood availability in the near future. These considerations highlight the importance of developing alternative blood products. RECENT FINDINGS: Knowledge about the processes that control RBC production has been applied to the establishment of culture conditions allowing ex-vivo generation of RBCs in numbers close to those (2.5 x 10 cells/ml) present in a transfusion, from cord blood, donated blood units or embryonic stem cells. In addition, experimental studies demonstrate that such cells protect mice from lethal bleeding. Therefore, erythroid cells generated ex vivo may be suitable for transfusion provided they can be produced safely in adequate numbers. However, much remains to be done to translate a theoretical production of approximately 2.5 x 10 RBCs in the laboratory into a 'clinical grade production process'. SUMMARY: This review summarizes the state-of-the-art in establishing ex-vivo culture conditions for erythroid cells and discusses the most compelling issues to be addressed to translate this progress into a clinical grade transfusion product. PMID- 19444100 TI - Adjuvant trials design in colon cancer. PMID- 19444101 TI - New insights into the hemangiopericytoma/solitary fibrous tumor spectrum of tumors. AB - PURPOSE OF REVIEW: This review provides an overview of the hemangiopericytoma/solitary fibrous tumor (HPC/SFT) spectrum of tumors, focusing on the histopathologic characteristics, clinical features, diagnosis, and treatment of HPC/SFT. RECENT FINDINGS: Due to the relatively insensitive nature of HPC/SFT to radiotherapy and cytotoxic chemotherapy, new therapies are needed for treatment of advanced disease. Inhibition of angiogenic pathways may provide a novel therapeutic mechanism for targeting this malignancy. Combination therapy with temozolomide and bevacizumab has recently emerged as a potentially promising regimen for HPC/SFT. SUMMARY: With many novel targeted therapies currently in development for soft tissue sarcomas, a better understanding of the molecular pathogenesis and aberrations of HPC/SFT is needed to determine optimal therapeutic agents. Identifying appropriate targets and designing rational prospective clinical trials will not only improve treatment of HPC/SFT but will also lead to a new paradigm of personalized, targeted therapy. PMID- 19444102 TI - Giant cell tumour of bone. AB - PURPOSE OF REVIEW: Giant cell tumour of bone (GCT) is the most common benign bone tumour and afflicts a young population. Treatment options for patients with unresectable disease have remained fairly static for the past three decades. RECENT FINDINGS: Recent discoveries have identified a key role for the osteoclast differentiation factor, receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL), in the genesis of GCT. The development of the fully human monoclonal antibody to RANKL, denosumab, has led to a clinical trial in unresectable GCT. This study demonstrated an 86% response rate, with comparable evidence of clinical benefit, and was well tolerated. Other pathways that may present targets for therapy include the hypoxia-angiogenesis axis and the colony stimulating factor 1 receptor. SUMMARY: Denosumab presents a new treatment option for patients with previously untreatable GCT. The eventual role of denosumab and other targeted agents in the treatment of GCT and related disorders is currently the subject of active study. PMID- 19444103 TI - Novel agents in development for pediatric sarcomas. AB - PURPOSE OF REVIEW: The survival curves for many pediatric sarcomas have remained flat for the past 2 decades or more and novel therapeutics - those small molecule medicines that selectively inhibit specific signaling molecules - have been slow to enter into pediatric practice. The preclinical basis for their use is reviewed here. RECENT FINDINGS: Preclinical and phase I studies showing efficacy of antiinsulin-like growth factor receptor 1 therapies for Ewing sarcoma have led to numerous ongoing clinical trials using these agents for Ewing and other sarcomas. Early studies of ERBB signaling as a target in sarcoma therapy have been tantalizing, but progress in this area has been controversial. In-vitro analysis of Src inhibitors suggested that these agents would prevent metastasis in osteosarcoma, whereas in-vivo analysis showed no effect on metastasis, underscoring the need for thorough preclinical investigations of promising new therapies to guide future clinical trials. Antiangiogenic and immunomodulatory therapies are gaining momentum in the pediatric arena and should be tested in combination with traditional cytotoxic agents for recurrent and high-risk primary pediatric sarcomas. SUMMARY: Pediatric sarcomas have diverse biology and distinct signaling pathways, making detailed preclinical evaluation of small molecule inhibitors essential to guiding the design of further clinical investigations. PMID- 19444104 TI - Clinical implications of microsatellite instability in sporadic colon cancers. AB - PURPOSE OF REVIEW: To review data demonstrating the prognostic and predictive impact of microsatellite instability (MSI) in human colon carcinomas. RECENT FINDINGS: MSI is a molecular marker of defective DNA mismatch repair that is detected in approximately 15% of sporadic colon cancers. Most, but not all retrospective studies, have shown that colon cancers with MSI have better stage adjusted survival rates compared with non-MSI tumors. Furthermore, analyses of colon cancers from participants in randomized adjuvant therapy trials have suggested that MSI tumors do not benefit from treatment with 5-fluorouracil. Recent studies, including a pooled analysis, validate prior data demonstrating the prognostic and predictive impact of MSI status in colon cancer. SUMMARY: MSI is a molecular marker that can provide valuable prognostic and predictive information in colon cancer patients. In the appropriate clinical setting, MSI data can be used in clinical decision-making. Specifically, the favorable outcome of stage II colon cancers with MSI indicates that such patients should not receive adjuvant chemotherapy. Although data for stage III colon cancers with MSI suggest a lack of benefit from 5-fluorouracil alone, the benefit of the current standard treatment, 5-fluorouracil, leucovorin, and oxaliplatin, in this subgroup remains unknown and awaits further study. PMID- 19444105 TI - The relevance of minor histocompatibility antigens in solid organ transplantation. AB - PURPOSE OF REVIEW: Disparities in minor histocompatibility antigens between HLA matched organ and hematopoietic stem cell donors and recipients create the risks of graft failure and graft-versus-host disease (GvHD) respectively. A decade ago, technical advances combined with genomic information resulted in the identification of the chemical nature of the first series of minor histocompatibility antigens, facilitating their molecular typing. A new era of research had begun in exploring the role of minor histocompatibility antigens in physiological and nonphysiological settings. Here we summarize, to the best of our knowledge, human studies on the relevance of minor histocompatibility antigens in solid organ transplantation with a main focus on renal allografting. RECENT FINDINGS: The minor histocompatibility antigen HY is associated with acute rejection, and male grafts in female recipients have reduced graft survival; both cellular and humoral responses are observed. Studies on autosomal minor histocompatibility antigens on graft rejection are less conclusive; their role in transplant tolerance, however, offers perspective. SUMMARY: Information on the clinical relevance of minor histocompatibility antigen allo-immune responses in solid organ allografting is still scarce. The possible implications of the minor histocompatibility allo-immune responses for future clinical practice in solid organ transplantation are discussed in relation to their possible detrimental or beneficial effects on the host. PMID- 19444107 TI - Management of liver transplant recipients with recurrent hepatitis C. AB - PURPOSE OF REVIEW: Hepatitis C virus infection is the leading indication for liver transplantation, with recurrent hepatitis C almost universal. Although posttransplant treatment of hepatitis C virus infection remains suboptimal, active investigation continues to inform patient selection and risk-benefit analysis. RECENT FINDINGS: Several key studies have identified components in the immunological response that are associated with the necroinflammatory and fibrotic response. Hepatitis C virus infection is associated with a higher rate of diabetes mellitus after transplant. Patients with diabetes and metabolic syndrome have poorer outcomes, and aggressive management is necessary. Differentiation of acute rejection from recurrent hepatitis C is difficult; however, the use of hepatitis C virus RNA tissue levels, immunohistochemistry and Councilman body/portal tract ratio may help with this diagnostic dilemma. The use of a specific calcineurin inhibitor appears not to influence recurrent hepatitis C, but rapid steroid taper is detrimental and, if steroids are used, long slow taper should be used. Use of rapid and early virological responses is very helpful in the management of hepatitis C after transplantation. In the patients with sustained virological response, histological and survival benefits are noted. SUMMARY: The present review highlights advances in our understanding of the pathophysiology and treatment of hepatitis C virus infection after liver transplantation in the last few years. PMID- 19444106 TI - Extracorporeal photopheresis-induced immune tolerance: a focus on modulation of antigen-presenting cells and induction of regulatory T cells by apoptotic cells. AB - PURPOSE OF REVIEW: This review is intended to introduce recent advances in the research surrounding extracorporeal photopheresis (ECP) with a focus on how apoptotic cells modulate antigen-presenting cells and induce regulatory T cells, given that ECP therapy induces apoptosis of leukocytes collected through leukapheresis. RECENT FINDINGS: It has been suggested that ECP therapy, unlike other immunosuppressive regimens, does not cause global immunosuppression, but induces immune tolerance. Recent clinical and animal studies demonstrate that ECP therapy induces antigen-specific regulatory T cells, including CD4+CD25+FoxP3+ T cells and IL-10-producing Tr1 cells, that may arise secondarily to the induction of tolerogenic antigen-presenting cells (APCs) by infusion of apoptotic cells. It has also been suggested that ECP therapy may induce IL-10-producing regulatory B cells and regulatory CD8+ T cells. Finally, several recent studies, which examined the cellular elements involved in the uptake of apoptotic cells, demonstrated that apoptotic cells modulate APCs through binding to specific receptors, particularly TAM receptors that provide inhibitory signals that block APC activation. SUMMARY: ECP therapy induces immune tolerance through modulation of antigen-presenting cells as well as induction of regulatory T cells. ECP therapy has great potential in the management of allogeneic transplantation and autoimmune diseases. PMID- 19444108 TI - Some new insights in intestinal failure-associated liver disease. AB - PURPOSE OF REVIEW: To point new insights in the cholestasis that is a complication of both intestinal failure and parenteral nutrition. View on liver disease has recently evolved with the onset of fish oil-based intravenous lipid emulsions (ILE). RECENT FINDINGS: Focused on the role of ILE in causing liver disease. Reversal of cholestasis was recently achieved in infants with short bowel syndrome, by replacing the 'reference' soybean oil-based ILE by fish oil based ILE. SUMMARY: It is likely that this reversal involves several factors such as the change in n-6: n-3 ratio, the reduction in phytosterol load, the increased provision of alpha-tocopherol as antioxidant agent. Alternative issue might be based on the use of a new generation of ILE aiming to provide n-3 and to reduce n 6 fatty acids load while enhancing alpha-tocopherol intake. New data are based on the use of an ILE containing a balanced proportion of four types of oil as a physical mixture of 30% soybean oil, 30% medium-chain triglycerides, 25% olive oil and 15% fish oil with amounts of alpha-tocopherol calculated according to the number of double bonds. This new emulsion was reported to be beneficial in reversing or preventing liver disease. PMID- 19444109 TI - Computer modeling and navigation in maxillofacial surgery. AB - PURPOSE OF REVIEW: To review the accuracy and effectiveness of current technology available for computer-aided maxillofacial surgery. RECENT FINDINGS: New developments in computer technology can help surgeons with preoperative planning and intraoperative navigation in the management of maxillofacial injuries. SUMMARY: Computer-aided surgery is improving the surgical outcomes in maxillofacial reconstruction, particularly in complex cases. Several recent articles are presented that explore the clinical outcomes using computer-aided surgery, investigate the precision of various intraoperative optical navigation systems, compare several registration strategies and examine the impact of natural facial asymmetry on planning and reconstruction. In all cases, preoperative computed tomography (CT) data are imported to computer modeling programs in which virtual reconstructions can be performed. These reconstructions are then used by intraoperative navigation systems to guide the surgeon and increase the precision of surgical outcomes. Evaluation of various registration strategies used to orient navigation systems to patient anatomical markers demonstrates that the optimum strategy is dependent on injury type. Some degree of error when repairing maxillofacial injuries is negated by the fact that people have naturally asymmetrical craniofacial skeletons. PMID- 19444110 TI - Advances in free flap monitoring: have we gone too far? AB - PURPOSE OF REVIEW: Timely recognition of vascular compromise of free flaps is crucial to salvaging failing flaps. This review summarizes the most recent available literature about free flap monitoring over the period of 2008-2009. Novel techniques are discussed. RECENT FINDINGS: Several case series have been published that highlight interesting methods for free flap monitoring; however, concerns of impracticality abound. The implantable Doppler has been used in a large case series with good success. Externalization of a flap component has undergone refinement in technique with success. Measurement of tissue oxygen tension and blood flow with PET is possible. Microendoscopy has been proposed as a possible technique for accessible flaps to assess capillary blood flow. Several retrospective studies elucidated trends in free flap compromise in the postoperative period, which confirm prior findings. SUMMARY: We provide an overview of recent techniques for free flap monitoring. No single technique provides an ideal method for free flap monitoring, but these methods may prove promising with future research and refinement. New techniques in free flap monitoring largely remain out of the scope of reasonable implementation. PMID- 19444111 TI - Utility of the gastro-omental free flap in head and neck reconstruction. AB - PURPOSE OF REVIEW: In the current era of organ-preservation therapies, surgical salvage and reconstruction of defects following ablation of mucosa and soft tissue in the head and neck is extremely challenging because of the toxic effects of chemoradiation and intensive radiotherapy on wounds. The anatomical, physiological and immunological properties of the gastro-omental flap make it an ideal reconstructive technique in head and neck surgery. RECENT FINDINGS: Several case series published in the past 12 months highlight the utility of this flap in inhospitable wounds and particularly in restoration of circumferential pharyngeal defects. The gastro-omental flap produces satisfactory functional results and morbidity in this group of high-risk patients. SUMMARY: The gastro-omental free flap provides an alternative to traditional reconstructive techniques that is ideally suited to high-risk complex wounds in the head and neck. PMID- 19444112 TI - The metabolic syndrome and nonalcoholic fatty liver disease in children. AB - PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in pediatric-age individuals, in parallel with increasing obesity, and can lead to liver inflammation, fibrosis, and even cirrhosis. NAFLD appears tightly linked with features of the metabolic syndrome (MetS). This review aims to reconsider the clinical presentation, laboratory and pathologic assessment, and treatment of NAFLD, with a focus on its relationship with the MetS. RECENT FINDINGS: NAFLD occurs with a high prevalence and severity in obese, insulin resistant adolescents, especially Hispanic males. Pediatric NAFLD may improve with lifestyle therapy and agents that improve insulin sensitivity. In youth, NAFLD appears tightly correlated with components of the MetS, especially visceral fat, which appears to predict fibrosis as well as liver fat. In addition, noninvasive techniques such as transient elastography may help provide data on fibrosis in youth with NAFLD and avoid biopsy. SUMMARY: The close association between NAFLD and the MetS supports screening for other comorbidities associated with the MetS. Further research is urgently required to best identify effective therapies to prevent and treat NAFLD, but its close association with MetS argues for a focus on strategies designed to improve insulin resistance and components of the MetS. PMID- 19444113 TI - Assignment of the sex of rearing in the neonate with a disorder of sex development. AB - PURPOSE OF REVIEW: Infants born with ambiguous genitalia [henceforth referred to as Disorder of Sex Development (DSD)] present a unique set of clinical challenges requiring an organized yet practical approach. Given the low frequency with which these types of patients are encountered, their management is best accomplished by practitioners experienced with DSDs. The goal is to discuss, in light of recent publications, information required to make rational management decisions and provide our perspective. RECENT FINDINGS: An overview of DSD with recent publications germane to diagnosis, management, and sex of rearing decisions is presented. Most DSD etiologies are rare and outcome studies are scarce. A high degree of uncertainty and low level of scientific support have led to most of the controversies in this field. SUMMARY: Care of a DSD infant must be individualized. Management decisions are based on multiple factors including reproductive anatomy, DSD etiology, parental/cultural factors, and most importantly outcome. Parents should be provided with an objective, realistic, and complete assessment of their child's condition including a discussion of the level of uncertainty (regarding outcome) inherent in each individual case. The medical care team must strike a balance between presenting available outcome data and differing opinions on DSD management in helping parents reach management decisions, particularly concerning sex of rearing. PMID- 19444114 TI - BMI report cards: will they pass or fail in the fight against pediatric obesity? AB - PURPOSE OF REVIEW: Pediatric obesity has reached epidemic proportions in the USA and Europe. The use of BMI report cards is one approach to addressing the epidemic that is gaining popularity across the USA and in the UK. RECENT FINDINGS: Recent findings suggest that parents of overweight children underestimate child weight status and the majority of pediatric overweight and obesity goes undiagnosed in primary care settings in the USA. Although there is no argument against the efficacy of tracking a child's BMI and informing parents of their child's weight status, there is considerable controversy surrounding whether schools should be involved in BMI screening. Research on the efficacy of BMI report cards suggests that parental awareness of weight status is not improved by BMI report cards. Findings are inconclusive on whether BMI report cards lead to changes in weight-related health behaviors, and there is no evidence to suggest that report cards ultimately impact weight status. Additionally, research indicates that BMI report cards may increase dieting, a risk factor for both increased weight and eating disorders in adolescents. SUMMARY: Research does not suggest that BMI report cards will be effective in reducing rates of pediatric overweight and obesity. Instead, recent findings show that the potential for harm may outweigh possible benefits. States and countries that mandate the use of BMI report cards should make evaluation of these policies a priority. PMID- 19444115 TI - Update on epinephrine (adrenaline) for pediatric emergencies. AB - PURPOSE OF REVIEW: Epinephrine (adrenaline) is a medication widely used in the pediatric emergency department. This article reviews the most recent evidence and recommendations behind the many applications of epinephrine as they apply to the care of children in emergency departments. RECENT FINDINGS: Recent publications address epinephrine's role in the treatment of anaphylaxis, croup, asthma, bronchiolitis and as an adjunct to local anesthesia. Additionally, authors discuss epinephrine autoinjectors and the various routes of epinephrine administration. SUMMARY: Epinephrine is the recommended first-line treatment for anaphylaxis and moderate-to-severe croup. Its role in asthma and bronchiolitis is less clear. Traditional beta2-agonists are seen as first-line therapies for moderate bronchiolitis and asthma exacerbations. Epinephrine may have a role for subsets of patients with both of these illnesses. The preferred route for parenteral treatment is intramuscular. Epinephrine is well tolerated as an adjunct to local anesthesia when used in digital blocks in digits with normal perfusion. Although autoinjectors allow faster access to epinephrine for anaphylaxis, there are many issues surrounding their use and indications. PMID- 19444116 TI - Rheumatic manifestations associated with HIV in the highly active antiretroviral therapy era. AB - PURPOSE OF REVIEW: To evaluate the rheumatic manifestations associated with HIV infection in the highly active antiretroviral therapy (HAART) era. RECENT FINDINGS: The overall prevalence of rheumatic manifestations in HIV population is approximately 9% with various clinical features. Anti-TNF agents do not appear to adversely affect the CD4 cell counts or viral load if the HIV infection is well controlled prior to initiation of therapy. SUMMARY: In the HAART era, HIV infected individuals can be affected by various rheumatic syndromes including arthritis, spondyloarthritis, DILS, vasculitides, connective tissue disease, myopathies, and musculoskeletal diseases. With the use of HAART, the prevalence of spondyloarthritis and Diffuse Infiltrative Lymphocytosis Syndrome has decreased, whereas the musculoskeletal complications of HIV and HAART, such as osteopenia, osteonecrosis, and infection continue to be a concern. With immune restoration, various inflammatory and autoimmune diseases, such as SLE, rheumatoid arthritis, and polymyositis may occur de novo or exacerbate. Most antirheumatic therapies used in HIV-negative individuals appear to be safe and effective in the setting of HIV infection as long as prudent guidelines are followed. PMID- 19444117 TI - Infection prophylaxis in antirheumatic therapy: emphasis on vaccination. AB - PURPOSE OF REVIEW: To assess data concerning vaccination among persons with rheumatic diseases, focusing on the effects of immune-modulating therapeutic agents on the responses. RECENT FINDINGS: Patients with rheumatic diseases receiving certain therapeutic agents may exhibit less robust responses to vaccination. However, data in various studies are conflicting. In general, even in studies demonstrating attenuation of vaccine response, increases in titers are observed and may be protective. SUMMARY: Vaccinations are an important strategy to prevent infections. Although antirheumatic therapies may affect responses, patients should still be considered candidates for all appropriate vaccinations. PMID- 19444118 TI - Lower urinary tract symptoms in women. AB - PURPOSE OF REVIEW: To summarize recent population-based literature on the prevalence and consequences of urinary incontinence and overactive bladder (OAB) symptoms in women and describe our present knowledge regarding known risk factors. RECENT FINDINGS: The prevalence of urinary incontinence in women ranged from 5 to 69%, with most studies reporting a prevalence of any urinary incontinence in the range of 25-45%. In a longitudinal population study in which women were followed for 16 years, the overall prevalence of urinary incontinence increased from 15 to 28%, and the incidence rate of urinary incontinence was 21%, whereas the corresponding remission rate was 34%. Increasing evidence is now available regarding a genetic component in the cause of stress urinary incontinence. The reported prevalence of OAB in women varied between 7.7 and 31.3%, and in general, prevalence rates increased with age. In a longitudinal study, the prevalence of OAB, nocturia and daytime micturition frequency of eight or more times per day increased by 9, 20 and 3%, respectively, in a cohort of women followed from 1991 to 2007. The incidence of OAB was 20%, and the corresponding remission rate was 43%. SUMMARY: Urinary incontinence and OAB are highly prevalent conditions. The cost of illness for urinary incontinence and OAB is a substantial economic and human burden and is likely to increase further in the future, highlighting the need for effective forms of management. PMID- 19444119 TI - Is it possible to diagnose intrinsic sphincter deficiency in women? AB - PURPOSE OF REVIEW: The diagnosis of intrinsic sphincter deficiency became important about 20 years ago when it influenced the choice of operative procedure for women with stress urinary incontinence. However, it was ill-defined and diagnosed by a variety of techniques. The contemporary surgical treatment of urinary stress incontinence is by suburethral sling; so this review addresses three questions: is it still important to identify intrinsic sphincter deficiency prior to surgical intervention for stress incontinence? What techniques are available to do so? How robust are these measurements? RECENT FINDINGS: There is some evidence that women with intrinsic sphincter deficiency have a poorer outcome if they are treated by a transobturator tape compared with a tension-free vaginal tape or a pubovaginal sling. Intrinsic sphincter deficiency continues to be mainly identified by low urethral closure pressures or low abdominal leak point pressures or both but the methodology is variable. There have been some attempts at using ultrasound to identify intrinsic sphincter deficiency but without any definite conclusions. SUMMARY: Intrinsic sphincter deficiency is an imprecise diagnosis, which continues to be defined by a low pressure urethra. This can be measured in different ways but there is poor standardization of the tests to do so. Intrinsic sphincter deficiency appears to be clinically important but the full implications of this diagnosis will remain unknown until this imprecision is addressed. PMID- 19444120 TI - Should we train urologists in female urology? A European view. AB - PURPOSE OF REVIEW: Training in female urology in Europe so far has been a national focus of individual European countries. Because of reasons like differentiation in pathology, activities of other specialisms like gynaecology and reimbursement issues, the way in which extra training in female urology is organized varies a lot. RECENT FINDINGS: We have already encountered big changes in legislation of working hours and the way in which patients are more and better informed about diseases and treatments. This situation compels us to change and synchronize training in female urology on an international level. In Europe the answers to needs from individual urologists in a pluriform European setting comprise among others Residency Training Programmes in Urology, accredited by the European Board of Urology; a European Training Program for residents (EUREP) and a European Subspeciality Certification certified by the European Board of Urology (EBU). For training in Female Urology the lastest development is the organization of a Masterclass in Female and Functional Urology. SUMMARY: This manuscript explains the European Situation and the European answer to the identified challenges. PMID- 19444121 TI - Has botulinum toxin therapy come of age: what do we know, what do we need to know, and should we use it? AB - PURPOSE OF REVIEW: To review the most recent data concerning the clinical use of botulinum toxin type A (BoNT/A) in different human lower urinary tract dysfunctions, with particular emphasis on neurogenic detrusor overactivity. RECENT FINDINGS: The most recent findings indicate that the repeated application of BoNT/A is effective in patients with neurogenic detrusor overactivity, maintaining sustained control of incontinence, protection of upper urinary tract and reduction of urinary infectious complications. In addition, BoNT/A injections have proved to be well tolerated and the risk of bladder fibrosis nonexistent. Other BoNT/A indications under investigation are idiopathic detrusor overactivity, benign prostatic enlargement and bladder pain syndrome/interstitial cystitis. SUMMARY: Although still waiting for approval, BoNT/A detrusor injections can be safely offered to well informed patients with refractory neurogenic detrusor overactivity, as an alternative to more invasive therapies, such as bladder augmentation. Ongoing studies are expected to come up with the necessary information for definitive approval of BoNT/A in neurogenic detrusor overactivity patients. Regarding other possible applications such as idiopathic detrusor overactivity, benign prostatic enlargement and bladder pain syndrome/interstitial cystitis, its use should still be restricted to research centres in well designed clinical trials. PMID- 19444122 TI - The benefits of hearing aids and closed captioning for television viewing by older adults with hearing loss. AB - OBJECTIVE: Although watching television is a common leisure activity of older adults, the ability to understand televised speech may be compromised by age related hearing loss. Two potential assistive devices for improving television viewing are hearing aids (HAs) and closed captioning (CC), but their use and benefit by older adults with hearing loss are unknown. The primary purpose of this initial investigation was to determine if older hearing-impaired adults show improvements in understanding televised speech with the use of these two assistive devices (HAs and CC) compared with conditions without these devices. A secondary purpose was to examine the frequency of HA and CC use among a sample of older HA wearers. DESIGN: The investigation entailed a randomized, repeated measures design of 15 older adults (59 to 82 yr) with bilateral sensorineural hearing losses who wore HAs. Participants viewed three types of televised programs (news, drama, and game show) that were each edited into lists of speech segments and provided an identification response. Each participant was tested in four conditions: baseline (no HA or CC), HA only, CC only, and HA + CC. Also, pilot testing with young normal-hearing listeners was conducted to establish list equivalence and stimulus intelligibility with a control group. All testing was conducted in a quiet room to simulate a living room, using a 20 in flat screen television. Questionnaires were also administered to participants to determine the frequency of HA and CC use while watching television. RESULTS: A significant effect of viewing condition was observed for all programs. Participants exhibited significantly better speech recognition scores in conditions with CC than those without CC (p < 0.01). Use of personal HAs did not significantly improve recognition of televised speech compared with the unaided condition. The condition effect was similar across the three different programs. Most of the participants (73%) regularly wore their HAs while watching television; very few of them (13%) had ever used CC. CONCLUSIONS: On average, use of CC while watching television dramatically improved speech understanding by a sample of older hearing-impaired adults compared with conditions without CC, including when HAs were worn. PMID- 19444123 TI - Laryngeal mask airway vs. uncuffed endotracheal tube for nasal and paranasal sinus surgery: paediatric airway protection. AB - BACKGROUND AND OBJECTIVE: Risks are anticipated for laryngeal mask airway (LMA) anaesthesia during nasal and sinus surgeries because blood can trickle posteriorly into the hypopharynx and contaminate the airway. This study was conducted to determine whether a LMA could provide adequate airway protection from the expected intraoperative bleeding. METHODS: After obtaining ethics committee approval, 60 children ASA status I or II, 1-12 years of age, and scheduled for nasal and sinus surgery were randomized to one of two groups, endotracheal tube (ETT) or LMA, with 30 patients in each. Topical lidocaine with adrenaline was used in all patients, and throat packs were used for the ETT group. The airway was examined using a fibreoptic endoscope in order to determine whether blood or tissue debris soiled the supraglottic airway or trachea. After extubation, LMAs and ETTs were examined for soiling by blood and graded on a scale of 0-3. For ETT, the grades were 0, none; 1, contamination above the mark for vocal cord depth; 2, contamination below the mark for vocal cord depth; and 3, contamination interiorly. For LMA, they were 0, no staining; 1, staining on the anterior aspect of the cuff of the LMA; 2, staining inside the cup of the LMA; and 3, staining found in the tube. RESULTS: Blood stains were found in the larynx of one child in the LMA group. In the ETT group, there were three cases of staining (two supraglottic and one in the trachea, P = 0.161). With the LMA, 12 (40%) and 18 (60%) patients had visual contamination scores of 0 and 1, respectively. With the ETT, 14 (46.7%), 10 (33.3%), and six (20%) patients had visual contamination scores of 0, 1, and 2, respectively (P = 0.0123). CONCLUSION: LMA is a suitable method for paediatric patients undergoing sinonasal surgery because it offers airway protection from blood contamination comparable to that of a standard uncuffed ETT with throat pack. PMID- 19444124 TI - Effect of inhaled and intravenous lidocaine on inflammatory reaction in endotoxaemic rats. AB - BACKGROUND AND OBJECTIVE: Systemically administered lidocaine has been shown to have anti-inflammatory properties. Inhalation is an attractive way of application because of high pulmonary compound concentrations and potentially fewer systemic side effects. The aim of this study was to clarify whether inhaled or, likewise, intravenous lidocaine can attenuate the inflammatory response in a model of experimental endotoxaemia in the rat. METHODS: Animals randomly received (nine animals in each group) lidocaine, either aerosolized 4 mg kg(-1) (Lid(Ae4.0)) and 0.4 mg kg(-1) (Lid(Ae0.4)) or 4 mg kg(-1) intravenously (Lid(iv)) before intravenous injection of 5 mg kg(-1) lipopolysaccharide (LPS). Administration of lidocaine was repeated after 2 h. Additional control animals were observed either without (sham) or with the infusion of LPS. Following 5 h of experimental endotoxaemia, the concentrations of tumour necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta) and IL-6 were measured in bronchoalveolar lavage fluid and blood plasma. Release of nitrite in ex-vivo cultured alveolar macrophages was measured by Griess assay. RESULTS: Bronchoalveolar lavage fluid levels of IL-1beta and TNFalpha in Lid(Ae4.0) (IL-1beta, -47%; TNFalpha, -41%; P < 0.05) and Lid(iv) (IL-1beta, -55%; TNFalpha, -54%; P < 0.05) but not in Lid(Ae0.4) were significantly lower than in LPS. Plasma cytokine levels were not attenuated. Nitrite was found to be significantly reduced in Lid(Ae4.0) (-46%), Lid(Ae0.4) (-39%) and Lid(iv) (-41%) when compared with LPS (P < 0.05, respectively). CONCLUSION: Pretreatment of endotoxaemic rats either with Lid(Ae4.0) or with Lid(iv) attenuated the levels of proinflammatory mediators in bronchoalveolar lavage fluid. Plasma cytokine levels were not affected. Nebulized lidocaine (0.4 mg kg(-1)) inhibited the nitrite release but did not affect the cytokine levels. PMID- 19444125 TI - Chinese medicinal herb Scutellaria barbata modulates apoptosis and cell survival in murine and human prostate cancer cells and tumor development in TRAMP mice. AB - Scutellaria barbata (SB) has been used in Chinese medicine to treat various cancers. This study investigated the effects of SB on prostate cancer prevention. Male TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) mice at 9 weeks were randomly divided into four groups and given daily oral feedings of 8, 16, or 32 mg SB or sterilized water. In the control group, palpable tumors initially appeared at 19 weeks of age and were present in all mice by 32 weeks. In the respective treatment groups, palpable tumor development was delayed by 2, 4, and 7 weeks and 22, 30, and 38% of the mice were free of palpable tumors. Palpable tumor development in 50% of the mice occurred at 25 weeks in the placebo group, 29 weeks in the low-dose and mid-dose treatment groups, and 33 weeks in the high dose group (log rank, P = 0.0211). Histological assessment further showed that the SB treatment (32 mg) delayed prostate tumor progression in the TRAMP mice. Caspase 3 activation was observed in SB-treated prostate tissue. Positive TUNEL assay results were detected in TRAMP-C1 and LNCaP cells treated with SB (1 mg/ml), which indicated significant apoptosis induction. Western blotting of SB treated LNCaP cells also showed elevated expression of Bax, p53, Akt, and JNK. In vivo data showed that the SB delayed tumor development in TRAMP mice. Complementary in-vitro data indicated that SB might exert this function by upregulating the apoptotic pathway and downregulating the survival pathway in prostate cancer cells, thus suggesting that SB possesses chemopreventive properties and has potential for cancer treatment. PMID- 19444126 TI - Geographical variations in the incidence of childhood acute leukaemia in France over the period 1990-2004. AB - Spatial variations in childhood acute leukaemia (AL) incidence rates were investigated by departement, in mainland France, over the period 1990-2004. This is the first spatial study of this incidence to cover a 15-year period. French National Registry of Childhood Haematological Malignancies data and population counts by type of leukaemia (AL, acute lymphoblastic leukaemia, acute myeloblastic leukaemia), time period (1990-2004, 1990-1994, 1995-1999 and 2000 2004), sex, and age group (0-14, 0-4, 5-9 and 10-14 years of age) were considered. The overall homogeneity of the relative risks of leukaemia was tested, as well as comparison to 1 of each relative risk by the exact Poisson test. To give a more stable estimate of the underlying relative risk pattern than that provided by the local standardized incidence ratios (SIRs), Bayesian hierarchical models using four different spatial priors have been produced: the parametric BYM and CAR models, and two semiparametric models. Very slight overall heterogeneity was observed on the whole AL data set (SIR overdispersion 18.6%, P=0.10). Irrespective of the model, the ranges of the smoothed SIRs exhibited considerable shrinkage relative to the ranges of the local SIRs. The associated maps were slightly heterogeneous; the smoothed SIRs of overall acute lymphoblastic leukaemia of the south-west departements were slightly higher than those of the north-east. The results, however, did not remain stable when investigated by leukaemia type, time period, sex or age group. No spatial heterogeneity of childhood AL incidence on the departement scale was observed but that does not exclude spatial heterogeneity on other scales. PMID- 19444127 TI - Emergency preparedness for newborn screening and genetic services. AB - Patients identified in newborn screening programs can be among the most vulnerable during a disaster due to their need to have prompt diagnosis and medical management. Recent disasters have challenged the ability of newborn screening programs to maintain the needed continuity during emergency situations. This has significant implications for the newborn screening laboratories, the diagnostic confirmation providers, and the patients who either require diagnosis or maintenance of their therapeutic interventions. In 2007, the National Coordinating Center (NCC) for the Regional Genetics and Newborn Screening Collaboratives (RCs) sponsored a meeting involving representatives of the Regional Genetics and Newborn Screening Collaborative Groups, state newborn screening programs, providers of diagnosis and confirmation services, manufacturers of equipment, medical foods, and other treatments used in patients identified in newborn screening programs, and individuals from agencies involved in disaster response including the National Disaster Medical Service, the Centers for Disease Control and Prevention, the Emergency Management Assistance Compact, the Federal Emergency Management Agency, and others. In addition to developing contingency plans for newborn screening, we have considered other uses of genetics as it is used in DNA-based kinship identification of mass casualties. The meeting resulted in the description of a wide range of issues facing newborn screening programs, provider groups, and patients for which emergency preparedness development is needed in order that appropriate response is enabled. PMID- 19444128 TI - Distress and burnout among genetic service providers. AB - PURPOSE: To determine the nature, sources, prevalence, and consequences of distress and burnout among genetics professionals. METHODS: Mailed survey of randomly selected clinical geneticists (MDs), genetic counselors, and genetic nurses. RESULTS: Two hundred and fourteen providers completed the survey (55% response rate). Eight discrete sources of distress were identified forming a valid 28-item scale (alpha = 0.89). The greatest sources of distress were compassion stress, the burden of professional responsibility, negative patient regard, and concerns about informational bias. Genetic counselors were significantly more likely to experience personal values conflicts, burden of professional responsibility, and concerns about informational bias than MDs or nurses. Burnout scores were lower among those practicing more than 20 years and nurses. Distress scores were positively correlated with burnout and professional dissatisfaction (P < 0.0001). Eighteen percent of respondents think about leaving patient care, and burnout was the most significant predictor. Predictors of burnout included greater distress, fewer years in practice, working in university based settings, being a genetic counselor or an MD, and deriving less meaning from patient care. CONCLUSIONS: Genetic service providers experience various types of distress that may be risk factors for burnout and professional dissatisfaction. Interventions to reduce distress and burnout are needed for both trainees and practitioners. PMID- 19444129 TI - The emerging role of genetics professionals in forensic kinship DNA identification after a mass fatality: lessons learned from Hurricane Katrina volunteers. AB - PURPOSE: To explore the experience of medical genetics professionals who volunteered in the DNA identification efforts after Hurricane Katrina to identify "lessons learned" and plan for future recovery efforts. METHODS: A web-based survey was administered to volunteers in the Fall of 2007. RESULTS: Sixty-six individuals (75%) completed the survey. Eighty-six percent volunteered because they felt their skills as genetics professional were needed and 46% desired additional training on the molecular aspects of kinship analysis. Most (97%) reported that they would like to see the genetics community become actively involved in further developing the role of genetics professionals in mass fatality response. All respondents (100%) would volunteer again. CONCLUSION: Developing a registry of volunteers and educational materials tailored to the needs of genetics professionals should be explored as a mechanism to prepare the genetics community to play an active role in future mass fatality response. PMID- 19444130 TI - Individual pathogens, pathogen burden and markers of subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. AB - METHODS: We examined the cross-sectional relationships of subclinical atherosclerosis - expressed by carotid intimal-medial thickness and coronary calcification - with antibodies to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex virus, hepatitis A virus, and pathogen burden (number of positive pathogens). A random sample of 1056 individuals chosen from 5030 Multi-Ethnic Study of Atherosclerosis cohort participants were included. RESULTS: After multiple adjustment, no associations were found between atherosclerosis measures and either individual pathogens or pathogen burden. Interactions with inflammatory and endothelial function markers, demographic factors, BMI, high-density lipoprotein, diabetes, and smoking were also explored. The only interaction that was large, qualitative, statistically significant (P < 0.05) and in the expected direction was that between hepatitis A virus and soluble intercellular adhesion molecule-1 with regard to Agatston calcium score: the difference between hepatitis A virus-positive and hepatitis A virus-negative participants was -186 units in participants with soluble intercellular adhesion molecule-1 below the median, and +162 units in those with soluble intercellular adhesion molecule-1 equal or above the median. However, given the number of interactions that were explored, these results must be interpreted cautiously. CONCLUSION: Findings from the present analyses do not provide support for an infectious etiology for subclinical atherosclerosis. However, the study's limitations, which include its cross-sectional design and insufficient statistical power, suggest that inferences from its findings should be made cautiously. PMID- 19444131 TI - Single coronary artery with anomalous origin of right coronary artery from left main stem. AB - We report the case of a 57-year-old man with unstable angina that was taken up for coronary angiography, which showed an anomalous right coronary artery originating from left main stem. PMID- 19444132 TI - Diagnostic accuracy and clinical relevance of brain natriuretic peptide assay in pediatric patients with congenital heart diseases. AB - BACKGROUND: The clinical usefulness of B-type natriuretic peptide (BNP) assay in congenital heart diseases is still controversial. We evaluated the diagnostic accuracy and clinical relevance of this assay in different cardiovascular hemodynamic conditions in pediatric patients with congenital heart diseases. MATERIALS AND METHODS: BNP was measured in 173 healthy individuals and in 382 pediatric patients with congenital heart diseases. We identified five subgroups of hemodynamic conditions: left ventricular volume overload, right ventricular volume overload, left ventricular pressure overload, right ventricular pressure overload, and biventricular volume overload. RESULTS: BNP was higher (P<0.0001) in patients (median 49.0 ng/l, range 0.45-14363 ng/l) than in the reference population (median 6.1 ng/l, range 1.0-29.7 ng/l). BNP assay showed a good diagnostic accuracy in discriminating between healthy individuals and patients (area under the receiver operating characteristic curve 0.95, SE 0.009). Lower BNP values were found in right ventricular pressure overload than in left ventricular pressure overload, left ventricular volume overload, or biventricular volume overload. In the left ventricular volume overload subgroup, BNP significantly correlated with peak systolic gradients (rho=0.622, P<0.001) and left ventricular dilatation (rho=0.35, P=0.03). In the right ventricular volume overload subgroup, BNP correlated with right ventricular pressure (rho=0.622, P<0.001) and right ventricular dilatation (rho=0.377, P=0.0077). Moreover, in cyanotic defects, BNP showed a significant correlation with O2 saturation (rho=0.204 P=0.0128). CONCLUSION: BNP assay showed a good diagnostic accuracy in discriminating between healthy individuals and patients. Congenital heart disease with left ventricular pressure overload and biventricular volume overload has higher BNP values than that with right ventricular pressure overload. PMID- 19444133 TI - Atheromatous degeneration of the neointima in a bare metal stent: intravascular ultrasound evidence. AB - We report intravascular ultrasound evidence of a ruptured plaque within a bare metal stent restenosis. In the traditional view, in-stent restenosis is considered to be a benign condition associated with progressive apposition of inert extracellular matrix. The clinical correlate of this pathology would be stable angina. In contrast, recent data have shown that at least one-third of patients with in-stent restenosis present with acute coronary syndromes. This case provides in-vivo evidence that the neointima can undergo atheromatous degeneration and rupture. This matches evidence from recent registries and in vitro data suggesting that bare metal stent restenosis should not be considered a clinically benign entity. PMID- 19444134 TI - Anomalous left coronary artery origin from the pulmonary artery: an unusual late presentation of Bland-Garland-White syndrome. AB - A 43-year-old woman presented with exertional dyspnea. On investigation, she was found to have ischemic left ventricular dysfunction on the basis of an anomalous left coronary artery originating from the pulmonary artery. She underwent successful surgical correction of this congenital anomaly that usually presents in childhood. PMID- 19444135 TI - Baseline and 6-month B-type natriuretic peptide changes are independent predictors of events in patients with advanced heart failure awaiting cardiac transplantation. AB - OBJECTIVE: To assess the prognostic role of B-type natriuretic peptide (BNP) measured at baseline and after 6 months in advanced heart failure patients, candidates for heart transplantation. METHODS: Ninety-nine patients with BNP evaluation (mean age 50.8 years, 85% men) were admitted in the heart transplantation waiting list; 39% were in New York Heart Association functional class IV; with hemodynamic patterns of severe heart failure, the cause was ischemic in 45% and idiopathic in 44%. In order to identify more severe patients, BNP values and changes at 6 months were dichotomized according to their upper tertile (>1100 and >or=70 pg/ml, respectively). RESULTS: Median baseline BNP was 719 pg/ml. After a median of 45 months, 40 events were observed (three cardiac assist device implants, 16 urgent heart transplantations, 13 sudden deaths and eight deaths from heart failure). The event rate was 10.0 and 32.3 per 100 person years in patients with low and high BNP, respectively. In a bivariable Cox regression, BNP at entry in the list and change in BNP at 6 months were independent predictors of events, with hazard ratios of 4.10 (95% confidence interval 2.14-7.88, P<0.001) and 4.55 (95% confidence interval 2.36-8.80, P<0.001), respectively. Furthermore, the risk increased from neither BNP/BNP change, to one of them and to both of them present. CONCLUSION: Both high baseline and further increase in BNP levels during midterm follow-up are strong predictors of events in patients with advanced heart failure awaiting heart transplantation. PMID- 19444136 TI - Uneventful electroconvulsive therapy in a patient with dopa-responsive dystonia (Segawa syndrome). AB - BACKGROUND: The Segawa syndrome is an autosomal dominant form of guanosine triphosphate cyclohydrolase deficiency, resulting in decreased dopamine and serotonin levels, typically presenting as a dopa-responsive dystonia. METHOD: Case presentation of a 56-year-old man with dopa-responsive dystonia, treated with electroconvulsive therapy for a psychotic depression. RESULTS: Scores on the Inventory of Depressive Symptomatology dropped from 35 before treatment to 3 after the eighth treatment session. Etomidate and succinylcholine were used as anesthetics. Apart from 2 sessions with postictal agitation, the course of electroconvulsive therapy was finished uneventfully. Electroconvulsive therapy and anesthesia had no untoward effects on motor function. CONCLUSIONS: Electroconvulsive therapy can be administered safely and effectively in a patient with dopa-responsive dystonia (Segawa syndrome). PMID- 19444137 TI - A survey of the practice of electroconvulsive therapy in Asia. AB - OBJECTIVE: To describe a comprehensive survey of the practice of electroconvulsive therapy (ECT) in Asia. METHOD: Between 2001 and 2003, a 29-item questionnaire was sent to 977 psychiatric facilities in 45 Asian countries. RESULTS: Completed questionnaires were returned by 334 (34.2%) institutions in 29 (64.4%) countries. Electroconvulsive therapy was available in 257 institutions in 23 countries. During the year before the survey, 39,875 patients (62% men) received a mean of 7.1 ECT treatments. Most patients (73.1%) were 18 to 44 years old; few were younger than 18 years (6.0%) or older than 64 years (4.4%). Indications for ECT were schizophrenia (41.8%), major depression (32.4%), mania (14.0%), catatonia (6.9%), drug abuse (1.8%), dysthymia (1.6%), and others. Brief pulse ECT devices were used in only 115 (58.4%) of 197 institutions. Routine electroencephalographic monitoring was conducted in only 59 (23.0%) institutions. Bilateral electrode placement was invariable in 202 (78.6%) institutions. Unmodified ECT was administered to 22,194 (55.7%) patients at 141 (54.9%) institutions in 14 countries. Continuation ECT was available in only 115 (44.7%) institutions in 17 countries. No institution had a formal ECT training program. CONCLUSIONS: The practice of ECT in Asia may seem suboptimal: schizophrenia, not depression, is the most common indication; most institutions offer sine-wave ECT; unmodified ECT is commonly administered; bilateral electrode placement is invariable in most institutions; electroencephalographic monitoring is uncommon; continuation ECT is infrequent; and no formal training in ECT is available. We speculate that the suboptimal practices reflect felt needs and ground realities in standards of medical care in developing countries rather than a misuse of ECT. PMID- 19444138 TI - What is it really like to have electroconvulsive therapy? PMID- 19444139 TI - The depiction of electroconvulsive therapy in the British press. AB - BACKGROUND AND OBJECTIVES: It has been suggested that electroconvulsive therapy (ECT) tends to be described in negative terms by some sections of the media. The aim of this survey was to examine the depiction of ECT in the British press. METHODS: The word "ECT" and other related terms were entered into the Web site search facility of every British national newspaper. RESULTS: The search returned 348 articles. Only 11% depicted ECT in a positive light, whereas 32% were negative. Among the negative articles, discourse analysis revealed 2 main semantic domains: "cruelty" and "ECT as a tool for repression." CONCLUSIONS: Depictions of ECT in the British press tend to be either neutral or negative. Negative depictions of ECT may contribute to the stigma of mental illness, by marginalizing this treatment and therefore those severely ill patients who receive it. PMID- 19444140 TI - Measuring electroencephalographic seizure adequacy during electroconvulsive therapy: a comparison of 2 definitions. AB - The second edition of The ECT Handbook of the Royal College of Psychiatrists gives importance to the pattern of electroencephalographic (EEG) seizure rather than to the duration for measuring seizure adequacy. We examined the potential effect of this change in definition by estimating the restimulation rates in electroconvulsive therapy. The new definition of EEG seizure was applied to 102 computerized EEG recordings obtained during electroconvulsive therapy sessions in an academic institute in India. The EEGs were read by 2 independent researchers blind to each other's ratings and blind to the motor seizure status. All 41 seizures considered "adequate" by the old definition also satisfied the new definition. Only 1 (2%) of the 58 "inadequate" seizures by the old definition was found to be adequate by the new definition. We had a very good interrater agreement on this reclassification (kappa = 0.86). In this sample, a seizure with polyspikes and a 3-Hz activity (new definition) tended to last longer than 25 seconds (old definition), satisfying both definitions. An estimated 2% of the patients with adequate seizures could have been restimulated during the study period. PMID- 19444141 TI - Masked hypertension: different blood pressure measurement methodology and risk factors in a working population. AB - OBJECTIVES: To estimate the prevalence of masked hypertension when the same ambulatory device is used for both manual and ambulatory blood pressure measurements and to measure associations with lifestyle risk factors in a working population. METHODS: White-collar workers were recruited from three public organizations. Blood pressure was measured at the workplace using Spacelabs 90207 for manual measurements (mean of the first three readings taken by a trained assistant) followed by ambulatory measurements (mean of every other reading obtained during the working day). Masked hypertension was defined as manual blood pressure measurement of less than 140/90 mmHg and ambulatory blood pressure measurement of at least 135/85 mmHg. Smoking, alcohol intake, BMI and leisure physical activity were also assessed. RESULTS: Blood pressure measurements were obtained from 2370 workers (80% participation, 61% women; mean age = 44 years). Masked hypertension was diagnosed in 15.02% of the participants. The prevalence was higher in men [adjusted odds ratio (OR) = 2.38, 95% confidence interval (CI) = 1.86-3.05]. The prevalence in men increased with age (adjusted OR = 2.08 for 40 49 years, 95% CI = 1.33-3.26 and adjusted OR = 1.91 for > or =50 years, 95% CI = 1.20-3.04) and BMI (adjusted OR = 1.78 for BMI > or = 27, 95% CI = 1.21-2.64). The prevalence in women increased with BMI (adjusted OR = 1.65 for BMI > or =27, 95% CI = 1.14-2.39) and alcohol intake (adjusted OR = 2.12 for at least six drinks per week, 95% CI = 1.34-3.35). CONCLUSION: Masked hypertension is frequent and still present when blood pressure is measured out of the office, using the same device for manual and ambulatory measurements. Sex, age, BMI and alcohol intake are associated with masked hypertension. PMID- 19444142 TI - Aliskiren-based therapy lowers blood pressure more effectively than hydrochlorothiazide-based therapy in obese patients with hypertension: sub analysis of a 52-week, randomized, double-blind trial. AB - OBJECTIVES: To compare the long-term efficacy, safety and tolerability of the direct renin inhibitor aliskiren against the diuretic hydrochlorothiazide (HCTZ) in obese patients with hypertension. METHODS: A post hoc analysis of 396 obese patients (body mass index > or = 30 kg/m2) in a 52-week study in 1124 patients with hypertension was performed. Patients were randomized to receive aliskiren 150 mg or HCTZ 12.5 mg for 3 weeks, or placebo for 6 weeks. At week 3, active treatment doses were doubled. Patients receiving placebo were randomized to aliskiren 300 mg or HCTZ 25 mg at week 6. Add-on amlodipine 5-10 mg was permitted from week 12 to achieve blood pressure (BP) control (<140/90 mmHg). RESULTS: In the subgroup of obese patients, aliskiren monotherapy provided significantly greater BP reductions than HCTZ at week 12 endpoint (-16.7/-12.3 vs. -12.2/-9.1 mmHg, P < or = 0.001). Reductions were also greater with aliskiren-based therapy than HCTZ-based therapy at week 52 endpoint (-19.9/-15.5 vs. -17.5/-13.3 mmHg; P = 0.138 for systolic BP and P = 0.007 for diastolic BP). Mean BP reductions from baseline with aliskiren-based therapy were similar in obese and nonobese patients. By contrast, HCTZ-based therapy provided significantly smaller mean reductions in BP from baseline in obese patients vs. nonobese patients (P < 0.05). Aliskiren-based therapy was generally well tolerated in obese patients, and was associated with a significantly lower incidence of hypokalemia (1.0 vs. 14.0%, P < 0.0001) than HCTZ-based therapy. CONCLUSION: Aliskiren-based therapy provided superior BP reductions to HCTZ-based therapy with good tolerability in obese patients with hypertension. PMID- 19444143 TI - Is kidney ischemia the central mechanism in parallel activation of the renin and sympathetic system? AB - In chronic kidney disease simultaneous activation of the renin-angiotensin and sympathetic systems occurs. Kidney ischemia seems to play a key role in the pathogenesis. This review firstly summarizes experimental and clinical evidence in chronic kidney disease supporting this idea and addresses the possibility that this mechanism is also relevant in some other disease conditions. PMID- 19444144 TI - Single-stage open reduction, Salter innominate osteotomy, and proximal femoral osteotomy for the management of developmental dysplasia of the hip in children between the ages of 2 and 4 years. AB - The management of neglected developmental dysplasia of the hip in walking children has always been a challenge to orthopedic surgeons. The aim of this study was to access the early clinical and radiographic results of surgical treatment of such cases using one-stage open reduction, Salter innominate osteotomy, and proximal femoral osteotomy. Seventy-one surgeries were performed in 55 patients. Favorable clinical and radiographic outcomes were comparable to other studies. We concluded that this single-stage surgery is a technically demanding, but satisfactory procedure in the management of neglected developmental dysplasia of the hip patients, and when performed adequately in indicated patients in specialized centers, it is expected to give good short-term results. PMID- 19444146 TI - Update: novel influenza A (H1N1) virus infections - worldwide, May 6, 2009. AB - Since mid-April 2009, CDC, state and local health authorities in the United States, the World Health Organization (WHO), and health ministries in several countries have been responding to an outbreak of influenza caused by a novel influenza A (H1N1) virus. In March and early April 2009, Mexico experienced outbreaks of respiratory illness subsequently confirmed by CDC and Canada to be caused by the novel virus. The influenza strain identified in U.S. patients was genetically similar to viruses isolated from patients in Mexico. Since recognition of the novel influenza A (H1N1) virus in Mexico and the United States, as of May 6, a total of 21 additional countries had reported cases, with a total of 1,882 confirmed cases worldwide. Several WHO member states are conducting ongoing investigations of this worldwide outbreak, and WHO is monitoring and compiling surveillance data and case reports. On April 29, WHO raised the level of pandemic alert from phase 4 to phase 5, indicating that human to-human spread of the virus had occurred in at least two countries in one WHO region. This report provides an update of the initial investigations and spread of novel influenza A (H1N1) virus worldwide. PMID- 19444147 TI - False-positive results with a commercially available West Nile virus immunoglobulin m assay - United States, 2008. AB - In September 2008, CDC, the Food and Drug Administration (FDA), and state health departments began a nationwide investigation into an increase in false-positive test results obtained with a commercially available West Nile virus (WNV) immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (ELISA). The investigation revealed that, in the United States, one lot of the commercially available test kits was the source of the false-positive results. That lot was recalled, and a second lot distributed outside the United States also was recalled. During July 1--September 30, 2008, the kit lot implicated in the United States resulted in positive tests on 568 specimens collected from 518 patients in 42 states and the District of Columbia (DC). A total of 166 (29%) specimens were retested at CDC, and 119 (72%) had false-positive results. A higher false positive percentage were found among patients without evidence of neuroinvasive disease (77%) than patients with evidence of neuroinvasive disease (47%). Of the 518 patients, 249 (48%) had been reported to CDC as persons with WNV disease; however, only 45 (18%) had confirmatory testing that supported their inclusion in national surveillance data. Commercially available WNV test kits should be used to determine a presumptive diagnosis of WNV neuroinvasive disease. These kits should not be used to test specimens from persons without compatible illness, and any positive result should be confirmed by additional testing at a state health department or CDC. PMID- 19444148 TI - Assessment of body mass index screening of elementary school children - Florida, 2007-2008. AB - The prevalence of childhood obesity has increased substantially in the United States and is associated with chronic diseases. State level surveillance is needed to monitor trends and investigate risk factors. In addition, data that identify at-risk communities can be used to inform those communities regarding childhood obesity. Body mass index (BMI) screening of Florida school children has been performed since 2001 as part of growth and development screening services and conducted by school districts and county health departments. Aggregated BMI data, by grade and county, are reported annually to the Florida Department of Health (FDOH). In 2008, FDOH considered establishing a more extensive statewide BMI surveillance system. To begin planning for such a system, during February March 2008, FDOH surveyed school health coordinators in Florida's 67 counties to assess qualities of BMI screening activities. Among 66 counties that provided complete surveys, 58 (88%) screened >or=75% of children in the first, third, and sixth grades, and 51 (77%) had written protocols or guidelines for measuring weight, height, or BMI. Nineteen counties (29%) were training >or=90% of their screeners, and 21 (32%) consistently used appropriate equipment for measuring height and weight. Thirty-one counties (47%) used appropriate electronic systems to calculate BMI percentile-for-age. BMI screening activities need improvement in policy and guideline development, training procedures, appropriate selection and use of equipment, and use of electronic data systems before Florida establishes a more extensive statewide surveillance system. PMID- 19444149 TI - Primary and secondary syphilis - Jefferson county, Alabama, 2002-2007. AB - In June 2006, the Alabama Department of Public Health (ADPH) requested assistance from CDC to investigate and control a multiyear epidemic of syphilis in Jefferson County. The county had experienced a decrease in primary and secondary (P&S) syphilis cases, from 279 in 1995 to nine in 2002. By 2005, the incidence had begun to rise substantially, culminating with 238 cases in 2006 and 166 in 2007. Beginning in August 2006, CDC assisted the Jefferson County Department of Health (JCDH) in investigating the increase in cases and in planning control measures. This report summarizes the results of that investigation, which found that the characteristics of cases during 2002-2004 differed substantially from cases during 2005-2007. Declines in U.S. syphilis rates, which reached their lowest point in 2000, led to optimism that syphilis elimination (defined as the absence of sustained syphilis transmission) in the United States was possible, and CDC's National Syphilis Elimination Plan was launched in 1999. Although increased U.S. syphilis rates in the early 2000s have been reported to be associated primarily with transmission among men who have sex with men (MSM), the findings from this investigation indicate reemergence of syphilis among women and heterosexual men in Jefferson County. Public health officials in other areas should remain alert for similar epidemiologic shifts. Public health departments should facilitate access to effective treatment in sexually transmitted disease (STD) clinics or other settings, consider selective screening in high-prevalence populations (e.g., in correctional settings), and ensure adequate partner notification and treatment. PMID- 19444150 TI - Outbreak of swine-origin influenza A (H1N1) virus infection - Mexico, March-April 2009. AB - In March and early April 2009, Mexico experienced outbreaks of respiratory illness and increased reports of patients with influenza-like illness (ILI) in several areas of the country. On April 12, the General Directorate of Epidemiology (DGE) reported an outbreak of ILI in a small community in the state of Veracruz to the Pan American Health Organization (PAHO) in accordance with International Health Regulations. On April 17, a case of atypical pneumonia in Oaxaca State prompted enhanced surveillance throughout Mexico. On April 23, several cases of severe respiratory illness laboratory confirmed as swine-origin influenza A (H1N1) virus (S-OIV) infection were communicated to the PAHO. Sequence analysis revealed that the patients were infected with the same S-OIV strain detected in two children residing in California. This report describes the initial and ongoing investigation of the S-OIV outbreak in Mexico. PMID- 19444151 TI - Swine-origin influenza A (H1N1) virus infections in a school - New York City, April 2009. AB - On April 24, 2009, CDC reported eight confirmed cases of swine-origin influenza A (H1N1) virus (S-OIV) infection in Texas and California. The strain identified in U.S. patients was confirmed by CDC as genetically similar to viruses subsequently isolated from patients in Mexico. Since April 24, the number of cases in the United States and elsewhere has continued to rise. As of April 28, approximately half (45) of all U.S. cases of S-OIV infection had been confirmed among students and staff members at a New York City (NYC) high school. This report describes the initial outbreak investigation by the NYC Department of Health and Mental Hygiene (DOHMH) and provides preliminary details about 44 of the 45 patients (the remaining patient resides outside of NYC and was not included in the analysis). The preliminary findings from this investigation indicate that symptoms in these patients appear to be similar to those of seasonal influenza. DOHMH will continue monitoring for changes in the epidemiology and/or clinical severity of S-OIV infection. PMID- 19444152 TI - Pool chemical--associated health events in public and residential settings - United States, 1983-2007. AB - Swimming is the second most popular exercise in the United States, with approximately 339 million swimming visits to recreational water venues, including disinfected ones (e.g., pools, water parks, and interactive fountains), each year. Pool chemicals are added to the water in these venues to prevent transmission of infectious pathogens. These chemicals can cause injury when handled inappropriately or when operators fail to use appropriate personal protective equipment. This report summarizes 36 pool chemical--associated health events reported to the New York State Department of Health (NYSDOH) for public aquatic venues during 1983--2006 and includes analyses of 1998-2007 data from the National Electronic Injury Surveillance System (NEISS) and 2007 data from the National Poison Data System (NPDS). NYSDOH reported primarily summertime health events resulting in acute respiratory illness. NEISS and NPDS data revealed that pool chemical--associated injuries or exposures led to thousands of estimated annual emergency department (ED) visits or actual poison center consultations, respectively. These pool chemical--associated health events can be prevented through 1) improved design and engineering and 2) education and training that stresses safe pool-chemical handling and storage practices and safe and preventive maintenance of equipment. PMID- 19444153 TI - Pediatric bacterial meningitis surveillance - African region, 2002--2008. AB - Sub-Saharan Africa has one of the world's greatest disease burdens of Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis infections. In 2000, Hib and S. pneumoniae infections accounted for approximately 500,000 deaths in the region; during the past 10 years, N. meningitidis has been responsible for recurring epidemics resulting in approximately 700,000 cases of meningitis. Introduction of vaccines against bacterial pathogens in Africa has been constrained by competing public health priorities, limited availability of Hib and S. pneumoniae vaccines, suboptimal N. meningitidis vaccine, inadequate funding, and limited information regarding the disease burden associated with these infections. The World Health Organization (WHO) and CDC analyzed data for 2002--2008 from the Pediatric Bacterial Meningitis (PBM) Surveillance Network, which collects information on laboratory-confirmed bacterial meningitis cases among children aged <5 years at sentinel hospitals in countries throughout the WHO African Region. The results of that analysis determined that, during 2002 2008, a total of 74,515 suspected cases of meningitis were reported. Among the 69,208 suspected cases with known laboratory results, 4,674 (7%) samples were culture-positive for the three bacterial infections under surveillance: 2,192 (47%) were positive for S. pneumoniae, 1,575 (34%) for Haemophilus influenzae, and 907 (19%) for N. meningitidis. The majority of the remaining culture results were negative. These and other PBM network findings will help guide strategies for strengthening laboratory and data management capacity at existing sentinel hospitals and for planning future network expansion in the WHO African Region. PMID- 19444154 TI - Novel influenza A (H1N1) virus infections in three pregnant women - United States, April-May 2009. AB - CDC first identified cases of respiratory infection with a novel influenza A (H1N1) virus in the United States on April 15 and 17, 2009. During seasonal influenza epidemics and previous pandemics, pregnant women have been at increased risk for complications related to influenza infection. In addition, maternal influenza virus infection and accompanying hyperthermia place fetuses at risk for complications such as birth defects and preterm birth. As part of surveillance for infection with the novel influenza A (H1N1) virus, CDC initiated surveillance for pregnant women who were infected with the novel virus. As of May 10, a total of 20 cases of novel influenza A (H1N1) virus infection had been reported among pregnant women in the United States, including 15 confirmed cases and five probable cases. Among the 13 women from seven states for whom data are available, the median age was 26 years (range: 15-39 years); three women were hospitalized, one of whom died. This report provides preliminary details of three cases of novel influenza A (H1N1) virus infection in pregnant women. Pregnant women with confirmed, probable, or suspected novel influenza A (H1N1) virus infection should receive antiviral treatment for 5 days. Oseltamivir is the preferred treatment for pregnant women, and the drug regimen should be initiated within 48 hours of symptom onset, if possible. Pregnant women who are in close contact with a person with confirmed, probable, or suspected novel influenza A (H1N1) infection should receive a 10-day course of chemoprophylaxis with zanamivir or oseltamivir. PMID- 19444155 TI - Outbreak of Salmonella serotype Saintpaul infections associated with eating alfalfa sprouts - United States, 2009. AB - On February 24, 2009, the Nebraska Department of Health and Human Services identified six isolates of Salmonella serotype Saintpaul with collection dates from February 7--14. Salmonella Saintpaul is not a commonly detected serotype; during 2008, only three Salmonella Saintpaul isolates were identified in Nebraska. This report summarizes the preliminary results of the investigation of this outbreak, which has identified 228 cases in 13 states and implicated the source as alfalfa sprouts produced at multiple facilities using seeds that likely originated from a common grower. On April 26, the Food and Drug Administration (FDA) and CDC recommended that consumers not eat raw alfalfa sprouts, including sprout blends containing alfalfa sprouts, until further notice. On May 1, FDA alerted sprout growers and retailers that a seed supplier was withdrawing voluntarily from the market all lots of alfalfa seeds with a specific three-digit prefix. PMID- 19444156 TI - Knowing what counts: unbiased stereology in the non-human primate brain. AB - The non-human primate is an important translational species for understanding the normal function and disease processes of the human brain. Unbiased stereology, the method accepted as state-of-the-art for quantification of biological objects in tissue sections, generates reliable structural data for biological features in the mammalian brain. The key components of the approach are unbiased (systematic random) sampling of anatomically defined structures (reference spaces), combined with quantification of cell numbers and size, fiber and capillary lengths, surface areas, regional volumes and spatial distributions of biological objects within the reference space. Among the advantages of these stereological approaches over previous methods is the avoidance of all known sources of systematic (non-random) error arising from faulty assumptions and non-verifiable models. This study documents a biological application of computerized stereology to estimate the total neuronal population in the frontal cortex of the vervet monkey brain (Chlorocebus aethiops sabeus), with assistance from two commercially available stereology programs, BioQuant Life Sciences and Stereologer (Figure 1). In addition to contrast and comparison of results from both the BioQuant and Stereologer systems, this study provides a detailed protocol for the Stereologer system. PMID- 19444160 TI - Bracing for the unknown. PMID- 19444161 TI - Politics proves its worth. PMID- 19444162 TI - A measure of marine life. PMID- 19444169 TI - Journal club. A stem-cell researcher considers an accusation of dullness. PMID- 19444174 TI - Vaccine decisions loom for new flu strain. PMID- 19444175 TI - Exome sequencing takes centre stage in cancer profiling. PMID- 19444176 TI - Stem-cell therapy faces more scrutiny in China. PMID- 19444177 TI - Deep concerns. PMID- 19444178 TI - Austria quits CERN after 50 years. PMID- 19444185 TI - Seismology: The sleeping dragon. PMID- 19444186 TI - Microbiology: Tinker, bacteria, eukaryote, spy. PMID- 19444187 TI - Water: resistance on the route towards a fair share for all. PMID- 19444188 TI - Water: conflicts set to arise within as well as between states. PMID- 19444189 TI - Leading the tributes to editor John Maddox. PMID- 19444190 TI - Is free will an illusion? PMID- 19444195 TI - Q&A: Origami unfolded. Interview by Roxanne Khamsi. PMID- 19444196 TI - Origins of life: Systems chemistry on early Earth. PMID- 19444197 TI - Molecular microbiology: A key event in survival. PMID- 19444198 TI - Astrophysics: Cosmic crystals caught in the act. PMID- 19444199 TI - Microbiology: Signals for change. PMID- 19444200 TI - Archaeology: Origins of the female image. PMID- 19444202 TI - Microbial oceanography. PMID- 19444203 TI - Microbial oceanography in a sea of opportunity. AB - Plankton use solar energy to drive the nutrient cycles that make the planet habitable for larger organisms. We can now explore the diversity and functions of plankton using genomics, revealing the gene repertoires associated with survival in the oceans. Such studies will help us to appreciate the sensitivity of ocean systems and of the ocean's response to climate change, improving the predictive power of climate models. PMID- 19444204 TI - The life of diatoms in the world's oceans. AB - Marine diatoms rose to prominence about 100 million years ago and today generate most of the organic matter that serves as food for life in the sea. They exist in a dilute world where compounds essential for growth are recycled and shared, and they greatly influence global climate, atmospheric carbon dioxide concentration and marine ecosystem function. How these essential organisms will respond to the rapidly changing conditions in today's oceans is critical for the health of the environment and is being uncovered by studies of their genomes. PMID- 19444205 TI - Microbial community structure and its functional implications. AB - Marine microbial communities are engines of globally important processes, such as the marine carbon, nitrogen and sulphur cycles. Recent data on the structures of these communities show that they adhere to universal biological rules. Co occurrence patterns can help define species identities, and systems-biology tools are revealing networks of interacting microorganisms. Some microbial systems are found to change predictably, helping us to anticipate how microbial communities and their activities will shift in a changing world. PMID- 19444206 TI - The microbial ocean from genomes to biomes. AB - Numerically, microbial species dominate the oceans, yet their population dynamics, metabolic complexity and synergistic interactions remain largely uncharted. A full understanding of life in the ocean requires more than knowledge of marine microbial taxa and their genome sequences. The latest experimental techniques and analytical approaches can provide a fresh perspective on the biological interactions within marine ecosystems, aiding in the construction of predictive models that can interrelate microbial dynamics with the biogeochemical matter and energy fluxes that make up the ocean ecosystem. PMID- 19444207 TI - Viruses manipulate the marine environment. AB - Marine viruses affect Bacteria, Archaea and eukaryotic organisms and are major components of the marine food web. Most studies have focused on their role as predators and parasites, but many of the interactions between marine viruses and their hosts are much more complicated. A series of recent studies has shown that viruses have the ability to manipulate the life histories and evolution of their hosts in remarkable ways, challenging our understanding of this almost invisible world. PMID- 19444208 TI - A surface transporter family conveys the trypanosome differentiation signal. AB - Microbial pathogens use environmental cues to trigger the developmental events needed to infect mammalian hosts or transmit to disease vectors. The parasites causing African sleeping sickness respond to citrate or cis-aconitate (CCA) to initiate life-cycle development when transmitted to their tsetse fly vector. This requires hypersensitization of the parasites to CCA by exposure to low temperature, conditions encountered after tsetse fly feeding at dusk or dawn. Here we identify a carboxylate-transporter family, PAD (proteins associated with differentiation), required for perception of this differentiation signal. Consistent with predictions for the response of trypanosomes to CCA, PAD proteins are expressed on the surface of the transmission-competent 'stumpy-form' parasites in the bloodstream, and at least one member is thermoregulated, showing elevated expression and surface access at low temperature. Moreover, RNA interference-mediated ablation of PAD expression diminishes CCA-induced differentiation and eliminates CCA hypersensitivity under cold-shock conditions. As well as being molecular transducers of the differentiation signal in these parasites, PAD proteins provide the first example of a surface marker able to discriminate the transmission stage of trypanosomes in their mammalian host. PMID- 19444209 TI - Episodic formation of cometary material in the outburst of a young Sun-like star. AB - The Solar System originated in a cloud of interstellar gas and dust. The dust is in the form of amorphous silicate particles and carbonaceous dust. The composition of cometary material, however, shows that a significant fraction of the amorphous silicate dust was transformed into crystalline form during the early evolution of the protosolar nebula. How and when this transformation happened has been a question of debate, with the main options being heating by the young Sun and shock heating. Here we report mid-infrared features in the outburst spectrum of the young Sun-like star EX Lupi that were not present in quiescence. We attribute them to crystalline forsterite. We conclude that the crystals were produced through thermal annealing in the surface layer of the inner disk by heat from the outburst, a process that has hitherto not been considered. The observed lack of cold crystals excludes shock heating at larger radii. PMID- 19444210 TI - Radiation-pressure mixing of large dust grains in protoplanetary disks. AB - Dusty disks around young stars are formed out of interstellar dust that consists of amorphous, submicrometre grains. Yet the grains found in comets and meteorites, and traced in the spectra of young stars, include large crystalline grains that must have undergone annealing or condensation at temperatures in excess of 1,000 K, even though they are mixed with surrounding material that never experienced temperatures as high as that. This prompted theories of large scale mixing capable of transporting thermally altered grains from the inner, hot part of accretion disks to outer, colder disk regions, but all have assumptions that may be problematic. Here I report that infrared radiation arising from the dusty disk can loft grains bigger than one micrometre out of the inner disk, whereupon they are pushed outwards by stellar radiation pressure while gliding above the disk. Grains re-enter the disk at radii where it is too cold to produce sufficient infrared radiation-pressure support for a given grain size and solid density. Properties of the observed disks suggest that this process might be active in almost all young stellar objects and young brown dwarfs. PMID- 19444211 TI - Thermal vestige of the zero-temperature jamming transition. AB - When the packing fraction is increased sufficiently, loose particulates jam to form a rigid solid in which the constituents are no longer free to move. In typical granular materials and foams, the thermal energy is too small to produce structural rearrangements. In this zero-temperature (T = 0) limit, multiple diverging and vanishing length scales characterize the approach to a sharp jamming transition. However, because thermal motion becomes relevant when the particles are small enough, it is imperative to understand how these length scales evolve as the temperature is increased. Here we used both colloidal experiments and computer simulations to progress beyond the zero-temperature limit to track one of the key parameters-the overlap distance between neighbouring particles-which vanishes at the T = 0 jamming transition. We find that this structural feature retains a vestige of its T = 0 behaviour and evolves in an unusual manner, which has masked its appearance until now. It is evident as a function of packing fraction at fixed temperature, but not as a function of temperature at fixed packing fraction or pressure. Our results conclusively demonstrate that length scales associated with the T = 0 jamming transition persist in thermal systems, not only in simulations but also in laboratory experiments. PMID- 19444212 TI - White organic light-emitting diodes with fluorescent tube efficiency. AB - The development of white organic light-emitting diodes (OLEDs) holds great promise for the production of highly efficient large-area light sources. High internal quantum efficiencies for the conversion of electrical energy to light have been realized. Nevertheless, the overall device power efficiencies are still considerably below the 60-70 lumens per watt of fluorescent tubes, which is the current benchmark for novel light sources. Although some reports about highly power-efficient white OLEDs exist, details about structure and the measurement conditions of these structures have not been fully disclosed: the highest power efficiency reported in the scientific literature is 44 lm W(-1) (ref. 7). Here we report an improved OLED structure which reaches fluorescent tube efficiency. By combining a carefully chosen emitter layer with high-refractive-index substrates, and using a periodic outcoupling structure, we achieve a device power efficiency of 90 lm W(-1) at 1,000 candelas per square metre. This efficiency has the potential to be raised to 124 lm W(-1) if the light outcoupling can be further improved. Besides approaching internal quantum efficiency values of one, we have also focused on reducing energetic and ohmic losses that occur during electron photon conversion. We anticipate that our results will be a starting point for further research, leading to white OLEDs having efficiencies beyond 100 lm W(-1). This could make white-light OLEDs, with their soft area light and high colour rendering qualities, the light sources of choice for the future. PMID- 19444213 TI - Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. AB - At some stage in the origin of life, an informational polymer must have arisen by purely chemical means. According to one version of the 'RNA world' hypothesis this polymer was RNA, but attempts to provide experimental support for this have failed. In particular, although there has been some success demonstrating that 'activated' ribonucleotides can polymerize to form RNA, it is far from obvious how such ribonucleotides could have formed from their constituent parts (ribose and nucleobases). Ribose is difficult to form selectively, and the addition of nucleobases to ribose is inefficient in the case of purines and does not occur at all in the case of the canonical pyrimidines. Here we show that activated pyrimidine ribonucleotides can be formed in a short sequence that bypasses free ribose and the nucleobases, and instead proceeds through arabinose amino oxazoline and anhydronucleoside intermediates. The starting materials for the synthesis-cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphate-are plausible prebiotic feedstock molecules, and the conditions of the synthesis are consistent with potential early-Earth geochemical models. Although inorganic phosphate is only incorporated into the nucleotides at a late stage of the sequence, its presence from the start is essential as it controls three reactions in the earlier stages by acting as a general acid/base catalyst, a nucleophilic catalyst, a pH buffer and a chemical buffer. For prebiotic reaction sequences, our results highlight the importance of working with mixed chemical systems in which reactants for a particular reaction step can also control other steps. PMID- 19444214 TI - Interior pathways of the North Atlantic meridional overturning circulation. AB - To understand how our global climate will change in response to natural and anthropogenic forcing, it is essential to determine how quickly and by what pathways climate change signals are transported throughout the global ocean, a vast reservoir for heat and carbon dioxide. Labrador Sea Water (LSW), formed by open ocean convection in the subpolar North Atlantic, is a particularly sensitive indicator of climate change on interannual to decadal timescales. Hydrographic observations made anywhere along the western boundary of the North Atlantic reveal a core of LSW at intermediate depths advected southward within the Deep Western Boundary Current (DWBC). These observations have led to the widely held view that the DWBC is the dominant pathway for the export of LSW from its formation site in the northern North Atlantic towards the Equator. Here we show that most of the recently ventilated LSW entering the subtropics follows interior, not DWBC, pathways. The interior pathways are revealed by trajectories of subsurface RAFOS floats released during the period 2003-2005 that recorded once-daily temperature, pressure and acoustically determined position for two years, and by model-simulated 'e-floats' released in the subpolar DWBC. The evidence points to a few specific locations around the Grand Banks where LSW is most often injected into the interior. These results have implications for deep ocean ventilation and suggest that the interior subtropical gyre should not be ignored when considering the Atlantic meridional overturning circulation. PMID- 19444215 TI - A female figurine from the basal Aurignacian of Hohle Fels Cave in southwestern Germany. AB - Despite well over 100 years of research and debate, the origins of art remain contentious. In recent years, abstract depictions have been documented at southern African sites dating to approximately 75 kyr before present (bp), and the earliest figurative art, which is often seen as an important proxy for advanced symbolic communication, has been documented in Europe as dating to between 30 and 40 kyr bp. Here I report the discovery of a female mammoth-ivory figurine in the basal Aurignacian deposit at Hohle Fels Cave in the Swabian Jura of southwestern Germany during excavations in 2008. This figurine was produced at least 35,000 calendar years ago, making it one of the oldest known examples of figurative art. This discovery predates the well-known Venuses from the Gravettian culture by at least 5,000 years and radically changes our views of the context and meaning of the earliest Palaeolithic art. PMID- 19444216 TI - Metatranscriptomics reveals unique microbial small RNAs in the ocean's water column. AB - Microbial gene expression in the environment has recently been assessed via pyrosequencing of total RNA extracted directly from natural microbial assemblages. Several such 'metatranscriptomic' studies have reported that many complementary DNA sequences shared no significant homology with known peptide sequences, and so might represent transcripts from uncharacterized proteins. Here we report that a large fraction of cDNA sequences detected in microbial metatranscriptomic data sets are comprised of well-known small RNAs (sRNAs), as well as new groups of previously unrecognized putative sRNAs (psRNAs). These psRNAs mapped specifically to intergenic regions of microbial genomes recovered from similar habitats, displayed characteristic conserved secondary structures and were frequently flanked by genes that indicated potential regulatory functions. Depth-dependent variation of psRNAs generally reflected known depth distributions of broad taxonomic groups, but fine-scale differences in the psRNAs within closely related populations indicated potential roles in niche adaptation. Genome-specific mapping of a subset of psRNAs derived from predominant planktonic species such as Pelagibacter revealed recently discovered as well as potentially new regulatory elements. Our analyses show that metatranscriptomic data sets can reveal new information about the diversity, taxonomic distribution and abundance of sRNAs in naturally occurring microbial communities, and indicate their involvement in environmentally relevant processes including carbon metabolism and nutrient acquisition. PMID- 19444217 TI - qiRNA is a new type of small interfering RNA induced by DNA damage. AB - RNA interference pathways use small RNAs to mediate gene silencing in eukaryotes. In addition to small interfering RNAs (siRNAs) and microRNAs, several types of endogenously produced small RNAs have important roles in gene regulation, germ cell maintenance and transposon silencing. The production of some of these RNAs requires the synthesis of aberrant RNAs (aRNAs) or pre-siRNAs, which are specifically recognized by RNA-dependent RNA polymerases to make double-stranded RNA. The mechanism for aRNA synthesis and recognition is largely unknown. Here we show that DNA damage induces the expression of the Argonaute protein QDE-2 and a new class of small RNAs in the filamentous fungus Neurospora crassa. This class of small RNAs, known as qiRNAs because of their interaction with QDE-2, are about 20-21 nucleotides long (several nucleotides shorter than Neurospora siRNAs), with a strong preference for uridine at the 5' end, and originate mostly from the ribosomal DNA locus. The production of qiRNAs requires the RNA-dependent RNA polymerase QDE-1, the Werner and Bloom RecQ DNA helicase homologue QDE-3 and dicers. qiRNA biogenesis also requires DNA-damage-induced aRNAs as precursors, a process that is dependent on both QDE-1 and QDE-3. Notably, our results suggest that QDE-1 is the DNA-dependent RNA polymerase that produces aRNAs. Furthermore, the Neurospora RNA interference mutants show increased sensitivity to DNA damage, suggesting a role for qiRNAs in the DNA-damage response by inhibiting protein translation. PMID- 19444219 TI - Molecular Systems Biology: a new journal for a new biology? PMID- 19444220 TI - Allosteric activation mechanism of the cys-loop receptors. AB - Binding of a neurotransmitter to its ionotropic receptor opens a distantly located ion channel, a process termed allosteric activation. Here we review recent advances in the molecular mechanism by which the cys-loop receptors are activated with emphasis on the best studied nicotinic acetylcholine receptors (nAChRs). With a combination of affinity labeling, mutagenesis, electrophysiology, kinetic modeling, electron microscopy (EM), and crystal structure analysis, the allosteric activation mechanism is emerging. Specifically, the binding domain and gating domain are interconnected by an allosteric activation network. Agonist binding induces conformational changes, resulting in the rotation of a beta sheet of amino-terminal domain and outward movement of loop 2, loop F, and cys-loop, which are coupled to the M2-M3 linker to pull the channel to open. However, there are still some controversies about the movement of the channel-lining domain M2. Nine angstrom resolution EM structure of a nAChR imaged in the open state suggests that channel opening is the result of rotation of the M2 domain. In contrast, recent crystal structures of bacterial homologues of the cys-loop receptor family in apparently open state have implied an M2 tilting model with pore dilation and quaternary twist of the whole pentameric receptor. An elegant study of the nAChR using protonation scanning of M2 domain supports a similar pore dilation activation mechanism with minimal rotation of M2. This remains to be validated with other approaches including high resolution structure determination of the mammalian cys-loop receptors in the open state. PMID- 19444221 TI - Primary aldosteronism: diagnostic accuracy of the losartan and captopril tests. AB - BACKGROUND: To assess whether angiotensin-II receptor blockers (ARBs) offer any additional advantage in confirming the diagnosis of primary aldosteronism (PA) and their use in the differentiation of PA subtypes. METHODS: A prospective, cohort, head-to-head study was conducted between July 2003 and July 2006. A total of 135 patients received captopril and losartan tests to confirm the diagnosis of PA in the TAIPAI (Taiwan Primary Aldosteronism Investigation) intervention. RESULTS: In total, 71 patients were diagnosed with PA. The area under the receiver-operating characteristic (ROC) curve of the postcaptopril plasma aldosterone concentration (PAC) was significantly less than that of the postlosartan PAC (0.744 vs. 0.829, P = 0.038). Using an aldosterone-renin ratio (ARR, ng/dl per ng/ml/h) >35 with a PAC >10 ng/dl, the specificity was 89.1% vs. 93.8% and the sensitivity was 66.2% vs. 84.5 % for the captopril test vs. the losartan test, respectively. With respect to the losartan test, the accuracy was 88.9%, the agreement was good (k = 0.778), and there was no disagreement with the McNemar test (P = 0.118). Losartan had the advantage of a better negative predictive value to exclude PA when patients were referred with a serum potassium (SK) level <3.8 mmol/l. When a postlosartan ARR >60 was the cutoff value, the positive predictive value was 82% with a negative predictive value of 57% in distinguishing aldosterone-producing adenomas (APAs) from idiopathic hyperaldosteronism (IHA). CONCLUSIONS: The postlosartan ARR and PAC were shown to have better accuracy for the diagnosis of PA than the captopril test. With a postlosartan ARR >60, APAs can be adequately differentiated from IHA. PMID- 19444223 TI - AT2 receptor deficiency attenuates adipocyte differentiation and decreases adipocyte number in atherosclerotic mice. AB - BACKGROUND: Previous reports indicated that blockade of AT(1) receptor stimulation attenuated adipocyte dysfunction. However, the effects of AT(2) receptor stimulation on adipose tissue were not yet clear. In the present study, we examined the adipose tissue dysfunction in atherosclerotic apolipoprotein E knockout (ApoEKO) mice with AT(2) receptor deficiency. METHODS: Male ApoEKO and AT(2) receptor/ApoE knockout (AT(2)/ApoEKO) mice at 6 weeks of age were treated with a normal diet or a high-cholesterol diet (HCD: 1.25% cholesterol). Markers for adipocyte differentiation and inflammation in adipose tissue were assayed with real-time reverse-transcription-PCR and western blot. RESULTS: Compared with ApoEKO mice, AT(2)/ApoEKO mice with a normal diet showed only a decrease in expression of adiponectin and CCAAT/enhancer binding protein delta (C/EBPdelta) in epididymal adipose tissue without changes in body weight, adipose tissue weight, and adipocyte number even at 6 months of age. After HCD for 4 weeks, the weight of both epididymal and retroperitoneal adipose tissue in AT(2)/ApoEKO mice was greater than that in ApoEKO mice without a change in body weight. Plasma concentrations of cholesterol and fatty acids were higher in AT(2)/ApoEKO mice than in ApoEKO mice. In adipose tissue of AT(2)/ApoEKO mice, the adipocyte number was decreased and the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), C/EBPalpha, and aP2 was lower than that in ApoEKO mice, in association with an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. CONCLUSIONS: These results suggest that AT(2) receptor stimulation in adipose tissue is involved in the improvement of adipocyte differentiation and adipose tissue dysfunction in atherosclerotic model. PMID- 19444222 TI - Association of 25-hydroxyvitamin D with blood pressure in predominantly 25 hydroxyvitamin D deficient Hispanic and African Americans. AB - BACKGROUND: Several observational studies have recently suggested an inverse association of circulating levels of vitamin D with blood pressure. These findings have been based mainly on Caucasian populations; whether this association also exists among Hispanic and African Americans has yet to be definitively determined. This study investigates the association of 25 hydroxyvitamin D (25[OH]D) with blood pressure in Hispanic and African Americans. METHODS: The data source for this study is the Insulin Resistance Atherosclerosis Family Study (IRASFS), which consists of Hispanic- and African-American families from three US recruitment centers (n =1,334). A variance components model was used to analyze the association of plasma 25[OH]D levels with blood pressure. RESULTS: An inverse association was found between 25[OH]D and both systolic (beta for 10 ng/ml difference = -2.05; P < 0.01) and diastolic (beta for 10 ng/ml difference = -1.35; P < 0.001) blood pressure in all populations combined, after adjusting for age, sex, ethnicity, and season of blood draw. Further adjustment for body mass index (BMI) weakened this association (beta for 10 ng/ml difference = -0.94; P = 0.14 and beta for 10 ng/ml difference = -0.64; P = 0.09, respectively). CONCLUSIONS: 25[OH]D levels are significantly inversely associated with blood pressure in Hispanic and African Americans from the IRASFS. However, this association was not significant after adjustment for BMI. Further research is needed to determine the role of BMI in this association. Large, well-designed prospective studies of the effect of vitamin D supplementation on blood pressure may be warranted. PMID- 19444224 TI - Serum leptin levels in obese males during over- and underfeeding. AB - Leptin levels in lean adults vary in response to short-term alterations in energy balance. We tested whether leptin responded to short-term changes in energy balance in obese males in a similar manner to lean individuals. We enrolled eight obese, healthy males in a 12-day study composed of four consecutive dietary treatment periods of 3 days each: baseline eucaloric feeding followed by randomized crossover periods of overfeeding (130% of total energy expenditure (TEE)) or underfeeding (70% of TEE), separated by a eucaloric (100% of TEE) washout period. We measured TEE with doubly labeled water prior to baseline. Leptin levels were measured throughout the third day of each treatment and 24-h weighted averaged were calculated. Subjects' ad libitum intake during a breakfast buffet following each treatment period was recorded. During underfeeding, leptin levels decreased by 21 +/- 6% (P < 0.01) from the previous eucaloric period. During overfeeding, leptin levels increased by 25 +/- 11% (P < 0.01) when subjects were underfed first, but did not increase (5 +/- 8%, nonsignificant (n.s.)) when subjects were overfed first. Changes in ad libitum intake from baseline were calculated for each subject after over-, under-, and eucaloric feeding and did not to correlate with the changes in mesor leptin levels from baseline (R(2) = 0.006, n.s). Leptin levels in obese males were acutely responsive to negative energy balance, but not to positive energy balance unless subjects were previously underfed. Consequently, leptin levels in obese males do not respond to changes in energy intake in a manner that would protect against weight gain. PMID- 19444225 TI - Toward objective monitoring of ingestive behavior in free-living population. AB - Understanding of eating behaviors associated with obesity requires objective and accurate monitoring of food intake patterns. Accurate methods are available for measuring total energy expenditure and its components in free-living populations, but methods for measuring food intake in free-living people are far less accurate and involve self-reporting or subjective monitoring. We suggest that chews and swallows can be used for objective monitoring of ingestive behavior. This hypothesis was verified in a human study involving 20 subjects. Chews and swallows were captured during periods of quiet resting, talking, and meals of varying size. The counts of chews and swallows along with other derived metrics were used to build prediction models for detection of food intake, differentiation between liquids and solids, and for estimation of the mass of ingested food. The proposed prediction models were able to detect periods of food intake with >95% accuracy and a fine time resolution of 30 s, differentiate solid foods from liquids with >91% accuracy, and predict mass of ingested food with >91% accuracy for solids and >83% accuracy for liquids. In earlier publications, we have shown that chews and swallows can be captured by noninvasive sensors that could be developed into a wearable device. Thus, the proposed methodology could lead to the development of an innovative new way of assessing human eating behavior in free-living conditions. PMID- 19444226 TI - Sex-dependent associations of leptin with metabolic syndrome-related variables: the Stanislas study. AB - Serum leptin has been reported to be associated in a sex-dependent manner with C reactive protein (CRP), independently of adiposity. We tested the hypothesis that leptin is associated, independently of anthropometry indexes and in a sex dependent way, with other inflammatory markers and variables related to metabolic syndrome (MS). In 384 healthy middle-aged adults (192 men and 192 women) total fat mass (FM), waist circumference (WC), serum leptin and 15 MS-related parameters (systolic and diastolic blood pressure, triglycerides, cholesterol, high density lipoprotein (HDL)-cholesterol, apo AI and B, fasting glucose, uric acid, CRP, orosomucoid and haptoglobin levels and aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities) were measured. After adjustment for age, alcohol and cigarette consumption, WC, and total FM, leptin concentration was significantly associated with serum triglycerides, total cholesterol, apo B, uric acid and haptoglobin concentrations and liver enzyme activity only in men, and with apo AI, HDL cholesterol (only borderline) and CRP only in women. Sex interaction terms were significant for total cholesterol, apo B, HDL cholesterol, uric acid, ALAT and GGT, and borderline significant for triglycerides, apo AI and ASAT. In this healthy population, leptin is significantly associated with various MS factors, independently of WC and total FM, depending on gender. Our study provides further evidence of sex-related differences mediated by leptin in inflammatory mechanisms and other MS-related metabolic pathways. PMID- 19444227 TI - Antiobesity effects of yerba mate extract (Ilex paraguariensis) in high-fat diet induced obese mice. AB - Because the potential of yerba mate (Ilex paraguariensis) has been suggested in the management of obesity, the aim of the present study was to evaluate the effects of yerba mate extract on weight loss, obesity-related biochemical parameters, and the regulation of adipose tissue gene expression in high-fat diet induced obesity in mice. Thirty animals were randomly assigned to three groups. The mice were introduced to standard or high-fat diets. After 12 weeks on a high fat diet, mice were randomly assigned according to the treatment (water or yerba mate extract 1.0 g/kg). After treatment intervention, plasma concentrations of total cholesterol, high-density lipoprotein cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, and glucose were evaluated. Adipose tissue was examined to determine the mRNA levels of several genes such as tumor necrosis factor-alpha (TNF-alpha), leptin, interleukin-6 (IL-6), C-C motif chemokine ligand-2 (CCL2), CCL receptor-2 (CCR2), angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), adiponectin, resistin, peroxisome proliferator-activated receptor-gamma(2) (PPAR-gamma(2)), uncoupling protein-1 (UCP1), and PPAR-gamma coactivator-1 alpha (PGC-1 alpha). The F4/80 levels were determined by immunoblotting. We found that obese mice treated with yerba mate exhibited marked attenuation of weight gain, adiposity, a decrease in epididymal fat-pad weight, and restoration of the serum levels of cholesterol, triglycerides, LDL cholesterol, and glucose. The gene and protein expression levels were directly regulated by the high-fat diet. After treatment with yerba mate extract, we observed a recovery of the expression levels. In conclusion, our data show that yerba mate extract has potent antiobesity activity in vivo. Additionally, we observed that the treatment had a modulatory effect on the expression of several genes related to obesity. PMID- 19444228 TI - Genome-wide linkage analysis of multiple metabolic factors: evidence of genetic heterogeneity. AB - The metabolic syndrome is a highly complex disease and has become one of the major public-health challenges worldwide. We sought to identify genetic loci with potential influence on multiple metabolic factors in a white population in Beaver Dam, Wisconsin, and to explore the possibility of genetic heterogeneity by family history of diabetes (FHD). Three metabolic factors were generated using principal component factor analysis, and they represented: (i) glycemia, (ii) blood pressure, and (iii) combined (BMI, high-density lipoprotein (HDL) cholesterol, and serum uric acid) factors. Multipoint model-free linkage analysis of these factors with 385 microsatellite markers was performed on 1,055 sib-pairs, using Haseman-Elston regression. Genome-wide suggestive evidence of linkage was found at 30 cM on chromosome 22q (empirical P (P(e)) = 0.0002) for the glycemia factor, at 188-191 cM on chromosome 1q (P(e) = 0.0007) for the blood pressure factor, and at 82 cM on chromosome 17q (P(e) = 0.0007) for the combined factor. Subset analyses of the families by FHD showed evidence of genetic heterogeneity, with divergent linkage signals in the subsets on at least four chromosomes. We found evidence of genetic heterogeneity by FHD for the three metabolic factors. The results also confirmed findings of previous studies that mapped components of the metabolic syndrome to a chromosome 1q region. PMID- 19444229 TI - Altered phenotype of NK cells from obese rats can be normalized by transfer into lean animals. AB - In diet-induced obese rats, leptin-mediated natural killer (NK) cell activation has been demonstrated to be impaired by abrogated intracellular JAK2-STAT3 signaling. The contribution of the obese microenvironment to this NK cell dysfunction and its reversibility remains elusive. In this study, the functions of NK cells from diet-induced obese rats after adoptive transfer into lean littermates were investigated using in vivo and in vitro approaches. Endogenous NK cells of normal-weight and diet-induced obese F344 rats were depleted in vivo. Then, NK cells from either normal-weight or obese donors were transferred. The numbers of peripheral blood NK cells were analyzed by fluorescence-activated cell sorting (FACS) and the distribution pattern of NK cells in lung and spleen by immunohistochemistry. Ob-R expression was evaluated by immunohistology and activation of intracellular target proteins of Ob-R by immunoblotting. The numbers of NK cells in blood and lung were significantly higher in obese animals compared to lean ones after transfer of NK cells from obese F344 rats. This was correlated with increased postreceptor signaling (JAK-2p, PKBpT308, ERK-2p) without altered Ob-R expression in those NK cells transferred to lean (ob-->nw) vs. obese (ob-->ob) animals. These results show for the first time that the altered phenotype of NK cells from obese rats can be normalized by generation of a physiological (metabolic) environment of lean rats. PMID- 19444230 TI - Ethnic-specific correlations of visfatin with circulating markers of endothelial inflammation and function. AB - Sub-Saharan Africa is afflicted by high hypertension prevalence that is expected to rise even further along with increasing obesity rates. The present study aimed to investigate the role of visfatin in obesity and to explore associations of visfatin with markers of endothelial function and hemodynamics in African women compared to a well-matched white sample. The present study involved urban African (n = 102) and white (n = 115) women from South Africa, individually matched for age and BMI. We measured blood pressure, cardiac output, and arterial compliance noninvasively, and analyzed visfatin as well as circulating markers of vascular function and inflammation in serum. Serum visfatin concentration did not differ between African and white women. Visfatin was unrelated to obesity in African women but positive associations for total and abdominal obesity were found in white women. Age- and obesity-adjusted univariate and multivariate analyses revealed significant positive associations of visfatin with endothelin-1 and fibrinogen in African women. Identical analyses in white women indicated a positive association of visfatin with C-reactive protein and von Willebrand factor. Our findings suggest a possible role of visfatin in the cardiovascular system that seems to be independent of obesity in the African women. PMID- 19444232 TI - Association of two CETP polymorphisms with HDL levels in the Chinese obese population. AB - The association of two cholesterol ester transfer protein (CETP) polymorphisms, D442G and TAQIB (B1-->B2), with high-density lipoprotein (HDL) levels in 932 Chinese obese individuals (BMI >or= 27) was investigated in comparison with normal controls (BMI or =9.6+/-0.9 g/dl, should be the standard for pregnant women on hemodialysis. PMID- 19444268 TI - Shiga-like toxins and HIV-1 'go through' glycosphingolipids and lipid rafts in renal cells. AB - The binding of Shiga-like toxins (Stx) to globotriaosyl ceramide (Gb(3)) in renal cells plays a central role in Stx-induced hemolytic uremic syndrome (Stx-HUS). Khan et al. show that the presence of Gb(3) within lipid raft microdomains in glomerular but not tubular cells may be the basis for the glomerular- and age restricted pathology of Stx-HUS. They also propose that the binding of the HIV-1 glycoprotein gp120 to Gb(3) in renal tubules may play a role in HIV nephropathy. PMID- 19444269 TI - Ablation of klotho and premature aging: is 1,25-dihydroxyvitamin D the key middleman? AB - The reversal of soft-tissue abnormalities and prolonged lifespan observed in klotho(-/-) mice following genetic inactivation of 1alpha-hydroxylase underscores the pathophysiological role of 1,25-dihydroxyvitamin D in mediating some of the premature aging-like features observed in klotho(-/-) mice. PMID- 19444271 TI - Helicobacter pylori infection and hypertension in end-stage renal disease. PMID- 19444276 TI - The Case: An unusual cause of renovascular hypertension. PMID- 19444277 TI - Obstructive uropathy from Ascaris lumbricoides. PMID- 19444278 TI - Improvement of neovascularization capacity of bone marrow mononuclear cells from diabetic mice by ex vivo pretreatment with resveratrol. AB - Implantation of bone marrow-derived mononuclear cells (BMMCs) is known to accelerate blood flow recovery in a hindlimb ischemia model in mice. However, the neovascularization capacity of BMMCs from diabetic mice is impaired. Resveratrol, a natural polyphenolic compound abundant in red wine, is known to extend the lifespan of high cholesterol-fed mice. We tested whether resveratrol improves the neovascularization capacity of BMMCs from diabetic mice. Diabetes was induced by the injection of streptozotocin into C57B/6 mice. BMMCs from normal mice and diabetic mice were implanted into the ischemic limb induced by ligation of the unilateral femoral artery. Blood flow recovery measured by the laser Doppler method was significantly decreased in mice that received BMMCs from diabetic mice compared with BMMCs from normal mice. However, ex vivo treatment of BMMCs from diabetic mice, but not from normal mice, with resveratrol for 30 min significantly improved blood flow recovery. Capillary density measured by PECAM-1 positive cells was significantly increased in mice that received either normal BMMCs or diabetic BMMCs treated with resveratrol. Treatment of BMMCs from diabetic mice with resveratrol increased mRNA expression of vascular endothelial growth factor and endothelial nitric oxide synthase and decreased production of reactive oxygen species. Resveratrol improved the impaired neovascularization capacity of BMMCs derived from diabetic mice. The effects of resveratrol may be due to a reduction of oxidative stress and an induction of angiogenic factors. Resveratrol may be beneficial by improving the neovascularization capacity of BMMCs in patients with diabetes mellitus. PMID- 19444279 TI - A blunted decrease in nocturnal blood pressure is independently associated with increased aortic stiffness in patients with resistant hypertension. AB - Increased arterial stiffness may be causally related to resistant hypertension. Our objective was to investigate the variables, particularly those derived from ambulatory blood pressure (BP) monitoring (ABPM), associated with increased aortic stiffness in resistant hypertensives. In a cross-sectional study, 600 resistant hypertensive patients without peripheral arterial disease were evaluated. Arterial stiffness was assessed by aortic pulse wave velocity (PWV), and was considered increased if >12 m s(-1). Statistical analyses included multiple linear and logistic regressions to assess the independent correlates of increased aortic stiffness. One hundred and sixty-eight patients (28%) had aortic PWV >12 m s(-1). Patients with increased PWV were older and had a higher prevalence of cardiovascular risk factors than did those patients with low PWV. On ABPM, patients with elevated PWV had higher daytime and night time systolic BP (SBP) and pulse pressures (PP), less nocturnal decrease in SBP and a higher prevalence of non-dipping pattern. On multiple linear regression, the independently associated variables with aortic PWV were age (P<0.001), 24-h PP (P<0.001), high-density lipoprotein (HDL)-cholesterol (P<0.001), microalbuminuria (P<0.001), fasting glycemia (P=0.001) and a decrease in nocturnal SBP (P=0.002). Multivariate logistic regression confirmed these results, with the non-dipping patients having a 72% higher likelihood of presenting with increased aortic stiffness (95% confidence interval: 1.12-2.65, P=0.013). This association was observed in both the reduced and reverted dipping patterns, but not in the extreme dipping pattern. In conclusion, a blunted nocturnal decrease in BP is independently associated with increased aortic stiffness in resistant hypertensive patients. Other independent correlates are older age, diabetes, microalbuminuria, low HDL-cholesterol and a widened 24-h PP. PMID- 19444280 TI - Rationale, design and patient baseline characteristics of OlmeSartan and calcium antagonists randomized (OSCAR) study: a study comparing the incidence of cardiovascular events between high-dose angiotensin II receptor blocker (ARB) monotherapy and combination therapy of ARB with calcium channel blocker in Japanese elderly high-risk hypertensive patients (ClinicalTrials. gov no. NCT00134160). AB - Higher doses of angiotensin II receptor blockers (ARBs) are expected to exert more protective effects against cardiovascular diseases. However, the significance of treatment of hypertension with high-dose ARB remains to be defined. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) Study was designed to determine whether high-dose ARB monotherapy is superior to the combination therapy of ARB plus calcium channel blocker (CCB) in the prevention of cardiovascular morbidity/mortality in Japanese elderly high-risk hypertensive patients. The OSCAR study is a multicenter, active-controlled, two-arm parallel group comparison, using the prospective randomized open-blinded end-point method. In the 'Step 1' period, elderly hypertensive patients with diabetes or cardiovascular disease received monotherapy with ARB olmesartan medoxomil at a dose of 20 mg day(-1). If the target blood pressure control (less than 140/90 mm Hg) was not achieved by ARB monotherapy, the patients were randomized to receive either (1) the increased dose of olmesartan at 40 mg day(-1) (high-dose ARB monotherapy) or (2) the addition of a CCB (amlodipine or azelnidipine) to 20 mg day(-1) olmesartan (ARB plus CCB combination) in the 'Step 2' period. The follow up duration will be 3 years. The primary end points will be the composite of fatal and non-fatal cardiovascular events, and death from any cause. Recruitment for the OSCAR study (around 1200 patients) was completed by the end of May 2007. The OSCAR study is the first large clinical trial comparing the efficacy of high dose ARB monotherapy with that of an ARB plus CCB combination therapy in elderly high-risk hypertensive patients. PMID- 19444281 TI - Angiogenin protects motoneurons against hypoxic injury. AB - Cells can adapt to hypoxia through the activation of hypoxia-inducible factor-1 (HIF-1), which in turn regulates the expression of hypoxia-responsive genes. Defects in hypoxic signaling have been suggested to underlie the degeneration of motoneurons in amyotrophic lateral sclerosis (ALS). We have recently identified mutations in the hypoxia-responsive gene, angiogenin (ANG), in ALS patients, and have shown that ANG is constitutively expressed in motoneurons. Here, we show that HIF-1alpha is sufficient and required to activate ANG in cultured motoneurons exposed to hypoxia, although ANG expression does not change in a transgenic ALS mouse model or in sporadic ALS patients. Administration of recombinant ANG or expression of wild-type ANG protected motoneurons against hypoxic injury, whereas gene silencing of ang1 significantly increased hypoxia induced cell death. The previously reported ALS-associated ANG mutations (Q12L, K17I, R31K, C39W, K40I, I46V) all showed a reduced neuroprotective activity against hypoxic injury. Our data show that ANG plays an important role in endogenous protective pathways of motoneurons exposed to hypoxia, and suggest that loss of function rather than loss of expression of ANG is associated with ALS. PMID- 19444282 TI - Toll-like receptors in control of immunological autophagy. AB - Autophagy is a cell biological process, enabling cells to autodigest their own cytosol when starved, remove cytoplasmic protein aggregates too large for proteasomal degradation, eliminate aberrant or over-proliferated organelles, and sanitize the cytoplasm by killing intracellular microbes. The role of autophagy has been expanded in recent years to include diverse immunological effector and regulatory functions. In this review, we summarize the multiple immunological roles of autophagy uncovered to date and focus primarily on details of induction of autophagy by pattern recognition receptors, as a newly established Toll-like receptor output. Taken together with other links between autophagy and innate and adaptive immunity processes, this cell-autonomous antimicrobial defense may be evolutionarily positioned at the root of immunity with the multiple innate and adaptive immunity connections uncovered to date reflecting a co-evolution of this ancient cell-defense mechanism and more advanced immunological systems in metazoans. PMID- 19444283 TI - PUMA is directly activated by NF-kappaB and contributes to TNF-alpha-induced apoptosis. AB - Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that has an important role in immunity and inflammation by inducing cellular responses such as apoptosis. The transcription factor nuclear factor-kappaB (NF-kappaB) can paradoxically suppress and promote apoptosis in response to TNF-alpha. In this study, we found that p53 upregulated modulator of apoptosis (PUMA), a p53 downstream target and a BH3-only Bcl-2 family member, is directly regulated by NF-kappaB in response to TNF-alpha. TNF-alpha treatment led to increases in PUMA mRNA and protein levels in human colon cancer cells. The induction of PUMA was p53 independent, and mediated by the p65 component of NF-kappaB through a kappaB site in the PUMA promoter. The apoptotic effect of PUMA induction by TNF-alpha was unmasked by depleting the antiapoptotic protein Bcl-X(L). In mice, PUMA was also induced by TNF-alpha in an NF-kappaB-dependent manner. TNF-alpha-induced apoptosis in a variety of tissues and cell types, including small intestinal epithelial cells, hepatocytes, and thymocytes, was markedly reduced in PUMA-deficient mice. Collectively, these results demonstrated that PUMA is a direct target of NF kappaB and mediates TNF-alpha-induced apoptosis in vitro and in vivo. PMID- 19444284 TI - A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin. AB - Phenylketonuria (PKU) is an autosomal recessive defect in hepatic metabolism of phenylalanine, which is secondary to mutations in the phenylalanine hydroxylase (PAH) gene. Sixty-seven ethnically Polish PKU patients, followed at the Outpatient Department of Pediatrics and Developmental Medicine in Poznan, Poland, were assessed for mutations in the PAH gene. Two mutations were identified in 61 of 67 patients and a single mutation was identified in the remaining six patients. The four most prevalent mutations (p.R408W, 68%; c.1066-11G>A, 6%; c.1315+1G>A, 5.2%; c.822-832delGCCCATGTATA, 3.7%) accounted for 83% of the mutant alleles. Fifteen additional mutations were identified of which most (13/15) were observed in an individual patient. Before knowledge of PAH genotypes, 19 patients were challenged with a 20 mg kg(-1) dose of 6R tetrahydrobiopterin (BH(4)) and serum phenylalanine concentration was monitored in hospital over 24 h. Two patients responded to the BH(4) challenge with a reduction of serum phenylalanine concentration >30% from baseline. PAH genotypes of the two responsive patients would have been predicted, as they contained mutations recognized as BH(4) responsive, whereas the 17 patients who were unresponsive would have been predicted as their mutations were either recognized as non-responsive or were highly deleterious frame-shift mutations. Overall, only 7.5% (5/ 67) of patients had PAH mutations recognized as responsive to co-factor therapy. Among the PKU patients from western Poland, PAH mutations responsive to BH(4) therapy are poorly represented; therefore, genotyping may be useful for identifying candidate patients likely to respond to BH(4) before physiological challenge. PMID- 19444285 TI - Arg347Cys polymorphism of alpha1A-adrenoceptor gene is associated with blood pressure response to nifedipine GITS in Chinese hypertensive patients. AB - Our objectives were to evaluate whether polymorphisms in the alpha1A- and beta2 adrenoceptor genes influence blood pressure response to nifedipine gastrointestinal therapeutic system (GITS). Hypertensive patients received daily treatment with an oral dosage of 30 mg nifedipine GITS for 16 days. Genotypes of the Arg347Cys polymorphism in the alpha1A-adrenoceptor gene and the Arg16Gly and Gln27Glu polymorphisms in the beta2-adrenoceptor gene were determined by TaqMan single-nucleotide polymorphism genotyping assay. The sixteenth-day steady-state plasma concentration of nifedipine was measured using HPLC with UV detection. Multivariate linear regression was performed in a total of 447 patients to evaluate the effects of these polymorphisms on blood pressure response to nifedipine GITS. Patients carrying the Cys347 allele of the alpha1A-adrenoceptor gene had a greater systolic blood pressure reduction than did those carrying two Arg347 alleles of the alpha1A-adrenoceptor gene (32.5+/-14.0 versus 27.3+/-15.5 mm Hg, respectively, P=0.006). However, diastolic blood pressure reduction was not associated with the Arg347Cys polymorphism in the alpha1A-adrenoceptor gene. In addition, no significant associations were observed between blood pressure reduction and two polymorphisms in the beta2-adrenoceptor gene. Our data suggest that the Arg347Cys polymorphism in the alpha1A-adrenoceptor gene may be used to predict blood pressure response to nifedipine GITS in Chinese hypertensive patients. PMID- 19444286 TI - Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan. AB - 16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD SCA) characterized by late-onset pure cerebellar ataxia and -16C>T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C-T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17 msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan. PMID- 19444287 TI - Frequencies of genotypes and alleles of the functional SNPs in CYP2C19 and CYP2E1 in mainland Chinese Kazakh, Uygur and Han populations. AB - CYP2C19 and CYP2E1 show great genetic differences between Orientals and Caucasians. The objective of this study was to investigate the genotype and allele distribution patterns of CYP2C19 and CYP2E1 polymorphisms among healthy participants in mainland Chinese Kazakh, Uygur and Han populations by the PCR restriction fragment length polymorphism technique. The allele frequencies of CYP2C19 2, CYP2E1 5B and CYP2E1 6 were significantly lower in the Chinese Kazakh (15.4, 11.2 and 14.5%, respectively) (P<0.05) and Uygur (16.1, 12.1 and 18.8%) (P<0.05) populations than that in the Chinese Han population (28.8, 19.4 and 26.2%), but the frequencies of CYP2C19 3 were similar among the three populations (8.0, 9.4 and 7.2%). Frequencies of the three combined genotypes, one for predicted CYP2C19 poor metabolizers and two for predicted high levels of CYP2E1 transcription, were significantly lower in the Chinese Kazakh (7.5, 19.6 and 28.0%, respectively) (P<0.05, chi(2)-test) and Uygur (8.1, 22.8 and 33.6%) (P<0.05) populations compared with the Chinese Han population (16.5, 35.9 and 44.7%). The present research shows that frequencies of the functional single nucleotide polymorphisms in the CYP2C19 and CYP2E1 genes vary in the Chinese Kazakh, Uygur and Han populations, suggesting that disease susceptibilities or drug responses associated with enzyme activities of CYP2C19 and CYP2E1 may differ in the diverse ethnic populations in mainland China. PMID- 19444288 TI - Pre-operative Quality of Life and psychological factors that influence patient decision making in LASIK. AB - PURPOSE: To assess pre-operative visual function, psychological factors, personality traits and satisfaction in myopic patients seeking laser-assisted in situ keratomileusis (LASIK). METHODS: Eligible patients seeking LASIK (n=183) and successful contact lens wearers (n=23) not interested in LASIK completed the Institute for Eye Research Quality of Life (QOL) Scale. Of the 183 patients seeking LASIK who completed the QOL instrument before LASIK, 30 declined the procedure and 153 underwent LASIK. One hundred and two patients who underwent LASIK attended their 3-month post-operative follow-up appointment and 51 patients failed to present for their post-operative follow-up appointment. Multiple comparisons (One-way Analysis of Variance (ANOVA)) were conducted to determine differences in visual function, psychological factors, personality traits and satisfaction between patient groups. RESULTS: Successful soft contact lens (SCL) wearers reported better functional vision (P=0.001), felt more attractive (P=0.007), had a lower frequency of disturbing visual and ocular symptoms (P=0.027) and higher overall satisfaction with their current optical correction (P<0.001) than patients seeking LASIK. LASIK patients lost to follow-up showed higher self-efficacy, adaptability and well-being than the patients who completed their appointments and those who declined surgery (P<0.05). CONCLUSIONS: Psychological characteristics, the perception of visual and ocular symptoms and satisfaction with the current method of optical correction play an important role in the decision to undergo LASIK. The IER QOL Scale is a valid and reliable instrument able to discriminate between different groups seeking choices for myopic correction. Psychological factors may influence the level of satisfaction with LASIK. PMID- 19444289 TI - Bilateral lateral rectus recession considering the tendon width in intermittent exotropia. AB - PURPOSE: The tendon width of the lateral rectus muscle can be a useful indicator of the effect of unilateral lateral rectus recession in intermittent exotropia. The aim of this study was to determine whether the tendon width of lateral rectus would be useful for predicting the effect of bilateral lateral rectus (BLR) recession. METHODS: We studied a total of 45 patients between 3 and 15 years of age who had undergone bilateral rectus recession for the basic type of intermittent exotropia. The actual effect of lateral recession was calculated by adding the absolute value of the angle of preoperative deviation and the postoperative deviation on the second day and dividing the figure by the total amount of recession. We then calculated the hypothetical effect of lateral rectus recession, considering the tendon width of each eye, and added the effects of both eyes. The hypothetical effects were defined as 3 PD when the tendon width was 8-8.5 mm; 3.5 PD when it was 7-7.5 mm; and 2.5 PD when it was 9-9.5 mm, based upon earlier statistical analysis. We compared both effects using a paired t test. RESULTS: The mean difference between the actual and the hypothetical effects of BLR recession in all patients was 2.88 PD (P=0.001, range: 0-5.50 PD). However, when the amount of preoperative exodeviation was below 25 PD, the differences were not statistically significant (P=0.086). CONCLUSION: The tendon width may also be useful indicator in BLR recession if the preoperative exodeviation is below 25 PD. PMID- 19444290 TI - High-definition spectral domain OCT of a subretinal nematode. PMID- 19444291 TI - Prospective comparison of ultrasound biomicroscopy and anterior segment optical coherence tomography for evaluation of anterior chamber dimensions in European eyes with primary angle closure. AB - PURPOSE: To compare the accuracy in measurement of the anterior chamber (AC) angle by anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) in European patients with suspected primary angle closure (PACS), primary angle closure (PAC), or primary angle-closure glaucoma (PACG). DESIGN: Cross-sectional study. METHODS: In all, 55 eyes of 33 consecutive patients presenting with PACS, PAC, or PACG were examined with AS-OCT, followed by UBM. The trabecular-iris angle (TIA) was measured in all four quadrants. The angle-opening distance (AOD) was measured at 500 microm from the scleral spur. The Bland-Altman method was used for assessing agreement between the two methods. RESULTS: The mean (+/-SD) superior TIA was 19.3+/-15.8 degrees in AS-OCT and 15.7+/-15.0 degrees in UBM (P=0.50) and inferior TIA was 17.9+/-12.9 degrees (AS OCT) and 16.7+/-14.1 degrees (UBM) (P=0.71). The superior AOD(500) was 0.17+/ 0.16 mm in UBM and 0.21+/-0.16 mm in AS-OCT (P=0.06). Bland-Altman analysis showed a mean SD of+/-9.4 degrees for superior and inferior TIA and a mean SD of +/-0.10 mm for superior and inferior AOD(500). CONCLUSIONS: This comparative study shows that AS-OCT measurements are significantly correlated with UBM measurements but show poor agreement with each other. We do not believe that AS OCT can replace UBM for the quantitative assessment of the AC angle. PMID- 19444292 TI - The estimation of approximate sample size requirements necessary for clinical and epidemiological studies in vision sciences. AB - PURPOSE: The aim of this paper is to provide an overview of sample size estimations for the most frequent type of group studies that result in continuous, binary and ordered categorical outcomes. METHODS: The theory behind power and sample size calculations is explained using the basic probability concepts that underpin the most frequently used statistical significance tests. RESULTS: Simple formulae and tables are presented for the estimation of sample sizes necessary for efficient and effective clinical and epidemiological trials. These may be used without recourse to sophisticated and complex computer software packages. Mathematical complexity is kept to a minimum. Examples and applications from the vision sciences are specifically highlighted. CONCLUSIONS: The paper highlights, with practical examples, the concepts and computations necessary to make sample size estimations accessible to all eye professionals involved in research, diagnostic and statutory work. PMID- 19444293 TI - Extrafoveal vitreous traction associated with diabetic diffuse macular oedema. AB - PURPOSE: To present an association between diabetic diffuse macular oedema and extrafoveal vitreous traction by optical coherence tomography (OCT). METHODS: In a retrospective study, charts and OCT scans of diabetic patients with macular oedema were reviewed. Eyes with either vitreofoveal or extrafoveal traction were included. Eyes that had vitreoretinal adherence with no sign of traction, idiopathic vitreomacular traction syndrome, or vitreoretinal surgery were excluded. Macular maps were compared with normal controls (n=12). RESULTS: Of the 186 eyes of 122 consecutive patients, 45 eyes (41 patients) were analyzed. Vitreofoveal traction was detected in 25 eyes (56%) and extrafoveal traction in 20 (44%), either at the retina (16; 35%) or at the optic nerve head (4; 9%). Of these 20 eyes, related extrafoveal retinal oedema was in continuum with the central macular oedema, manifesting as diffuse macular oedema, in 16 (36% of all 45) eyes. Vitreous adherence was detected by the centrally fixated Automatic 6 radial lines program in 26 eyes (58%): 5 (25%) of 20 with extrafoveal traction and 21 (84%) of 25 with vitreofoveal traction. In the other 19 (42%) eyes, the vitreous traction site was detected only by the Line group OCT-2000 program, which is manually controllable during the scanning process. CONCLUSIONS: Diabetic diffuse macular oedema may be related to an extrafoveal vitreous traction. The traction sites were detected in a large proportion of eyes only by the OCT Line group program and not by the Automatic 6-radial lines program. Further studies are required to validate the clinical consequence of these findings. PMID- 19444294 TI - Dacryoadenitis as a presenting feature of the Churg Strauss syndrome. PMID- 19444295 TI - Second-eye cataract surgery in elderly women: a cost-utility analysis conducted alongside a randomized controlled trial. AB - AIM: The aim of this study was to evaluate the cost-effectiveness of second-eye cataract surgery for older women with minimal visual dysfunction in the eye to be operated on from a Health and Personal Social Services perspective, compared to waiting list controls who had already undergone first-eye cataract surgery. METHODS: A cost-utility analysis was undertaken alongside a randomized controlled trial of second-eye cataract surgery in secondary care ophthalmology clinics. A total of 239 women over 70 years old with one unoperated cataract were randomized to cataract surgery (expedited, approximately 4 weeks) or control (routine surgery, 12 months wait). Outcomes were measured in terms of quality-adjusted life years (QALYs), with health-related quality of life estimated using the EuroQol EQ-5D. RESULTS: The operated group had costs which were, on average, pound646 more than the control group (95% confidence interval, pound16-1276, P<0.04) and had a mean QALY gain of 0.015 (95% confidence interval, -0.039 to 0.068, P=0.59) per patient over 1 year. Therefore, the incremental cost-utility ratio was pound44,263 over the 1-year trial period. In an analysis modelling costs and benefits over patients' expected lifetime, the incremental cost per QALY was pound17,299, under conservative assumptions. CONCLUSIONS: Second-eye cataract surgery is not likely to be cost-effective in the short term for those with mild visual dysfunction pre-operation. In the long term, second-eye cataract surgery appears to be cost-effective unless carer costs are included. PMID- 19444296 TI - Retinal artery occlusion associated with a patent foramen ovale. PMID- 19444297 TI - Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis? AB - Retinopathy is a major complication of diabetes mellitus and this condition remains a leading cause of blindness in the working population of developed countries. As diabetic retinopathy progresses a range of neuroglial and microvascular abnormalities develop although it remains unclear how these pathologies relate to each other and their net contribution to retinal damage. From a haemodynamic perspective, evidence suggests that there is an early reduction in retinal perfusion before the onset of diabetic retinopathy followed by a gradual increase in blood flow as the complication progresses. The functional reduction in retinal blood flow observed during early diabetic retinopathy may be additive or synergistic to pro-inflammatory changes, leucostasis and vaso-occlusion and thus be intimately linked to the progressive ischaemic hypoxia and increased blood flow associated with later stages of the disease. In the current review a unifying framework is presented that explains how arteriolar dysfunction and haemodynamic changes may contribute to late stage microvascular pathology and vision loss in human diabetic retinopathy. PMID- 19444298 TI - A profile of drug resistance genes and integrons in E. coli causing surgical wound infections in the Faisalabad region of Pakistan. AB - Escherichia coli are one of the leading causes of infection in wounds. Emerging multiple drug resistance among E. coli poses a serious challenge to antimicrobial therapy for wounds. This study was conducted to ascertain a baseline profile of antimicrobial resistance in E. coli isolates infecting surgical wounds. A total of 64 pus samples from hospitalized patients were screened and 29 (45.3%) were found to have E. coli, which were identified biochemically and confirmed by molecular methods. Using the disc diffusion method, antimicrobial resistance was observed toward tetracycline (100%), cefradine (100%), nalidixic acid (93.1%), ampicillin (86.2%), gentamicin (86.2%), cefixime (82.8%), ceftriaxone (82.8%), aztreonam (82.8%), ciprofloxacin (75.9%), streptomycin (72.4%), cefoperazone (65.5%), chloramphenicol (58.6%) and amikacin (58.6%). In an effort to find relevant genes, 11 different genes were targeted by PCR. Among these, the mutated gyrA gene was found to be the most prevalent (82.8%), followed by the TEM (72.4%), catP (68.9%), catA1 (68.9%), tetB (62.1%), blt (58.6%), bla(CTX-M-15) (27.6%), bla(TEM) (20.7%), bla(OXA) (17.2%), tetA (17.2%) and aadA1 (13.8%) genes. The presence of integrons was also studied among these isolates. The prevalence of class 1 integrons was the highest (44.8%), followed by class 2 (27.6%). Three (10.3%) isolates carried both class 1 and class 2 integrons (first report from E. coli infecting wounds). The high incidence of integrons points toward their facilitation for carriage of antimicrobial resistance genes; however, in nearly 37% isolates, no integrons were detected, indicating the significance of alternative mechanisms of gene transfer. Another salient finding was that all isolates were multidrug-resistant E. coli. PMID- 19444299 TI - Development of a molecule-recognized promoter DNA sequence for inhibition of HER2 expression. PMID- 19444300 TI - Role of nsdA in negative regulation of antibiotic production and morphological differentiation in Streptomyces bingchengensis. AB - To investigate the function of nsdA in Streptomyces bingchengensis, it was cloned and sequenced, which presented an 89.89% identity with that of S. coelicolor. The lambdaRED-mediated PCR-targeting technique was used to create nsdA replacement in the S. bingchengensis_226541 chromosome. The nsdA disruption mutant, BC29, was obtained, which produced more pigment and spores than did the ancestral strain. HPLC analysis revealed that the disruption of nsdA efficiently increased milbemycin A(4) production and nanchangmycin production by 1.5-fold and 9-fold, respectively. Complementation of the nsdA mutation restored the phenotype and antibiotic production. These results showed that nsdA negatively affected sporulation and antibiotic production in S. bingchengensis. PMID- 19444301 TI - A cell-based screening system for detection of inhibitors toward mycobacterial cell wall core. AB - Mycobacterium tuberculosis and nonpathogenic bacteria, Corynebacterium glutamicum, possess a common and unusual cell wall architecture. A cell-based screening system was designed to identify novel compounds interacting with the synthesis, assembly or regulation of the M. tuberculosis cell wall. C. glutamicum was tested in a paired medium assay in 96-well plates with natural product extracts and pure chemical compounds in the presence and absence of the osmotic stabilizer, sorbitol and some ions. Growth was visually examined over a 12-h period and detected with a microplate reader for absorbance at 544 nm. Screening hits from the osmotic stabilizer rescue were then examined by mycolic acid analysis to confirm the effect on cell wall integrity. PMID- 19444302 TI - Translation of the radio- and chemo-inducible TNFerade vector to the treatment of human cancers. AB - Radiotherapy is a widely used treatment for localized malignancies that is often delivered in combination with cytotoxic chemotherapeutic agents. The concept that treatment of localized tumors can be improved with a radio- and chemo-inducible gene therapy strategy has been investigated in the laboratory and now translated to the clinic. The TNFerade (Ad.Egr-TNF11D) adenoviral vector was engineered by inserting radio- and chemo-inducible elements from the Egr-1 promoter upstream to a cDNA encoding tumor necrosis factor-alpha (TNF-alpha). Transduction of tumor cells with TNFerade and then treatment with radiation or chemotherapy is associated with spatial and temporal control of TNF-alpha secretion and enhanced antitumor activity. TNFerade has been evaluated in trials for patients with sarcomas, melanomas and cancers of the pancreas, esophagus, rectum and head and neck. If the ongoing phase III trial for pancreatic cancer is successful, TNFerade will likely become the first gene therapy approved for cancer in the United States. PMID- 19444303 TI - Conditional interleukin-12 gene therapy promotes safe and effective antitumor immunity. AB - We and others have previously demonstrated that (chronic) interleukin (IL)-12 gene therapy delivered intratumorally through ex vivo gene-engineered dendritic cell (DC) is competent to promote the regression of established murine tumors. In this report, we have developed a conditional expression system (rAd.RheoIL12) to determine the temporal requirements of transgenic IL-12p70 production by administered DC on therapeutic outcome in a subcutaneous B16 melanoma model. DCs infected with rAd.RheoIL12 (DC.RheoIL12) secreted IL-12p70 in a tightly regulated fashion in response to a synthetic diacylhydrazine small molecule ligand in vitro, and the treatment benefit of DC.RheoIL12 delivered into B16 lesions was strictly ligand dependent in vivo. Indeed, DC.RheoIL12-based therapy promoted the regression of established day 7 B16 tumor lesions after intratumoral injection, provided that ligand administration occurred within 24 h of DC injection and was sustained for approximately 5 or more days. Treatment efficacy was correlated to the magnitude of systemic anti-B16 CD8(+) T cells cross-primed in vivo, which in turn, appeared dependent on the early enhanced in vivo survival of adoptively transferred DC.RheoIL12 in tumor and tumor-draining lymph nodes. The unique safety feature of DC.RheoIL12 application was emphasized in a combined treatment model with rIL-2, where profound TNF-alpha-associated toxicity could be ameliorated upon discontinuation of activating ligand administration. PMID- 19444304 TI - Anticancer oncolytic activity of respiratory syncytial virus. AB - Oncolytic virotherapy is an emerging biotherapeutic platform for cancer treatment, which is based on selective infection/killing of cancer cells by viruses. Herein we identify the human respiratory syncytial virus (RSV) as an oncolytic virus. Using prostate cancer models, we show dramatic enhancement of RSV infectivity in vitro in the androgen-independent, highly metastatic PC-3 human prostate cancer cells compared to the non-tumorigenic RWPE-1 human prostate cells. The oncolytic efficiency of RSV was established in vivo using human prostate tumor xenografts in nude mice. Intratumoral and intraperitoneal injections of RSV led to a significant regression of prostate tumors. Furthermore, enhanced viral burden in PC-3 cells led to selective destruction of PC-3 cancer cells in vitro and in xenograft tumors in vivo due to apoptosis triggered by the downregulation of nuclear factor-kappaB (NF-kappaB) activity (and the resulting loss of anti-apoptotic function of NF-kappaB) in RSV-infected PC-3 cells. The intrinsic (mitochondrial) pathway constitutes the major apoptotic pathway; however, the death-receptor-dependent extrinsic pathway, mediated by the paracrine/autocrine action of tumor necrosis factor-alpha produced from infected cells, also partly contributed to apoptosis. Thus, the oncolytic property of RSV can potentially be exploited to develop targeted therapeutics for the clinical management of prostate tumors. PMID- 19444305 TI - Combination of human tumor necrosis factor-alpha (hTNF-alpha) gene delivery with gemcitabine is effective in models of pancreatic cancer. AB - Pancreatic adenocarcinoma is an aggressive and highly lethal malignancy. Currently, gemcitabine is commonly used in patients with pancreatic cancer. However, the life expectancy of pancreatic cancer patients remains poor. We explored the possibility of increased anti-tumor activity by combining human tumor necrosis factor-alpha (hTNF-alpha) with current front-line therapy. Human TNF-alpha displays potent anti-tumor activity, but its use is limited by the toxicity of systemic administration. We developed a gene delivery approach using intratumoral injections of an adenoviral vector expressing hTNF-alpha, AdEgr.TNF.11D (TNFerade), to increase local concentrations of hTNF-alpha within the tumor, thereby maximizing local anti-tumor activity and yet minimizing the systemic toxicities. An ongoing phase III clinical trial is testing the efficacy of AdEgr.TNF.11D-injected intratumorally and combining with chemotherapy in locally advanced pancreatic cancer. In this study, we show that treatment with AdEgr.TNF.11D and gemcitabine results in a high level of hTNF-alpha expression in human pancreatic cancer cell lines. The combined treatment was well tolerated, highly active and produced marked delays in the growth of human pancreatic xenograft tumors relative to either agent alone. Our results strongly suggest that combination of AdEgr.TNF.11D and gemcitabine may be a potentially useful therapeutic approach for the improved treatment of pancreatic cancer. PMID- 19444306 TI - From genes to function: the next challenge to understanding multiple sclerosis. AB - Susceptibility to multiple sclerosis is jointly determined by genetic and environmental factors, and progress has been made in defining some of these genetic associations, as well as their possible interactions with the environment. However, definitive proof for the involvement of specific genetic determinants in the disease will only come from studies that examine their functional roles in disease pathogenesis. New and combined approaches are needed to analyse the complexity of gene regulation and the functional contribution of each genetic determinant to disease susceptibility or pathophysiology. These studies should proceed in parallel with the use of genetically defined human populations to explore how both genetic and environmental factors affect the function of the pathways in individuals with and without disease, and how these determine the inherited risk of multiple sclerosis. PMID- 19444308 TI - A molecular trio in relapse and remission in multiple sclerosis. AB - Two thirds of patients with multiple sclerosis have the relapsing-remitting form, which often progresses to more debilitating disease. Striking clinical recovery, termed remission, often follows these periodic neurological defects, termed relapses. Recent work has revealed the role of three key molecules in relapse and remission: alpha4beta1 integrin (also known as VLA4) is an adhesion molecule that mediates T cell migration from the blood into the brain; osteopontin binds to alpha4beta1 integrin, stimulating the production of pro-inflammatory cytokines and inhibiting apoptosis; and alphaB crystallin inhibits inflammation in the brain. This Review discusses how this molecular trio interacts to initiate relapses (in the case of osteopontin and alpha4beta1 integrin) and then to terminate them as remissions in multiple sclerosis (in the case of alphaB crystallin). PMID- 19444307 TI - Autoimmune T cell responses in the central nervous system. AB - Autoreactive T cell responses have a crucial role in central nervous system (CNS) diseases such as multiple sclerosis. Recent data indicate that CNS autoimmunity can be mediated by two distinct lineages of CD4+ T cells that are defined by the production of either interferon-gamma or interleukin-17. The activity of these CD4+ T cell subsets within the CNS influences the pathology and clinical course of disease. New animal models show that myelin-specific CD8+ T cells can also mediate CNS autoimmunity. This Review focuses on recent progress in delineating the pathogenic mechanisms, regulation and interplay between these different T cell subsets in CNS autoimmunity. PMID- 19444309 TI - Sequoia regulates cell fate decisions in the external sensory organs of adult Drosophila. AB - The adult Drosophila external sensory organ (ESO), comprising the hair, socket, neuron, sheath and glia cells, arises through the asymmetric division of sensory organ precursor cells (SOPs). In a mosaic screen designed to identify new components in ESO development, we isolated mutations in sequoia, which encodes a putative zinc-finger transcription factor that has previously been shown to have a role in dendritogenesis. Here, we show that adult clones mutant for seq exhibit a loss of hair cells and a gain of socket cells. We propose that the seq mutant phenotype arises, in part, owing to the loss of several crucial transcription factors known to be important in peripheral nervous system development such as D Pax2, Prospero and Hamlet. Thus, Sequoia is a new upstream regulator of genes that orchestrates cell fate specification during development of the adult ESO lineage. PMID- 19444310 TI - COP9 signalosome controls the Carma1-Bcl10-Malt1 complex upon T-cell stimulation. AB - The Carma1-Bcl10-Malt1 (CBM) complex connects T-cell receptor (TCR) signalling to the canonical IkappaB kinase (IKK)/NF (nuclear factor)-kappaB pathway. Earlier studies have indicated that the COP9 signalosome (CSN), a pleiotropic regulator of the ubiquitin/26S proteasome system, controls antigen responses in T cells. The CSN is required for the degradation of the NF-kappaB inhibitor IkappaBalpha, but other molecular targets involved in T-cell signalling remained elusive. Here, we identify the CSN subunit 5 (CSN5) as a new interactor of Malt1 and Carma1. T cell activation triggers the recruitment of the CSN to the CBM complex, and CSN downregulation impairs TCR-induced IKK activation. Furthermore, the CSN is required for maintaining the stability of Bcl10 in response to T-cell activation. Taken together, our data provide evidence for a functional link between the evolutionarily conserved CSN and the adaptive immunoregulatory CBM complex in T cells. PMID- 19444311 TI - Plexin-B1 is a GTPase activating protein for M-Ras, remodelling dendrite morphology. AB - Plexins are receptors for axonal guidance molecules known as semaphorins. We recently reported that the semaphorin 4D (Sema4D) receptor, Plexin-B1, induces axonal growth cone collapse by functioning as an R-Ras GTPase activating protein (GAP). Here, we report that Plexin-B1 shows GAP activity for M-Ras, another member of the Ras family of GTPases. In cortical neurons, the expression of M-Ras was upregulated during dendritic development. Knockdown of endogenous M-Ras-but not R-Ras-reduced dendritic outgrowth and branching, whereas overexpression of constitutively active M-Ras, M-Ras(Q71L), enhanced dendritic outgrowth and branching. Sema4D suppressed M-Ras activity and reduced dendritic outgrowth and branching, but this reduction was blocked by M-Ras(Q71L). M-Ras(Q71L) stimulated extracellular signal-regulated kinase (ERK) activation, inducing dendrite growth, whereas Sema4D suppressed ERK activity and down-regulation of ERK was required for a Sema4D-induced reduction of dendrite growth. Thus, we conclude that Plexin B1 is a dual functional GAP for R-Ras and M-Ras, remodelling axon and dendrite morphology, respectively. PMID- 19444312 TI - Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM deficient cells. AB - The cellular response to DNA double-strand breaks involves direct activation of ataxia telangiectasia mutated (ATM) and indirect activation of ataxia telangiectasia and Rad3 related (ATR) in an ATM/Mre11/cell-cycle-dependent manner. Here, we report that the crucial checkpoint signalling proteins-p53, structural maintainance of chromosomes 1 (SMC1), p53 binding protein 1 (53BP1), checkpoint kinase (Chk)1 and Chk2-are phosphorylated rapidly by ATR in an ATM/Mre11/cell-cycle-independent manner, albeit at low levels. We observed the sequential recruitment of replication protein A (RPA) and ATR to the sites of DNA damage in ATM-deficient cells, which provides a mechanistic basis for the observed phosphorylations. The recruitment of ATR and consequent phosphorylations do not require Mre11 but are dependent on Exo1. We show that these low levels of phosphorylation are biologically important, as ATM-deficient cells enforce an early G2/M checkpoint that is ATR-dependent. ATR is also essential for the late G2 accumulation that is peculiar to irradiated ATM-deficient cells. Interestingly, phosphorylation of KRAB associated protein 1 (KAP-1), a protein involved in chromatin remodelling, is mediated by DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in a spatio-temporal manner in addition to ATM. We posit that ATM substrates involved in cell-cycle checkpoint signalling can be minimally phosphorylated independently by ATR, while a small subset of proteins involved in chromatin remodelling are phosphorylated by DNA-PKcs in addition to ATM. PMID- 19444313 TI - Structural basis for the nuclease activity of a bacteriophage large terminase. AB - The DNA-packaging motor in tailed bacteriophages requires nuclease activity to ensure that the genome is packaged correctly. This nuclease activity is tightly regulated as the enzyme is inactive for the duration of DNA translocation. Here, we report the X-ray structure of the large terminase nuclease domain from bacteriophage SPP1. Similarity with the RNase H family endonucleases allowed interactions with the DNA to be predicted. A structure-based alignment with the distantly related T4 gp17 terminase shows the conservation of an extended beta sheet and an auxiliary beta-hairpin that are not found in other RNase H family proteins. The model with DNA suggests that the beta-hairpin partly blocks the active site, and in vivo activity assays show that the nuclease domain is not functional in the absence of the ATPase domain. Here, we propose that the nuclease activity is regulated by movement of the beta-hairpin, altering active site access and the orientation of catalytically essential residues. PMID- 19444314 TI - SPT5-like, a new component in plant RdDM. PMID- 19444316 TI - Temperature rise within the pulp chamber during composite resin polymerisation using three different light sources. AB - The purpose of the study was to compare temperature rise during polymerisation of resin based composites (RBCs) with two LED light curing units (LCUs) compared to a halogen control light. METHODS: Forty-five extracted molars, patients aging 11 18 years were used. Thermocouples (TCs) were placed in contact with the roof of the pulp chamber using a 'split-tooth' method. Teeth were placed in a water bath with the temperature of the pulp chamber regulated at 37 degrees +/-1 degrees C. GROUP 1 (CONTROL): Prismatics((R)) Lite II (Dentsply Detrey, Konstanz, Germany), a halogen LCU, light intensity 500 mW/cm(2). GROUP 2: Bluephase((R)) ( Ivoclar Vivadent, Schaan, Liechtenstein), light intensity 1100 mW/cm(2). Group 3:Elipar Freelight2 (3M ESPE, Seefeld, Germany), light intensity 1000 mW/cm(2). Temperature changes were continuously recorded with a data logger connected to a PC. RESULTS: Significantly higher temperature rise was recorded during bond curing than RBC curing in all 3 groups. (Halogen; p =0.0003: Bluephase; p=0.0043: Elipar; p=0.0002.). Higher temperatures were recorded during polymerisation of both Bond and RBC with both LED sources than with the halogen control. There was no significant difference between the two LED,LCUs (Bond:p=0.0279: RBC p=0.0562: Mann-Whitney). CONCLUSION: The potential risk of pulpal injury during RBC polymerisation is increased when using light-curing units with high energy output compared to low energy output light sources. The rise is greatest when curing bonding agent alone and clinicians are advised to be aware of the potential hazard of thermal trauma to the pulp when using high intensity light sources. However the mean temperature rise with all three units was below the limits normally associated with permanent pulp damage. PMID- 19444317 TI - Oral and perioral piercing complications. AB - BACKGROUND.: The oral an perioral piercing has a long history as part of religious, tribal,cultural or sexual symbolism and nowdays there is a high incidence of oral and perioral piercing in the adolescent population. This practice has a long history as part of religious, tribal, cultural or sexual symbolism. This article reviews current knowledge on injuries or diseases that might be produced by piercing in the oral cavity. We propose a classification to diagnosed the pathologies related to oral an perioral piercing METHODS.: A search was conducted of articles in PubMed, Scielo published between 1997 and 2007, using the key words ;;oral and perioral, piercing , ;;oral, piercing and disease", ;;recessions and oral piercing . It has reviewed about twentythree articles 17 were narrative reviews and 6 case series RESULTS.: A review was carried out on the origins of oral and perioral body piercing and its local implications, classifying the different alterations like recessions, systemic implications that it can produce in the oral and perioral cavity. CONCLUSION.: Patients with oral and perioral piercing should be regularly followed up because of the possible development of different types of adverse effects. CLINICAL IMPLICATIONS.: Adverse effects of oral and perioral piercing can be systemic, with transmission of infectious diseases such as hepatitis B or C, or can be local, with alteration of oral mucosae or even of dental structures. PMID- 19444318 TI - Mast cells and angiogenesis in oral malignant and premalignant lesions. AB - Mast cell contribution to neoangiogenesis during tumorigenesis in oral squamous cell carcinoma is not determined yet. OBJECTIVES: To associate numerical mast cell density (MCD) to numerical microvessel density (MVD) during the progression of oral leukoplakia without dysplasia and leukoplakia with dysplasia to squamous cell carcinoma (OSCC). MATERIALS AND METHODS: MVD was analysed immunohistochemically (mouse monoclonal anti-human CD34) in 49 paraffin-embedded specimens, 35 OSCCs, 9 leukoplakias and 5 normal oral tissues. Toluidine blue counterstaining revealed mast cells. MCD and MVD were assessed at the same optical field. RESULTS: MVD increased between: normal oral mucosa, dysplasia (p=0.004), OSCC (p=0.001), leukoplakia and OSCC (p=0.041). MCD increased between: normal oral mucosa, dysplasia (p=0.003), OSCC (p=0.000), leukoplakia and OSCC (p=0.007). MVD was found to depend on MCD (p=0.000) in a percent 28.3% (power curve fit model). CONCLUSIONS: Mast cells are attracted at the lesion site and may turn on an angiogenic switch during tumorigenesis in OSCC. PMID- 19444319 TI - Microleakage and Resin-to-Dentin Interface Morphology of Pre-Etching versus Self Etching Adhesive Systems. AB - The purpose of this study was to compare the microleakage and tissue-adhesive interface morphology from Class V restorations using different systems of dentin adhesives. Class V cavities were prepared on buccal surfaces of 27 extracted caries-free molars and premolars. Teeth were randomly assigned to one of three groups: (1) Prime & Bond NT, a 5(th) generation system using an initial step of total etch followed by a second step of application of a self bonding primer (2) Clearfil SE Bond, a 5(th) generation adhesive system employing two separate steps of self-etch priming and subsequent bonding (3) One-up Bond F, a 6(th) generation one step self-etching, self-priming and self-bonding adhesive. Microleakage and interface morphology of teeth restored with these adhesives and a composite resin were evaluated. Kruskal-Wallis Test (p = 0.05) was used to analyze the results. SEM analysis was used to relate interface morphology to microleakage. The mean and (SD) values of microleakage were: Prime and Bond NT: 0.15 (0.33), Clearfil SE Bond: 0.06 (0.17) and One-up Bond F: 2.96 (0.63). The mean microleakage for One up Bond was significantly higher than for the other groups (p<0.05). Protruding tags in dentin channels were observed in Prime and Bond and Clearfil systems, but not in One-up Bond. The single step adhesive system, although more convenient for the clinician, uses a low viscosity formulation difficult to keep in place on cavity walls. It also tends to be too aggressive and hydrophilic to create an impermeable hybridized tissue-adhesive interfacial layer resistant to microleakage. Two-step adhesive systems, on the other hand, were retained on all segments of the cavosurface during application, and formed a hybridized interfacial layer resistant to microleakage. PMID- 19444320 TI - Microwave-Accelerated and Metal-Enhanced Fluorescence Myoglobin Detection on Silvered Surfaces: Potential Application to Myocardial Infarction Diagnosis. AB - In this short paper, we describe a novel approach to both significantly accelerate and optically amplify fluorescence-based immunoassays. Our approach utilizes metal-enhanced fluorescence (MEF) to intrinsically optically amplify fluorescence signatures, which, when combined with the use of low-power microwaves to kinetically accelerate assays, provides for both ultrafast and ultrabright immunoassays. Surprisingly, the use of low-power microwaves and silver nanostructures provides for localized heating, concentrating the effect to the particles themselves as compared to the generic heating of the high dielectric assay fluid. We have subsequently applied our microwave-accelerated MEF approach to the detection of myoglobin, where its rapid quantification is paramount for the clinical assessment of an acute myocardial infarction. PMID- 19444321 TI - RNAi Phenotypes and the Localization of a Protein::GUS Fusion Imply a Role for Medicago truncatula PIN Genes in Nodulation. AB - The symbiosis between legumes and rhizobia results in the development of a new plant organ, the nodule. A role for polar auxin transport in nodule development in Medicago truncatula has been demonstrated using molecular genetic tools. The expression of a DR5::GUS auxin-responsive promoter in uninoculated M. truncatula roots mirrored that reported in Arabidopsis, and expression of the construct in nodulating roots confirmed results reported in white clover. The localization of a root-specific PIN protein (MtPIN2) in normal roots, developing lateral roots and nodules provided the first evidence that a PIN protein is expressed in nodules. Reduced levels of MtPIN2, MtPIN3, and MtPIN4 mRNAs via RNA interference demonstrated that plants with reduced expression of various MtPINs display a reduced number of nodules. The reported results show that in M. truncatula, PIN proteins play an important role in nodule development, and that nodules and lateral roots share some early auxin responses in common, but they rapidly differentiate with respect to auxin and MtPIN2 protein distribution. PMID- 19444322 TI - Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents. AB - Aberrant signaling through protein-tyrosine kinase (PTK)-dependent pathways is associated with several proliferative diseases. Accordingly, PTK inhibitors are being developed as new approaches for the treatment of certain cancers. Growth factor receptor bound protein 2 (Grb2) is an important downstream mediator of PTK signaling that serves obligatory roles in many pathogenic processes. One of the primary functions of Grb2 is to bind to specific phosphotyrosyl (pTyr)-containing sequences through its Src homology 2 (SH2) domain. Agents that bind to the Grb2 SH2 domain and prevent its normal function could disrupt associated PTK signaling and serve as alternatives to kinase-directed inhibitors. Starting from the X-ray crystal structure of a lead peptide bound to the Grb2 SH2 domain, this review will summarize important contributions to these efforts. The presentation will be thematically arranged according to the region of peptide modified, proceeding from the N-terminus to the C-terminus, with a special section devoted to aspects of conformational constraint. PMID- 19444323 TI - The Use of Phage-Displayed Peptide Libraries to Develop Tumor-Targeting Drugs. AB - Monoclonal antibodies have been successfully utilized as cancer-targeting therapeutics and diagnostics, but the efficacies of these treatments are limited in part by the size of the molecules and non-specific uptake by the reticuloendothelial system. Peptides are much smaller molecules that can specifically target cancer cells and as such may alleviate complications with antibody therapy. Although many endogenous and exogenous peptides have been developed into clinical therapeutics, only a subset of these consists of cancer targeting peptides. Combinatorial biological libraries such as bacteriophage displayed peptide libraries are a resource of potential ligands for various cancer-related molecular targets. Target-binding peptides can be affinity selected from complex mixtures of billions of displayed peptides on phage and further enriched through the biopanning process. Various cancer-specific ligands have been isolated by in vitro, in vivo, and ex vivo screening methods. As several peptides derived from phage-displayed peptide library screenings have been developed into therapeutics in current clinical trials, which validates peptide-targeting potential, the use of phage display to identify cancer targeting therapeutics should be further exploited. PMID- 19444324 TI - Genetic and Environmental Effects of Serial Naming and Phonological Awareness on Early Reading Outcomes. AB - The current study involved 281 early-school-age twin pairs (118 monozygotic, 163 same-sex dizygotic) participating in the ongoing Western Reserve Reading Project (S. A. Petrill, K. Deater-Deckard, L. A. Thompson, & C. Schatschneider, 2006). Twins were tested in their homes by separate examiners on a battery of reading related skills including phonological awareness, rapid automatized naming, word knowledge, and phonological decoding. Results suggested that a core genetic factor accounted for a significant portion of the covariance between phonological awareness, rapid naming, and reading outcomes. However, shared environmental influences related to phonological awareness were also associated with reading skills. PMID- 19444325 TI - New classification of crown forms and gingival characteristics in taiwanese. AB - OBJECTIVES: The aim of the investigation was to examine the forms of the crowns in the maxillary anterior tooth segment and corresponding gingival characteristics among healthy Taiwanese subjects. MATERIALS AND METHODS: The crown width at the apical third (CW), length (CL), gingival angle (GA) and the interdental papilla height were assessed from the diagnostic stone model using a calibrated periodontal caliper. A CW/CL-ratio was calculated for each tooth and averaged for each tooth region. Gingival thickness (GT) and width of keratinized gingiva (WG) were measured clinically. RESULTS: The cluster analysis revealed 3 classifications of crown forms: narrow (N), compound (C) and square (S) types. There was a significant difference among the 3 classifications with respect to CW/CL-ratio, GT, and WG (p < 0.0001). CONCLUSIONS: The results demonstrated varied crown forms and corresponding gingival characteristics in Caucasian and Taiwanese. The new classifications hinted that there was a polymorphism in different races and could be a valuable esthetic guideline and reference for anterior tooth rehabilitation, including various periodontal and restorative treatments and anterior implant placement procedures in Taiwanese. PMID- 19444326 TI - Family Cohesion and its Relationship to Psychological Distress among Latino Groups. AB - This paper presents analyses of a representative sample of US Latinos (N=2540) to investigate whether family cohesion moderates the effects of cultural conflict on psychological distress. The results for the aggregated Latino group suggests a significant association between family cohesion and lower psychological distress and the combination of strong family cohesion with presence of family cultural conflict was associated with higher psychological distress. However, this association differed by Latino groups. We found no association for Puerto Ricans, Cuban results were similar to the aggregate group, family cultural conflict in Mexicans was associated with higher psychological distress, while family cohesion in Other Latinos was associated with higher psychological distress. Implications of these findings are discussed to unravel the differences in family dynamics across Latino subethnic groups. PMID- 19444327 TI - The Neural Basis of Selective Attention: Cortical Sources and Targets of Attentional Modulation. AB - Selective attention is an intrinsic component of perceptual representation in a visual system that is hierarchically organized. Modulatory signals originate in brain regions that represent behavioral goals; these signals specify which perceptual objects are to be represented by sensory neurons that are subject to contextual modulation. Attention can be deployed to spatial locations, features, or objects, and corresponding modulatory signals must be targeted within these domains. Open questions include how nonspatial perceptual domains are modulated by attention and how abstract goals are transformed into targeted modulatory signals. PMID- 19444328 TI - Patient-specific artery shrinkage and 3D zero-stress state in multi-component 3D FSI models for carotid atherosclerotic plaques based on in vivo MRI data. AB - Image-based computational models for atherosclerotic plaques have been developed to perform mechanical analysis to quantify critical flow and stress/strain conditions related to plaque rupture which often leads directly to heart attack or stroke. An important modeling issue is how to determine zero stress state from in vivo plaque geometries. This paper presents a method to quantify human carotid artery axial and inner circumferential shrinkages by using patient-specific ex vivo and in vivo MRI images. A shrink-stretch process based on patient-specific in vivo plaque morphology and shrinkage data was introduced to shrink the in vivo geometry first to find the zero-stress state (opening angle was ignored to reduce the complexity), and then stretch and pressurize to recover the in vivo plaque geometry with computed initial stress, strain, flow pressure and velocity conditions. Effects of the shrink-stretch process on plaque stress/strain distributions were demonstrated based on patient-specific data using 3D models with fluid-structure interactions (FSI). The average artery axial and inner circumferential shrinkages were 25% and 7.9%, respectively, based on a data set obtained from 10 patients. Maximum values of maximum principal stress and strain increased 349.8% and 249% respectively with 33% axial stretch. Influence of inner circumferential shrinkage (7.9%) was not very noticeable under 33% axial stretch, but became more noticeable under smaller axial stretch. Our results indicated that accurate knowledge of artery shrinkages and the shrink-stretch process will considerably improve the accuracy of computational predictions made based on results from those in vivo MRI-based FSI models. PMID- 19444329 TI - The Role of the NF-kappaB Transcriptome and Proteome as Biomarkers in Human Head and Neck Squamous Cell Carcinomas. AB - NF-kappaB is a family of signal activated transcription factors comprised of hetero- or homo-dimers from 5 different subunits, NF-kappaB1, NF-kappaB2, RELA, cREL and RELB. NF-kappaBs normally are transiently activated in response to infection or injury, but in cancers are aberrantly activated, regulating a transcriptome of hundreds of genes and corresponding proteome that promote pathogenesis and therapeutic resistance. In head and neck squamous cell carcinomas, an important role of NF-kappaB in regulation of the altered transcriptome and proteome has been established, providing a catalog of activating and target genes and proteins that may be useful as biomarkers of alterations in this pathway for this and other cancers. An emerging appreciation that NF-kappaB and other signal pathways form an altered regulatory network highlights the need to use biomarkers and combine targeted agents for personalized therapy of cancer. PMID- 19444331 TI - Semiparametric Analysis of Heterogeneous Data Using Varying-Scale Generalized Linear Models. AB - This article describes a class of heteroscedastic generalized linear regression models in which a subset of the regression parameters are rescaled nonparametrically, and develops efficient semiparametric inferences for the parametric components of the models. Such models provide a means to adapt for heterogeneity in the data due to varying exposures, varying levels of aggregation, and so on. The class of models considered includes generalized partially linear models and nonparametrically scaled link function models as special cases. We present an algorithm to estimate the scale function nonparametrically, and obtain asymptotic distribution theory for regression parameter estimates. In particular, we establish that the asymptotic covariance of the semiparametric estimator for the parametric part of the model achieves the semiparametric lower bound. We also describe bootstrap-based goodness-of-scale test. We illustrate the methodology with simulations, published data, and data from collaborative research on ultrasound safety. PMID- 19444330 TI - In silico preclinical trials: a proof of concept in closed-loop control of type 1 diabetes. AB - Arguably, a minimally invasive system using subcutaneous (s.c.) continuous glucose monitoring (CGM) and s.c. insulin delivery via insulin pump would be a most feasible step to closed-loop control in type 1 diabetes mellitus (T1DM). Consequently, diabetes technology is focusing on developing an artificial pancreas using control algorithms to link CGM with s.c. insulin delivery. The future development of the artificial pancreas will be greatly accelerated by employing mathematical modeling and computer simulation. Realistic computer simulation is capable of providing invaluable information about the safety and the limitations of closed-loop control algorithms, guiding clinical studies, and out-ruling ineffective control scenarios in a cost-effective manner. Thus computer simulation testing of closed-loop control algorithms is regarded as a prerequisite to clinical trials of the artificial pancreas. In this paper, we present a system for in silico testing of control algorithms that has three principal components: (1) a large cohort of n=300 simulated "subjects" (n=100 adults, 100 adolescents, and 100 children) based on real individuals' data and spanning the observed variability of key metabolic parameters in the general population of people with T1DM; (2) a simulator of CGM sensor errors representative of Freestyle NavigatorTM, Guardian RT, or DexcomTM STSTM, 7-day sensor; and (3) a simulator of discrete s.c. insulin delivery via OmniPod Insulin Management System or Deltec Cozmo((r)) insulin pump. The system has been shown to represent adequate glucose fluctuations in T1DM observed during meal challenges, and has been accepted by the Food and Drug Administration as a substitute to animal trials in the preclinical testing of closed-loop control strategies. PMID- 19444332 TI - Modeling CNS microglia: the quest to identify predictive models. AB - The mammalian central nervous system (CNS) is populated very early in development by tissue macrophages referred to as microglia. By adulthood, this CNS-resident population is found in all regions of the brain and spinal cord. Despite nearly a century of study, the in vivo function of microglia and the extent that they contribute to the onset, progression and recovery from neuroinflammatory disorders is still a subject of debate. Partly, the debate of whether activated microglia promote neuroprotection or neurodegeneration is fueled by the contrasting results derived from the different models used to assay microglial function. Here we discuss the strengths, weaknesses and utility of some of the most commonly used in vivo and in vitro models. PMID- 19444333 TI - Parallel Fuzzy Segmentation of Multiple Objects. AB - The usefulness of fuzzy segmentation algorithms based on fuzzy connectedness principles has been established in numerous publications. New technologies are capable of producing larger-and-larger datasets and this causes the sequential implementations of fuzzy segmentation algorithms to be time-consuming. We have adapted a sequential fuzzy segmentation algorithm to multi-processor machines. We demonstrate the efficacy of such a distributed fuzzy segmentation algorithm by testing it with large datasets (of the order of 50 million points/voxels/items): a speed-up factor of approximately five over the sequential implementation seems to be the norm. PMID- 19444334 TI - Proximate industrial activity and psychological distress. AB - This paper examines the role that gender, occupational status, and family status play in moderating the effect of industrial activity on the psychological well being of nearby residents. Using a unique spatial assessment of industrial activity and an environmental risk/social stressor framework in conjunction with individual-level data from the Detroit Area Study (DAS) and demographic data from the U.S. census, we find that residents of neighborhoods in close proximity to industrial activity report elevated levels of psychological distress compared to residents of neighborhoods removed from this type of activity. These influences are more pronounced among women but gender differences are also contingent upon occupational and family statuses. We show that specific combinations of work and family statuses make persons particularly vulnerable to the influence of this environmental stressor and women are two and a half times more likely than men to have these vulnerable statuses. This study makes an important contribution to the environmental health literature because it reminds researchers of the fundamental influence of social roles when examining the link between environmental risks and mental health. PMID- 19444335 TI - Nonparametric estimation and testing of fixed effects panel data models. AB - In this paper we consider the problem of estimating nonparametric panel data models with fixed effects. We introduce an iterative nonparametric kernel estimator. We also extend the estimation method to the case of a semiparametric partially linear fixed effects model. To determine whether a parametric, semiparametric or nonparametric model is appropriate, we propose test statistics to test between the three alternatives in practice. We further propose a test statistic for testing the null hypothesis of random effects against fixed effects in a nonparametric panel data regression model. Simulations are used to examine the finite sample performance of the proposed estimators and the test statistics. PMID- 19444337 TI - Use of the Time, Interaction and Performance Theory to Study Hospice Interdisciplinary Team Meetings. AB - Hospice agencies are required to schedule and conduct Interdisciplinary Team meetings; however, little guidance exists as to how these meetings should be conducted. The purpose of this study was to apply the Time, Interaction and Performance theory to gain a better understanding of Interdisciplinary Team meetings. A total of 81 patient care discussions on 24 patients by four interdisciplinary hospice teams were videotaped in the time frame from December 2006 to April 2007 and transcribed. A total of 1,982 utterances were recorded. The utterances were analyzed using thematic content analysis. Nurses had the most utterances in relation to team production, defining patient needs and meeting defined goals. Additionally, nurses had the most utterances in relation to scheduling and synchronization of activities. Two specific areas in need of enhancement were noted, improvement in team member support and communication effectiveness. Future interventions targeting these areas of need may increase coordination of services which results in patient and family satisfaction and reduced overall health care costs. PMID- 19444336 TI - A cross-linguistic and bilingual evaluation of the interdependence between lexical and grammatical domains. AB - The purpose of this study was to examine within and across language relationships between lexical and grammatical domains by focusing on measures of lexical diversity and grammatical complexity in Spanish and English. One hundred and ninety-six preschool and school-aged Latino children with different levels of English and Spanish proficiencies and different language abilities produced narratives in Spanish, English, or both. Analyses revealed strong associations between lexical (number of different words and number of different verbs) and grammatical measures (mean length of utterances in words and use of ditransitive predicates), supporting the domain interdependence hypothesis within a language. Cross-linguistic comparisons indicate a greater diversity of verbs and ditransitive predicates in Spanish compared to English for this population. In the language samples of children who produced narratives in the two languages, there was no relationship between the two domains across languages. The lack of cross-language correlations may be related to other variables influencing lexical and semantic development in bilingual learners. Methodological issues to be considered in future studies with bilingual speakers are discussed. PMID- 19444338 TI - Ultrafast Method for the Analysis of Fluorescence Lifetime Imaging Microscopy Data Based on the Laguerre Expansion Technique. AB - We report a new deconvolution method for fluorescence lifetime imaging microscopy (FLIM) based on the Laguerre expansion technique. The performance of this method was tested on synthetic and real FLIM images. The following interesting properties of this technique were demonstrated. 1) The fluorescence intensity decay can be estimated simultaneously for all pixels, without a priori assumption of the decay functional form. 2) The computation speed is extremely fast, performing at least two orders of magnitude faster than current algorithms. 3) The estimated maps of Laguerre expansion coefficients provide a new domain for representing FLIM information. 4) The number of images required for the analysis is relatively small, allowing reduction of the acquisition time. These findings indicate that the developed Laguerre expansion technique for FLIM analysis represents a robust and extremely fast deconvolution method that enables practical applications of FLIM in medicine, biology, biochemistry, and chemistry. PMID- 19444339 TI - Effect of flask closure method and post-pressing time on the displacement of maxillary denture teeth. AB - The purpose of this study was to verify the influence of flask closure methods and post-pressing times on tooth displacement in maxillary dentures. Twenty similar maxillary dentures were made using a heat-polymerized acrylic resin, and randomly assigned to 4 experimental groups (n=5) according to the protocol: 1 conventional flask closure and immediate polymerization; 2- conventional flask closure and polymerization after 6-hour post-pressing time; 3- RS flask closure system and immediate polymerization; and 4- RS flask closure system and polymerization after 6-hour post-pressing time. Three transverse and 2 anteroposterior linear distances between teeth were measured before and after the denture processing with an optical microscope with accuracy of 0.0005mm. Analysis of variance (ANOVA) and Tukey's test were performed to compare the results. The 6 hour post-pressing time (conventional = 0.44mm and RS = 0.33mm) showed no statistically significant difference in tooth movement, in relation to the flask closure methods, when compared to the immediate time (conventional = 0.40mm and RS = 0.28mm). The RS system standardized the tooth displacement, independently of the post-pressing times. Dimensional changes were more uniform when the dentures were submitted to the 6-hour post-pressing time and RS flask closure method, suggesting that these factors may reduce the magnitude of tooth movement. PMID- 19444340 TI - Acidogenic potential of "sugar-free" cough drops. AB - A patient presented with extensive marginal ditching around restorations recently placed during whole-mouth rehabilitation. The patient was not xerostomic and was otherwise normal except for the self-reported excessive use of "sugar-free" cough drops sweetened with sorbitol and Isomalt(r) (an equimolar mix of glucosyl mannitol and glucosylsorbitol). This prompted an in vitro investigation to determine whether Streptococcus sobrinus 6715, a cariogenic streptococcus, could grow and produce acid in growth medium containing an aqueous extract of such "sugar-free" cough drops. The results indicate that S. sobrinus 6715 uses Isomalt(r) and sorbitol extensively, producing terminal culture pH as low as 4.2 when grown on medium with cough drop extract containing these sugars. This pH is sufficient to demineralize dental enamel. Patients should be cautioned against the chronic overuse of "sugar-free" cough drops and other "sugar-free" confections sweetened with a mixture of Isomalt(r) and sorbitol. PMID- 19444341 TI - Short-term analysis of human dental pulps after direct capping with portland cement. AB - This study evaluated the short-term response of human pulp tissue when directly capped with Portland cement. In this series of cases, twenty human third molars that were scheduled for extraction were used. After cavity preparation, pulp exposure was achieved and Portland cement pulp capping was performed. Teeth were extracted after 1, 7, 14 and 21 days following treatment and prepared for histological examination and bacterial detection. Each group had 5 teeth. The results were descriptively analysed. Dentin bridge formation was seen in two teeth with some distance from the material interface (14 and 21 days). Soft inflammatory responses were observed in most of the cases. Bacteria were not disclosed in any specimen. PC exhibited some features of biocompatibility and capability of inducing mineral pulp response in short-term evaluation. The results suggested that PC has a potential to be used as a less expensive pulp capping material in comparison to other pulp capping materials. PMID- 19444342 TI - Continuous and short fiber reinforced composite in root post-core system of severely damaged incisors. AB - PURPOSE: The aim of this study was to determine the static load-bearing capacity of endodontically treated maxillary incisors restored with post-core complex made of experimental fiber composite resin (FC) and complete crown made of particulate filler composite (PFC). Further aim was to evaluate the effect of FC resin on the failure mode of the restoration. MATERIAL AND METHODS: The experimental composite resin (FC) was prepared by mixing 22.5 wt% of short E-glass fibers (3 mm in length) and 22.5 wt% of semi-interpenetrating polymer network (IPN) resin with 55 wt% of silane treated silica fillers. Thirty extracted sound upper central incisors were used. Twenty teeth were prepared by cutting the clinical crown 2 mm above the cemento-enamel junction horizontally. Restorations were made by two techniques (n=10). Group A (control group) contained samples of sound incisor teeth. Group B had teeth restored using glass fiber post (everStick, Stick- Teck) and PFC (Filtek Z250, 3M-ESPE) to build up core and complete crown. In Group C, the teeth were restored with FC as post-core and complete crown of PFC. The root canals were prepared and posts were cemented with a dual cure resin cement. The restorations were polymerized with a hand-light curing unit. All restored teeth were stored in water at room temperature for 24 h before they were statically loaded with speed of 1.0 mm/min until fracture. Data were analyzed using ANOVA (p=0.05). Failure modes were visually examined. RESULTS: ANOVA revealed that restored incisors (Group B and C) had a statistically significantly lower load bearing capacity (p<0.05) than the control group. Restorations made from FC post core and PFC coverage (Group C) gave force value of 363 N (112 SD), which was higher than the value of Group B (211 N, 50 SD). CONCLUSIONS: Within the limitations of this study, the teeth restored with experimental fiber composite post-core demonstrated higher load bearing capacity than those with fiber post and PFC core. PMID- 19444343 TI - Evaluation of oral mucosal lesions in 598 referred Iranian patients. AB - The mucosal membrane of the oral cavity displays at times classical developmental lesions considered to be variations of normal structures rather than having disease characteristics. Of these lesions leukoedema, Fordyce granules, geographic-, fissured- and hairy tongue, median rhomboid glossitis and lingual varices were studied in 598 patients referred to the School of Dentistry, Tehran, Iran. The prevalence was studied in relation to age, gender, occupation, education, smoking habits, general health, addictions and or drug therapies. Oral developmental lesions were seen in 295 patients (49.3%). Only Fordyce granules (27,9%), fissured tongue (12,9%), leukoedema (12,5%) and hairy tongue (8,9%) had enough cases for statistical analysis. Three of these lesions increased with age but not fissured tongue. All were more common in men. After adjusting for age, the parameters education, occupation and complaints upon referral had little influence on the prevalence of the lesions. Fewer Fordyce granules were seen in oral mucosa of smoking men. Leukoedema and hairy tongue were significantly associated with smoking, leukoedema with diabetes mellitus. We conclude that there was a highly significant association between these oral lesions and age, gender and smoking. Few significant associations were found between oral lesions and general diseases. PMID- 19444344 TI - The relationships between two different drinking water fluoride levels, dental fluorosis and bone mineral density of children. AB - This field study included the whole population of children aged 10-15 years (77 from a 0.19 mg/L F area; 89 from a 3.00 mg/L F area), with similar nutritional, dietary habits and similar ethnic and socioeconomic status. The fluoride concentration in the drinking water, the bone mineral content, the bone density and the degree of dental fluorosis were determined. The left radius was measured for bone width, bone mineral content, and bone mineral density. The mean fluorosis score was 1.3 in the low fluoride area and 3,6 in the high fluoride area. More than half the children in the low fluoride area had no fluorosis (scores 0 and 1) while only 5% in the high fluoride area had none. Severe fluorosis (30%) was only observed in the high fluoride area. The Wilcoxon Rank Sum Test indicated that fluorosis levels differed significantly (p < 0.05) between the two areas. No relationships were found between dental fluorosis and bone width or between fluorosis and bone mineral density in the two areas (Spearment Rank correlations). A significant increase in bone width was found with age but no differences amongst and boys and girls. A significant positive correlation was found in the high fluoride area between bone mineral density over age. In the 12-13 and 13-14 year age groups in the high fluoride area, girls had higher bone mineral densities. However, a significant negative correlation (p<0.02) was found for the low fluoride area (0.19 mg/L F) over age. PMID- 19444345 TI - Analysis of results using percutaneous vertebroplasty for the treatment of avascular necrosis of the vertebral body. AB - OBJECTIVE: Avascular necrosis (AVN) of the vertebral body is known as a relatively uncommon phenomenon in a vertebral compression fracture (VCF). The outstanding radiologic findings of AVN are intravertebral vacuum phenomenon with or without fluid collection. Several reports revealed that PVP or balloon kyphoplasty might be the effective treatment modalities for AVN. We also experienced excellent results when using PVP for the treatment of AVN of the vertebral body, and intend to describe the treatment's efficacy in this report. METHODS: Thirty-two patients diagnosed with AVN of the vertebral body were treated with PVP. We measured the pre- and post-operative anterior body height and kyphotic angulation. The visual analogue scale (VAS) was used to determine the relief of back pain. RESULTS: The anterior body height (pre-operative : 1.49 cm, post-operative : 2.22 cm) and kyphotic angulation (pre-operative : 14.47 degrees, post-operative : 6.57 degrees) were significantly restored (p<0.001). VAS was improved from 8.9 to 3.7. Pseudoarthrosis was corrected in all cases, which was confirmed by dynamic radiographs. Fluid collection was found in sixteen cases and was aspirated with serous nature. No organism and tumor cell were noted. CONCLUSION: PVP proved to be an effective procedure for the treatment of AVN of the vertebral body, which corrected dynamic instability and significantly restored the anterior body height and kyphotic angulation. PMID- 19444346 TI - Load sharing mechanism across graft-bone interface in static cervical locking plate fixation. AB - OBJECTIVE: This study is a retrospective clinical study over more than 4 years of follow up to understand the mechanism of load sharing across the graft-bone interface in the static locking plate (SLP) fixation compared with non-locking plate (NLP). METHODS: Orion locking plates and Top non-locking plates were used for SLP fixation in 29 patients and NLP fixation in 24 patients, respectively. Successful interbody fusion was estimated by dynamic X-ray films. The checking parameters were as follows : screw angle (SA) between upper and lower screw, anterior and posterior height of fusion segment between upper and lower endplate (AH & PH), and upper and lower distance from vertebral endplate to the end of plate (UD & LD). Each follow-up value of AH and PH were compared to initial values. Contributions of upper and lower collapse to whole segment collapse were estimated. RESULTS: Successful intervertebral bone fusion rate was 100% in the SLP group and 92% in the NLP group. The follow-up mean value of SA in SLP group was not significantly changed compared with initial value, but follow-up mean value of SA in NLP group decreased more than those in SLP group (p=0.0067). Statistical analysis did not show a significant difference in the change in AH and PH between SLP and NLP groups (p>0.05). Follow-up AH of NLP group showed more collapse than PH of same group (p=0.04). The upper portion of the vertebral body collapsed more than the lower portion in the SLP fixation (p=0.00058). CONCLUSION: The fused segments with SLP had successful bone fusion without change in initial screw angle, which was not observed in NLP fixation. It suggests that there was enough load sharing across bone-graft interface in SLP fixation. PMID- 19444347 TI - Localization of Broca's Area Using Functional MR Imaging: Quantitative Evaluation of Paradigms. AB - OBJECTIVE: Functional magnetic resonance imaging (fMRI) is frequently used to localize language areas in a non-invasive manner. Various paradigms for presurgical localization of language areas have been developed, but a systematic quantitative evaluation of the efficiency of those paradigms has not been performed. In the present study, the authors analyzed different language paradigms to see which paradigm is most efficient in localizing frontal language areas. METHODS: Five men and five women with no neurological deficits participated (mean age, 24 years) in this study. All volunteers were right handed. Each subject performed 4 tasks, including fixation (Fix), sentence reading (SR), pseudoword reading (PR), and word generation (WG). Fixation and pseudoword reading were used as contrasts. The functional area was defined as the area(s) with a t-value of more than 3.92 in fMRI with different tasks. To apply an anatomical constraint, we used a brain atlas mapping system, which is available in AFNI, to define the anatomical frontal language area. The numbers of voxels in overlapped area between anatomical and functional area were individually counted in the frontal expressive language area. RESULTS: Of the various combinations, the word generation task was most effective in delineating the frontal expressive language area when fixation was used as a contrast (p<0.05). The sensitivity of this test for localizing Broca's area was 81% and specificity was 70%. CONCLUSION: Word generation versus fixation could effectively and reliably delineate the frontal language area. A customized effective paradigm should be analyzed in order to evaluate various language functions. PMID- 19444348 TI - Analysis of clinical and radiological outcomes in microsurgical and endovascular treatment of basilar apex aneurysms. AB - OBJECTIVE: We aimed to analyze clinical and radiological outcomes retrospectively in patients with basilar apex aneurysms treated by coiling or clipping. METHODS: Outcomes of basilar bifurcation aneurysms were assessed retrospectively in 77 consecutive patients (61 women, 16 men), ranging in age from 25 to 79 years (mean, 53.7 years) from 1999 to 2007. RESULTS: Forty-nine patients out of 77 patients (63.6%) presented with subarachnoid hemorrhages of the 49 patients treated with coiling, 27 (55.1%) showed complete occlusion of the aneurysm sac. Of these, 13 patients (26.5%) developed coil compaction on angiographic or MRI follow-up, with recoiling required in 9 patients (18.4%). Procedural complications of coiling were acute infarction in nine patients and the bleeding of the aneurysms in six patients. The remaining 28 patients underwent microsurgery: twenty-six of these (92.9%) with microsurgery followed up with conventional angiography. Complete occlusion of the aneurysm sac was achieved in 19 patients (73.1%). Operation-related complications of microsurgery were thalamoperforating artery injuries in three patients, retraction venous injury in two, postoperative epidural hemorrhage (EDH) in one, and transient partial or complete occulomotor palsy in 14 patients. Glasgow Outcome Scores (GOS) were 4 or 5 in 21 of 28 (75%) patients treated with microsurgery at discharge, and at 6 month follow-up, 20 of 28 (70.9%) maintained the same GOS. In comparison, GOS of four or 5 was observed in 36 of 49 (73.5%) patients treated with coiling at discharge and at 6 month follow-up, 33 of 49 patients (67.3%) maintained the GOS from discharge. CONCLUSION: Basilar top aneurysms were still challenging lesions based on our series. Endovascular or microsurgery endowed with its inborn risks and procedural complications for the treatment of basilar apex aneurysms individually. Microsurgery provided better outcome in some specific basilar apex aneurysms. For reaching the most favorable outcome, endovascular modality as well as microsurgery was inevitably considered for each specific basilar apex aneurysm. PMID- 19444349 TI - Immunoreactivity of calcium-binding proteins in the central auditory nervous system of aged rats. AB - OBJECTIVE: While many factors contribute to aging, changes in calcium homeostasis and calcium related neuronal processes are likely to be important. High intracellular calcium is toxic to cells and alterations in calcium homeostasis are associated with changes in calcium-binding proteins, which confine free Ca(2+). We therefore assayed the expression of the calcium binding proteins calretinin and calbindin in the central auditory nervous system of rats. METHODS: Using antibodies to calretinin and calbindin, we assayed their expression in the cochlear nucleus, superior olivary nucleus, inferior colliculus, medial geniculate body and auditory cortex of young (4 months old) and aged (24 months old) rats. RESULTS: Calretinin and calbindin staining intensity in neurons of the cochlear nucleus was significantly higher in aged than in young rats (p<0.05) The number and staining intensity of calretinin-positive neurons in the inferior colliculus, and of calbindin-positive neurons in the superior olivary nucleus were greater in aged than in young rats (p<0.05). CONCLUSION: These results suggest that auditory processing is altered during aging, which may be due to increased intracellular Ca(2+) concentration, consequently leading to increased immunoreactivity toward calcium-binding proteins. PMID- 19444350 TI - Development of 'De novo' Aneurysm after Therapeutic Carotid Occlusion. AB - Carotid occlusion is an inevitable therapeutic modality for the treatment of complex aneurysms such as giant, traumatic, and intracavernous aneurysms. Late complications of carotid occlusion include 'de novo' aneurysm formation at a distant site because of hemodynamic changes in the circle of Willis. We report a case of de novo aneurysm in a vessel that appeared to be normal on initial angiography. The patient developed an anterior communicating artery aneurysm and marked growth of a basilar bifurcation aneurysm 9 years after trapping of the left internal carotid artery for the treatment of a ruptured large saccular aneurysm involving ophthalmic and cavernous segments. We propose that patients who undergo therapeutic carotid occlusion should be periodically followed by magnetic resonance angiography or computed tomographic angiography to evaluate the possibility of de novo aneurysm formation; this advice is in line with previous reports. PMID- 19444351 TI - Oculomotor nerve palsy associated with rupture of middle cerebral artery aneurysm. AB - Oculomotor nerve palsy (ONP) with subarachnoid hemorrhage (SAH) occurs usually when oculomotor nerve is compressed by growing or budding of posterior communicating artery (PcoA) aneurysm. Midbrain injury, increased intracranial pressure (ICP), or uncal herniation may also cause it. We report herein a rare case of ONP associated with SAH which was caused by middle cerebral artery (MCA) bifurcation aneurysm rupture. A 58-year-old woman with clear consciousness suffered from headache and sudden onset of unilateral ONP. Computed tomography showed SAH caused by the rupture of MCA aneurysm. The unilateral ONP was not associated with midbrain injury, increased ICP, or uncal herniation. The patient was treated with coil embolization, and the signs of oculomotor nerve palsy completely resolved after a few days. We suggest that bloody jet flow from the rupture of distant aneurysm other than PcoA aneurysm may also be considered as a cause of sudden unilateral ONP in patients with SAH. PMID- 19444352 TI - Combined anterior and posterior en bloc vertebrectomy for lumbar chordoma. AB - Chordoma is a rare bone tumor derived from remnants of the notochord. The majority of chordomas involve the sacrum or skull base. We report a rare case of a L4 vertebral body chordoma treated with anterior en bloc vertebrectomy and posterior stabilization. No tumor recurrence was observed at the 5 year follow-up examination. PMID- 19444353 TI - Atlantoaxial rotatory fixation in adults patient. AB - Atlantoaxial rotatory fixation (AARF) in adult is a rare disorder that occurs followed by a trauma. The patients were presented with painful torticollis and a typical 'cock robin' position of the head. The clinical diagnosis is generally difficult and often made in the late stage. In some cases, an irreducible or chronic fixation develops. We reported a case of AARF in adult patient which was treated by immobilization with conservative treatment. A 25-year-old female was presented with a posterior neck pain and limitation of motion of cervical spine after a traffic accident. She had no neurological deficit but suffered from severe defect on the scalp and multiple thoracic compression fractures. Plain radiographs demonstrated torticollis, lateral shift of odontoid process to one side and widening of one side of C1-C2 joint space. Immobilization with a Holter traction were performed and analgesics and muscle relaxants were given. Posterior neck pain and limitation of the cervical spine's motion were resolved. Plain cervical radiographs taken at one month after the injury showed that torticollis disappeared and the dens were in the midline position. The authors reported a case of type I post-traumatic AARF that was successfully treated by immobilization alone. PMID- 19444354 TI - Thrombosis of left common iliac artery following anterior lumbar interbody fusion: case report and review of literatures. AB - We report on a case of thrombosis of the left common iliac artery following anterior lumbar interbody fusion (ALIF) of L4-5 in a 79-year-old man with no previous medical problems, including peripheral vascular disease. After completing the ALIF procedure, the surgeon could not feel the pulsation of the left dorsalis pedis artery, and the oxygen saturation (SaO(2)) had fallen below 90% from pulse oxymetry on the left great toe. Thrombectomy was successfully performed after confirming the thrombus in the left common iliac artery using Computed Tomography (CT) angiography. Thrombosis of the common iliac artery is very rare following ALIF. However, delayed diagnosis can lead to disastrous outcome. Although elderly patients have no cardio-vascular disease or vessel calcification in pre-op evaluation, the possibility of a complication involving L4-5 should be considered. PMID- 19444355 TI - Spontaneous spinal subarachnoid hemorrhage with spontaneous resolution. AB - Spontaneous spinal subarachnoid hematoma (SSH) is a rare entity to cause spinal cord or nerve root compression and is usually managed as surgical emergencies. We report a case of spontaneous SSH manifesting as severe lumbago, which demonstrated nearly complete clinical resolution with conservative treatment. A 58-year-old female patient developed a large SSH, which was not related to blood dyscrasia, anticoagulation, lumbar puncture, or trauma. Patient had severe lumbago but no neurologic deficits. Because of absence of neurologicl deficits, she was treated conservatively. Follow-up magnetic resonance (MR) image showed complete resolution. Conservative treatment of SSH may be considered if the patient with spontaneous SSH has no neurologic deficits. PMID- 19444356 TI - Intraventricular Malignant Meningioma with CSF-Disseminated Spinal Metastasis : Case Report and Literature Review. AB - The authors report a case of 42-year-old woman with an intraventricular tumor in the trigone of the left lateral ventricle. The first operation achieved a microscopically complete resection. The tumor was histologically atypical meningioma. After 26 months, there were recurrences of intraventricular meningioma. Complete resection of the tumor and adjuvant radiation therapy were performed, and the histological diagnosis was malignant meningioma. Sixteen months after the second operation, spinal metastasis in cervicolumbar lesion was diagnosed and a subtotal removal of cervical intradural extramedullary mass was performed. We describe an unusual case of intraventricular malignant meningioma with cerebrospinal fluid-disseminated spinal metastases with review of the clinical courses of previous reports. PMID- 19444358 TI - Erratum. AB - [This corrects the article on p. 182 in vol. 45, PMID: 19352482.]. PMID- 19444357 TI - Ideal Internal Carotid Artery Trapping Technique without Bypass in a Patient with Insufficient Collateral Flow. AB - Internal carotid artery (ICA) trapping can be used for treating intracranial giant aneurysm, blood blister-like aneurysms and ICA rupture during the surgery. We present a novel ICA trapping technique which can be used with insufficient collaterals flow via anterior communicating artery (AcoA) and posterior communicating artery (PcoA). A patient was admitted with severe headache and the cerebral angiography demonstrated a typical blood blister-like aneurysm at the contralateral side of PcoA. For trapping the aneurysm, the first clip was placed at the ICA just proximal to the aneurysm whereas the distal clip was placed obliquely proximal to the origin of the PcoA to preserve blood flow from the PcoA to the distal ICA. The patient was completely recovered with good collaterals filling to the right ICA territories via AcoA and PcoA. This technique may be an effective treatment option for trapping the aneurysm, especially when the PcoA preservation is mandatory. PMID- 19444359 TI - Infants choking following blind finger sweep. AB - OBJECTIVES: In stressful situations, people usually use finger sweep to remove pharyngeal foreign bodies from the mouth. This article reports on three cases of death of infants following the use of this technique. METHODS: A total of 26 cases of choking caused by foreign bodies aspiration in the upper and lower respiratory passages involving children younger than 11 years of age autopsied at the Forensic Department of University of Jordan between 1996 and 2006 were reviewed. RESULTS: Blind finger sweep to remove pharyngeal foreign bodies were reported in three crying infants. All of these cases were younger than 1 year of age and choked on a chickpea, a marble and a short pencil. Diversity, size, shape and smoothness of the surface are the main characteristics that render the foreign bodies less easily caught by fingers and make them easily enter the respiratory passage. CONCLUSIONS: These cases showed that blind finger sweep in crying infants is not only dangerous but can be a fatal maneuver. PMID- 19444360 TI - Is the Cry1Ab protein from Bacillus thuringiensis (Bt) taken up by plants from soils previously planted with Bt corn and by carrot from hydroponic culture? AB - The uptake of the insecticidal Cry1Ab protein from Bacillus thuringiensis (Bt) by various crops from soils on which Bt corn had previously grown was determined. In 2005, the Cry1Ab protein was detected by Western blot in tissues (leaves plus stems) of basil, carrot, kale, lettuce, okra, parsnip, radish, snap bean, and soybean but not in tissues of beet and spinach and was estimated by enzyme-linked immunosorbent assay (ELISA) to be 0.05 +/- 0.003 ng g(-1) of fresh plant tissue in basil, 0.02 +/- 0.014 ng g(-1) in okra, and 0.34 +/- 0.176 ng g(-1) in snap bean. However, the protein was not detected by ELISA in carrot, kale, lettuce, parsnip, radish, and soybean or in the soils by Western blot. In 2006, the Cry1Ab protein was detected by Western blot in tissues of basil, carrot, kale, radish, snap bean, and soybean from soils on which Bt corn had been grown the previous year and was estimated by ELISA to be 0.02 +/- 0.014 ng g(-1) of fresh plant tissue in basil, 0.19 +/- 0.060 ng g(-1) in carrot, 0.05 +/- 0.018 ng g(-1) in kale, 0.04 +/- 0.022 ng g(-1) in radish, 0.53 +/- 0.170 ng g(-1) in snap bean, and 0.15 +/- 0.071 ng g(-1) in soybean. The Cry1Ab protein was also detected by Western blot in tissues of basil, carrot, kale, radish, and snap bean but not of soybean grown in soil on which Bt corn had not been grown since 2002; the concentration was estimated by ELISA to be 0.03 +/- 0.021 ng g(-1) in basil, 0.02 +/- 0.008 ng g(-1) in carrot, 0.04 +/- 0.017 ng g(-1) in kale, 0.02 +/- 0.012 ng g(-1) in radish, 0.05 +/- 0.004 ng g(-1) in snap bean, and 0.09 +/- 0.015 ng g( 1) in soybean. The protein was detected by Western blot in 2006 in most soils on which Bt corn had or had not been grown since 2002. The Cry1Ab protein was detected by Western blot in leaves plus stems and in roots of carrot after 56 days of growth in sterile hydroponic culture to which purified Cry1Ab protein had been added and was estimated by ELISA to be 0.08 +/- 0.021 and 0.60 +/- 0.148 ng g(-1) of fresh leaves plus stems and roots, respectively. No Cry1Ab protein was detected in the tissues of carrot grown in hydroponic culture to which no Cry1Ab protein had been added. Because of the different results obtained with different commercial Western blot (i.e., from Envirologix and Agdia) and ELISA kits (i.e., from Envirologix, Agdia, and Abraxis), it is not clear whether the presence of the Cry1Ab protein in the tissues of some plants under field condition and in carrot in sterile hydroponic culture was the result of the uptake of the protein by the plants or of the accuracy and sensitivity of the different commercial kits used. More detailed studies with additional techniques are obviously needed to confirm the uptake of Cry proteins from soil by plants subsequently planted after a Bt crop. PMID- 19444361 TI - COL3A1 2209G>A is a predictor of pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: A familial tendency has been demonstrated in the etiology of pelvic organ prolapse (POP), but the specific genetic defects have not been identified. Type III collagen is an important factor in the repair of connective tissue, and gene polymorphisms may impair the tensile strength. We hypothesized that polymorphisms in the alpha I chain of the type III collagen protein-encoding gene (COL3A1) pose women at risk for POP. METHODS: In this case control study, the prevalence of type III collagen polymorphisms was compared in women with and without signs and symptoms of POP. RESULTS: Two hundred and two POP patients and 102 normal parous controls were included. A homozygous single nucleotide substitution in the coding region of type III collagen (COL3A1 2209G>A, rs1800255) was identified in 27 (13%) POP patients and three (3%) controls (odds ratio, 5.0; 95% confidence interval, 1.4-17.1). CONCLUSIONS: The probability of POP was higher in women with COL3A1 2209G>A. This polymorphism showed to be a relevant risk factor for POP. PMID- 19444362 TI - "Evidence-based medicine" to support the surgical procedures we perform on patients with pelvic organ prolapse. PMID- 19444363 TI - Correlation of maximum urethral closure pressure with Valsalva leak point pressure using air-charged urodynamic catheters. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to measure the correlation of maximum urethral closure pressure (MUCP) with Valsalva leak point pressure (VLPP) in women with urodynamic stress incontinence using air-charged urodynamic catheters. METHODS: Records of all women who underwent urodynamic testing for urinary incontinence using air-charged catheters over a 3-year period were reviewed. Data included scores on the Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7). RESULTS: One hundred ninety-three women met the criteria for urodynamic stress incontinence. There was a modest correlation of MUCP with VLPP at 200 mL (r = 0.46, p < 0.001) and a low correlation of MUCP with VLPP at maximum capacity (r = 0.35, p < 0.001). There was no correlation of UDI-6 or IIQ-7 scores with MUCP or VLPP. CONCLUSIONS: The low to modest correlation of VLPP with MUCP with air-charged catheters is similar to what has been reported with water-filled and microtransducer catheters. PMID- 19444364 TI - The development of an Incontinence Treatment Motivation Questionnaire for patients undergoing pelvic floor physiotherapy in the treatment of stress incontinence. AB - INTRODUCTION AND HYPOTHESIS: The aim of this paper is to develop a motivation questionnaire regarding perseverance in pelvic floor muscle training (PFMT) supervised by physiotherapists for stress urinary incontinence. METHODS: Sixteen semi-structured interviews were conducted in women with stress urinary incontinence that revealed 15 common themes; 117 items were constructed and reviewed by continence advisors. Surviving items (n = 73) were administered to 210 women. Data were analysed for item properties, factor analysis was used to examine the questionnaire structure and tests of convergence/divergence used to check for sensitivity. RESULTS: The Incontinence Treatment Motivation Questionnaire (ITMQ) comprises 18-items in five scales, assessing attitudes towards treatment (72.62% of explained variance; alpha = 0.87), reasons for not doing PFMT (55.73%; alpha = 0.74), living with incontinence (62.70% variance; alpha = 0.70), desire for treatment (65.37% variance; alpha = 0.74) and the effect of incontinence severity on PFMT (51.62% variance, alpha = 0.68). Scales were generally sensitive to known group differences. CONCLUSIONS: This study represents the first effort to develop a motivation scale for PFMT. This validated Motivation Questionnaire is an instrument to test the impact of motivation upon cure, in PFMT. PMID- 19444365 TI - Pelvic floor disorders among indigenous women living in Xingu Indian Park, Brazil. AB - INTRODUCTION AND HYPOTHESIS: Current assessment for pelvic floor disorders (PFDs) allows comparison between different communities. METHODS: A total of 377 indigenous women living in Xingu Indian Park were evaluated. The pelvic organ prolapse quantification (POP-Q) was the system used to quantification the staging of pelvic support. The pelvic floor muscle strength was assessed by a perineometer. Logistic regression analysis was used to determine risk factors that were associated with prolapse. RESULTS: Only 5.8% of women reported urinary incontinence. The overall distribution of POP-Q stage system was the following: 15.6% stage 0, 19.4% stage I, 63.9% stage II and 0.8% stage III. Parity and age were the risk factors for pelvic organ prolapse (p < 0.0001). CONCLUSIONS: Urinary incontinence was uncommon in Xingu indigenous women. Like non-indigenous communities, age and parity were the most important risk factors to the genital prolapse. PMID- 19444366 TI - The effect of urethral dilatation on pressure flow studies in women with voiding dysfunction and overactive bladder. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess whether urethral dilatation (UD) leads to changes in pressure flow parameters in women with voiding dysfunction (VD) and whether this correlates with improvement in overactive bladder symptoms (OAB). METHODS: Forty three women with drug-resistant OAB and VD underwent cystoscopy and UD. Pressure flow studies were undertaken at 6 weeks with further follow-up at 6 months. Any significant changes in pressure flow parameters after UD were evaluated. RESULTS: Thirty three percent of the participants reported subjective improvement. This was maintained at 6 months in 19%. Improvement in OAB was associated with an increase in maximum flow rate centile (p = 0.02) and a decrease in detrusor pressure at maximum flow (p = 0.03). Thirteen percent developed urodynamic stress incontinence. CONCLUSIONS: Thirty three percent of women with drug-resistant OAB have a short-term improvement following UD. Improvement is associated with an increased maximum flow rate centile and a decreased detrusor pressure at maximum flow. The long term improvement rate is poor. PMID- 19444367 TI - Prediction model and prognostic index to estimate clinically relevant pelvic organ prolapse in a general female population. AB - INTRODUCTION AND HYPOTHESIS: Estimation on prevalence and distribution of pelvic organ prolapse (POP) signs in a general female population is difficult. We therefore developed and validated a prediction model and prognostic instrument. METHODS: Questionnaires were sent to a general female population (45-85 years). A random sample underwent vaginal examination for POP (POPQ). A prediction model was developed using multivariate analysis and validated in a subgroup of participants. RESULTS: Positive questionnaire-response rate was 46.8% (1,397 of 2,979). From the questionnaire group, 649 women were vaginally examined (46.5%). Prevalence of clinically relevant POP was 21%. Multivariate analysis demonstrated significantly higher odds ratios on the report of vaginal bulging, parity > or = 2 and a mother with POP. The receiver operating characteristic curve showed areas under the curve of 0.672 and 0.640. CONCLUSIONS: The prevalence of POP at or beyond the hymen could be estimated in a general female population using our prediction model with 17 questions and our POP score chart with eight questions. PMID- 19444368 TI - The prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female population. AB - INTRODUCTION AND HYPOTHESIS: In selected populations, pelvic organ prolapse (POP) was associated with bladder/bowel symptoms, but data on the general female population are lacking. Our aim was to obtain normative data on the prevalence of POP and pelvic floor dysfunction (PFD) symptoms and signs and to identify associations. METHODS: Validated questionnaires on POP and PFD (urogenital distress inventory, (UDI) and defaecation distress inventory (DDI)) were sent to a general population of 2,979 women (aged 45-85 years). Data were analysed using the Kruskal-Wallis test, chi square test and Spearman's rank correlation coefficient. RESULTS: Response rate was 62.7%. Associations between POP stage and parity (0.002) and vaginal bulging (<0.001) are significant. Anatomical locations of POP and PFD symptoms correlated significantly with incontinence of flatus, feeling anal prolapse, manual evacuation of stool, vaginal bulging, constipation and pain during faecal urge (p < or = 0.005). CONCLUSIONS: Strategies should be developed to alleviate obstructive bowel disorders associated with POP. PMID- 19444369 TI - Case of longitudinal vaginal septum with pelvic organ prolapse. AB - Longitudinal vaginal septum is a rare mullerian anomaly and its association with pelvic organ prolapse (POP) is unusual. A case of longitudinal vaginal septum with stage IV POP in a 35-year-old multiparous woman is being reported. Examination revealed an incomplete longitudinal vaginal septum (9 x 6 x 2 cm) with stage IV POP. Vaginal hysterectomy with repair and reconstruction was done along with excision of the longitudinal vaginal septum which was technically challenging due to proximity to rectum. This is the only case report of stage IV pelvic organ prolapse associated with a thick longitudinal vaginal septum in a multiparous woman without any obstetric complications. Surgery required increased caution per operatively while dissecting the septum from the vaginal wall and the adjacent organs. PMID- 19444370 TI - Fistulization between ectopic ureteral stump and uterus following nephroureterectomy: case report. AB - Ureterouterine fistulas are rare surgical complications with fewer than 30 reported cases in the literature to date. Rarer yet is a fistula between an ectopic ureter and the uterus, with only one case described previously (Shibata et al. in J Urol 153: 1208-1210, 1995). Herein, we present the first case, to our knowledge, of a fistula between an ectopic ureteral stump (from a prior nephroureterectomy) and the uterus. PMID- 19444371 TI - Intracoronary acid infusion as an alternative to ischemic postconditioning in pigs. AB - Previous studies suggested that prolongation of acidosis during reperfusion is protective and may be an important mechanism of postconditioning protection. The aim of this study was to analyze the therapeutic value of this intervention during in vivo coronary reperfusion, and to compare it with ischemic postconditioning. Pigs were submitted to 48 or 60 min of ischemia and 2 h of reperfusion. Animals were allocated to either intracoronary infusion of Krebs solution at dose and duration previously described as optimal in rat hears (pH 6.4 for the first 3 min of reperfusion), ischemic postconditioning (8 cycles of 30 s ischemia/reperfusion) or their respective control groups (n = 9-11 per group). Neither prolongation of acidosis nor postconditioning modified infarct size after 48 min of ischemia as compared to pooled controls. In contrast, in animals submitted to 60 min of coronary occlusion, infarct size was reduced both by infusion of acid Krebs and ischemic postconditioning (57.92 +/- 18.15% and 56.91 +/- 7.50 vs. 75.37 +/- 9.29% in controls, P < 0.01), despite having similar areas at risk. However, an increased incidence of ventricular fibrillation was observed in pigs reperfused with acid Krebs as compared to ischemic postconditioning (11 out of 20 vs. 3 out of 19 pigs, P < 0.05). In conclusion, in pigs submitted to coronary occlusion, intracoronary acid infusion and postconditioning offered protection against cell death only after prolonged coronary occlusion. Both interventions were equally effective, but intracoronary acid infusion was associated with high risk of ventricular fibrillation. These results are strongly against translation of acidic reperfusion to patients with acute myocardial infarction. PMID- 19444372 TI - Contact position analysis of deep brain stimulation electrodes on post-operative CT images. AB - PURPOSE: Groups performing deep brain stimulation advocate post-operative imaging [magnetic resonance imaging (MRI) or computer tomography (CT)] to analyse the position of each electrode contact. The artefact of the Activa 3389 electrode had been described for MRI but not for CT. We undertook an electrode artefact analysis for CT imaging to obtain information on the artefact dimensions and related electrode contact positions. METHODS: The electrode was fixed on a phantom in a set position and six acquisitions were run (in-vitro study). The artefacts were compared with the real electrode position. Ten post-operative acquisitions were analysed (in-vivo analysis). We measured: H (height of the lateral black artefact), D (distance between the beginning of the white and the lateral black artefacts) and W (maximal artefact width), representing respectively the lengths of the four contacts and the electrode tip and width of the contact zone. A Student t-test compared the results: in vivo vs in vitro and coronal vs sagittal reconstructions along the electrode. RESULTS: The limits of the lateral black artefact around the electrode contacts corresponded to the final electrode position. There was no significant difference for D (in vivo, 1.1 +/- 0.1 mm; in vitro, 1.2 +/- 0.2 mm; p = 0.213), while W and H differed slightly (in vivo, W = 3.3 +/- 0.2 mm, H = 7.7 +/- 0.2 mm; in vitro, W = 3.1 +/- 0.1 mm, H = 7.5 +/- 0.2 mm). Results obtained with sagittal and coronal reconstructions were similar (p > 0.6). CONCLUSIONS: Precise three-dimensional (3D) localisation of the four-contact zone of the electrode can be obtained by CT identification of the limits of the lateral black artefact. The relative position of the four contacts is deduced from the size of the contacts and the inter-contact distance. Sagittal and coronal reconstructions along the electrode direction should be considered for the identification of the four electrode contacts. CT offers a useful alternative to post-operative MRI. PMID- 19444373 TI - Surgical technique for anterior skull base reconstruction using hydroxyapatite cement and titanium mesh. PMID- 19444374 TI - Role of ERK1/2 and vascular cell proliferation in cerebral vasospasm after experimental subarachnoid hemorrhage. AB - BACKGROUND: Although there are still some unresolved aspects, current research has revealed that vascular cell proliferation probably plays an important part in the pathological formation process of cerebral vasospasm. Using a "two hemorrhage" model of subarachnoid hemorrhage (SAH), this study investigated the function of ERK1/2 and vascular wall cell proliferation in pathological development of cerebral vasospasm. METHODS: Fifty rabbits were randomly divided into five groups: (1) SAH day 1, (2) SAH day 3, (3) SAH day 7, (4) SAH + DMSO (dimethyl sufoxide) solution, (5) SAH + PD98059 (a mitogen-activated protein kinase inhibitor) dissolved in DMSO solution. In the SAH + PD98059/DMSO group and SAH + DMSO control group, PD98059 in DMSO (2 mmol/l) or an equal quantity of DMSO, respectively, was injected into the cisterna magna, once a day from SAH day 1 to day 3. Western protein blotting was used to detect the expression of proliferating cell nuclear antigen (PCNA) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in each group's basilar arteries. Light microscopy and electron microscopy were used for dynamic histological detection at each observation point of the SAH vascular wall under the effects of SAH and the mitogen-activated protein kinase inhibitor. Another 18 rabbits were randomly divided into three groups: SAH, SAH + DMSO and SAH + PD98059/DMSO; cerebral angiograpathy was conducted on SAH days 1 and 7, and the progression of angiographic vasospasm evaluated. RESULTS: Compared with the control group, the extent of vasospasm after SAH increased with time. PD98059 significantly reduced angiographic and morphological vasospasm. In cerebral vasospasm, the expression of T-ERK1/2 showed no significant change. However, expression of p-ERK1/2 and PCNA began to increase significantly on day 3, and achieved a peak on day 7. PD98059 significantly inhibited the expression of p-ERK1/2 and PCNA (p < 0.05). CONCLUSIONS: Cell proliferation on the vascular wall plays an important part in the pathological formation process of cerebral vasospasm. ERK1/2 phosphorylation, as an important signaling pathway, taking part in the process of vascular-wall pathological proliferation of cerebral vasospasm. PMID- 19444375 TI - Self-closing Nitinol U-Clips for intracranial arterial microanastomosis: a preliminary experience on seven cases. AB - PURPOSE: To report experience on the use of self-closing nitinol U-Clips for different types of intracranial arterial microanastomosis. METHODS: We treated 7 patients (3 females and 4 males, age ranging from 25 to 68 yo) admitted from November 2005 to January 2008 to the Neurological Institute C. Besta of Milan. One patient had cerebral hypoperfusion and the others a complex intracranial aneurysm. In each patient a bypass procedure was completed by using self-closing Nitinol U-Clips for intracranial arterial microanastomoses. RESULTS: The total time of temporary occlusion was 15.71 +/- 4.386 min. Bypass patency was confirmed intraoperatively by near-infrared indocyanine green videoangiography and microdoppler in each patient. No spasm of the graft was encountered and immediate post-operative bypass patency was confirmed in 6/7 patients. The graft thrombosed in 1 patient with antiphospholipid syndrome. 1 patient died from a massive Subarachnoid Hemorrhage due to rupture of an aneurysm while waiting for an endovascular procedure. In the 5 patients at the last follow-up, long-term patency of the bypass was confirmed and no neurological deficits occurred related to the procedure. CONCLUSION: This is the first report of the use of U-Clips for intracranial microanastomosis. Our data indicated that it is a safe technique, reduces the time taken to perform an anastomosis and the risk of an ischemic complication. Further studies of the longer-term patency of bypass as performed with U-Clips are required. PMID- 19444376 TI - Measuring our work: scenarios to value productivity in health care. PMID- 19444378 TI - Variation in lumbar spine bone mineral content by age and gender in apparently healthy Indians. AB - The aim of this study was to assess variation in bone mass from childhood through later age and to examine bone health status of Indian males and females. Lumbar spine (LS) bone mineral content (BMC) was measured by dual energy X-ray absorptiometry of lumbar vertebrae (L1-L4) in 683 males and 858 females (5-70 years) from Pune, India and apparent bone mineral density (BMAD) was calculated. A cubic regression model was fitted to describe the change in bone mineral content (BMC) with age in males and females separately. Regression analysis revealed that peak LS BMC was achieved around 26 years (63.6 +/- 11.0 g) for males and 30 years (54.1 +/- 11.6 g) for females. After 50 years of age, BMC showed an average annual decrease of 2.7% in males and 4.1% in females. Males had 11-15% higher mean BMAD than females after 50 years of age. T scores of 19% males and 28% females above 50 years, were less than -2.5 and T scores of 36% males and 43% females were between -1.0 and -2.5 when compared with the Lunar reference database. Low peak bone mass at a young age and higher bone loss in adults are alarming features of apparently healthy Indians. PMID- 19444377 TI - Effect of alpha lipoic acid on the tardive dyskinesia and oxidative stress induced by haloperidol in rats. AB - Haloperidol (HAL) is a widely used neuroleptic drug for the treatment of acute and chronic psychosis. Tardive dyskinesia (TD) is a complex hyperkinetic syndrome consisting of choreiform and athetoid movements, which persists for months or years after withdrawal. Increased levels of thiobarbituric acid reactive products are found in the cerebrospinal fluid and plasma of patients treated with neuroleptics, especially those with movement disorders. Alpha lipoic acid (ALA), a natural metabolic antioxidant, is effective in both prevention and treatment of numerous types of neurological disorders. It is proposed to study the effect of ALA on TD induced by HAL and to correlate it with oxidative stress by studying total antioxidant status and lipid peroxidation (LP). HAL (1 mg/kg/i.p.) was used to induce vacuous chewing movements in rats. ALA was suspended in 0.2% carboxy methyl cellulose at a dose of 25, 50 and 100 mg/kg and was administered orally by oral gavage 1 h before HAL on 21st day of treatment. ALA supplementation significantly decreased HAL-induced TD at a dose of 100 mg/kg and catalepsy dose dependently. ALA improved TD and catalepsy by decreasing HAL-induced LP. ALA and its metabolite dihydro lipoic acid protect against HAL-induced TD and catalepsy by scavenging reactive oxygen species and reactive nitrogen species. PMID- 19444379 TI - Effect of vitamin D supplementation in the institutionalized elderly. AB - An intervention study with vitamin D supplementation was conducted in order to study the amount of vitamin D required in the elderly. Sixty-four institutionalized elderly were randomly assigned to two groups: group (A) to take a beverage containing 200 mg calcium daily, and group (B) to take a beverage containing 200 mg calcium and 5 microg vitamin D daily for 30 days. Prior to the study, the subjects' average vitamin D intake was 7.3 microg/day, which is approximately 150% of the current adequate intake (AI), however their mean plasma 25 OH-D level at baseline was only 12 ng/mL, strongly indicating hypovitaminosis D. During the study, average plasma 25 OH-D concentration significantly increased to 14.7 ng/mL in group (B), but not in group (A). However, group (B) was still in the hypovitaminosis range. Thus, daily intake exceeding the current AI of 5 microg is required for the institutionalized elderly. PMID- 19444380 TI - Occurrence of ankylosing spondylitis and multiple sclerosis-like syndrome in a HLA-B27 positive patient. AB - Occurrence of multiple sclerosis (MS) in patients with ankylosing spondylitis (AS) has been reported in isolated cases. We describe a white 33-year-old male with a definite familial HLAB27 positive AS and MS-like syndrome. The patient developed acute onset of gait difficulty, postural unsteadiness, dysarthria and right side weakness that resolved within 1 month; after 6 months he presented right-sided face sensory loss, disappeared after 2 weeks. Brain and cervical MRI was performed twice and showed disseminated lesions in space (multiple foci of increased signal intensity in the periventricular white matter, in the corpus callosum, in the hypothalamus, in the brainstem and in the cervical spinal cord) and in time (a new enhancing lesion >3 months after the onset of the clinical event). Visual evoked potentials were markedly altered. Cerebrospinal fluid examination was negative for intrathecal production of oligoclonal bands. Differential diagnosis was considered and other pathologies were excluded. PMID- 19444382 TI - Transient Parkinsonism in isolated extrapontine myelinolysis. AB - Extrapontine myelinolysis (EPM) is a rare cause of Parkinsonism. In this case report, we describe a 63-year-old woman with Parkinsonism due to EPM after correction of hyponatremia. During a 4-year follow-up, both the clinical features of Parkinsonism and the changes on magnetic resonance imaging resolved. Parkinsonism due to EPM should be recognized as it has a good prognosis. PMID- 19444381 TI - Determination of nerve conduction abnormalities in patients with impaired glucose tolerance. AB - Recent studies have shown that impaired glucose tolerance (IGT) is associated with dysfunction in the peripheral and autonomic nerves. The aim of this study was to determine the electrophysiological abnormalities of IGT. To determine electrophysiological abnormality in the large sensorimotor and sudomotor autonomic nerves with IGT patients, 43 patients and 34 healthy subjects have been studied. Subjective neuropathy symptoms, neurological examination and the electrophysiological findings were evaluated. When conduction of large somatic fibers only was evaluated, the ratio of electrophysiological abnormality was found to be 21%. In addition, where sympathetic skin response was evaluated the sudomotor autonomic abnormality ratio was 28% in upper extremities, 53% in lower extremities, and 16% in upper and lower extremities together. The percentages of abnormal electrophysiological parameters in different motor and sensory nerves were 39.5% in the peroneal motor nerve, 20.9% in the median motor and sural sensory nerves, 18.6% in the median sensory nerve, 16.3% in the tibial motor nerve, 14% in the ulnar sensory nerve, and 2.3% in the ulnar motor nerve. While distal motor latency was the most frequent abnormal parameter in the median and tibial motor nerves, the amplitude changes in the peroneal and ulnar motor nerves were also prominent. In sensory evaluation, the onset latency in the median-ulnar sensory nerves and the amplitude in the sural sensory nerve were found to be evident abnormalities. PMID- 19444383 TI - Cardiac multidetector computed tomography (MDCT) of spontaneously closed ventricular septal defect. AB - PURPOSE: The authors present the findings of contrast-enhanced electrocardiogram (ECG)-gated cardiac computed tomography (CT) in 18 patients with probably spontaneous closure of muscular ventricular septal defect (VSD). MATERIALS AND METHODS: The study included 2,725 consecutive patients referred to our hospitals for multidetector computed tomography (MDCT) coronary angiography. The patients were between the ages of 5 and 78 [mean+/-standard deviation (SD) 59+/-13.86] years, and 1,816 (66.6%) were male. Evaluating the images for coronary artery pathologies revealed pouches or sacs in the central muscular location of the septa of some patients. RESULTS: All patient records were retrospectively reviewed, and 18 patients were found to have pouches or sacs in the interventricular septum location likely to be spontaneous closure of muscular VSD (0.66% prevalence). MDCT findings of these 18 patients correlated with their echocardiographic findings. Of the patients with muscular VSD, 13 were male and five were female. These 18 patients were initially referred due to indications such as chest pain (n=11), risk-factor assessment (n=3), coronary artery anomaly (n=1), suspected aberrant right subclavian artery due to dysphagia (n=1) and coronary artery bypass graft (n=2). CONCLUSIONS: Our study shows that the incidence of spontaneous closure of muscular VSD with central septum location is probably higher than expected. Thus, some patients initially diagnosed with ventricular diverticula with an apical and marginal septum location may actually have spontaneously closed muscular VSD. This finding may affect previously reported rates of both ventricular diverticula and spontaneous closure of muscular VSD. PMID- 19444384 TI - Acute nontraumatic adult knee pain: the role of MR imaging. AB - Acute nontraumatic pain in the adult knee can be seen in many settings, such as transient bone marrow oedema syndrome (TBMOS), regional migratory osteoporosis (RMO), spontaneous osteonecrosis (SONK) and insufficiency fractures. Early differentiation among them is crucial to avoid unnecessary treatment. TBMOS and RMO are considered to be self-limiting conditions without longterm sequelae. On the other hand, the clinical course of SONK is thought to be dependent on the size of osteonecrosis. Recent data suggest the term SONK is misleading one and should be replaced. Insufficiency fractures may demonstrate a similar clinical syndrome without a history of a single traumatic injury. The imaging pathway for knee pain has evolved considerably with the advent of magnetic resonance (MR) imaging, which is very sensitive in the early depiction of bone marrow oedema. Therefore, in patients with acute nontraumatic knee pain whose radiographs are negative or inconclusive, MR imaging is the method of choice for further evaluation. This article discusses the potential aetiologies and reviews MR imaging findings of the most common disorders afflicting the subchondral knee joint area. PMID- 19444385 TI - Pilot study of irinotecan/oxalipltin (IROX) combination chemotherapy for patients with gemcitabine- and 5-fluorouracil- refractory pancreatic cancer. AB - BACKGROUND: Gemcitabine- and 5-fluorouracil (5-FU)- based chemotherapy is a commonly used adjuvant or palliative treatment for patients with pancreatic cancer. However, a standard chemotherapy regimen has yet to be developed for patients refractory to gemcitabine and 5-FU treatment. We attempted to evaluate the efficacy and safety of a combination of irinotecan and oxaliplatin (IROX) as a salvage treatment for patients with gemcitabine- and 5-FU- refractory pancreatic cancer. PATIENTS AND METHODS: Patients with advanced pancreatic cancer who were refractory to prior gemcitabine- and 5-FU- based chemotherapy were enrolled in this study. IROX chemotherapy was administered as follows: Irinotecan, 150 mg/m(2) on day 1; and oxaliplatin, 85 mg/m(2) on day 1 over 90 min every 2 weeks. RESULT: From Mar. 2006 to Dec. 2008, a total of 14 patients were administered 50 cycles of chemotherapy. The male-to-female ratio of the patient group was 11:3. These patients ranged in age from 48 to 73 years (median 65.5 years old). 3 patients (21.4%) evidenced partial responses. four patients (28.6%) exhibited stable disease. The median time to progression and overall survival time were 1.4 (95% CI: 1.2-1.6) months and 4.1 (95% CI: 2.0-6.2) months, respectively. Major hematologic toxicities included grade 1-2 anemia (88%), neutropenia (36%), thrombocytopenia (30%), and grade 3-4 neutropenia (10%). The most frequently detected non-hematological toxicities were grade 3 diarrheas (14%). CONCLUSION: The IROX regimen appears to constitute a feasible and tolerable salvage therapy in patients with advanced pancreatic cancer who have been previously treated with gemcitabine- and 5-FU-based chemotherapy. PMID- 19444387 TI - Activity of gallium on prevention of fatal cage-layer osteoporosis. AB - The prevention of fatal cage-layer osteoporosis of gallium was studied in this paper. One-day-old hens were fed up to 68 weeks on a control diet and diets containing gallium. Plasma variables were measured during lay. End-of-lay trabecular and medullary bone volumes in the proximal tarsometatarsus and free thoracic vertebra were measured by histomorphometry. Medullary and trabecular bone volumes were increased significantly by supplementation with gallium. The experiment confirmed that dietary gallium supplementation was an effective way to enhance the egg production and reduce mortality percentage. The beneficial effects of gallium supplementation over the lifetime of the hens were attributable mainly to improved cage-layer osteoporosis. PMID- 19444386 TI - Hydrogen peroxide-induced cellular apoptosis is mediated by TGF-beta2 signaling pathway in cultured human lens epithelial cells. AB - The objective of this study was to investigate the signaling characteristics of transforming growth factor-beta2 (TGF-beta2) and the Smads (Caenorhabditis elegans, Sma; Drosophila mothers against dpp, Mad) signal pathway of cellular apoptosis induced by hydrogen peroxide with human lens epithelial cells (HLECs). HLECs were starved for 24 h before exposure to 0.1 mumol/ml of hydrogen peroxide in the presence and in the absence of 0.01 mug/ml of AF-302-NA, a monoclonal anti TGF-beta2 neutralization antibody. Non-stimulated cells served as controls. Cell apoptosis was examined by in situ immunocytochemistry using terminal deoxynucleotidyl transferase dUTP-mediated biotin nick end labeling (TUNEL) and by flow cytometry (FCM) using Annexin V-FITC apoptosis detection. Gene expression was assessed using the reverse transcription-polymerase chain reaction (RT-PCR). Smad-4 localization was observed by immunocytochemistry. Hydrogen peroxide induced the accumulation of Smad-4 in the nucleus of HLECs, and upregulated the expression of TGF-beta receptors (TbetaRs) mRNA in HLECs, as well as upregulated the expression of the apoptotic gene bax, which leads HLECs to apoptosis. AF-302 NA decreased cellular apoptosis induced by hydrogen peroxide in HLECs and inhibited the translocation of Smad-4 from the cytoplasm to the cell nucleus. Moreover, AF-302-NA upregulated the expression of TbetaRs mRNA and downregulated the expression of bax mRNA in HLECs incubated with hydrogen peroxide. Our study demonstrated that the TGF-beta2 signal pathway participated in the apoptotic signal transfer and might be an initiator of cellular apoptosis of HLECs after incubation with hydrogen peroxide. Interruption of the TGF-beta2 signal pathway could partially protect HLECs from apoptosis induced by incubation with hydrogen peroxide. PMID- 19444388 TI - Relative and combined effects of chronic alcohol consumption and HCV infection on serum zinc, copper, and selenium. AB - In alcoholic hepatitis, Kupffer cells are activated by intestinal gram-bacteria, leading to cytokine production and free radicals release, which, enhancing cytokine secretion, create a positive feedback loop which contributes to liver inflammation. Free radicals also damage the liver in chronic hepatitis C virus (HCV) infection, a condition frequently associated to alcohol consumption. In both situations, activity of antioxidant enzymes and of its cofactors zinc (Zn), selenium (Se), and copper (Cu) is important. This study was performed to assess the relative and combined effects of chronic alcoholism and HCV infection on serum Se, Zn, and Cu, and its relation with serum malondialdehyde (MDA) and tumor necrosis factor-alpha, interferon-gamma, and interleukins (IL) 4, 6, and 8, in 19 HCV- alcoholic patients, 12 HCV+ alcoholic patients, nine HCV+ non-alcoholic patients, and 20 controls. Serum Zn and Se were lower in both HCV+ and HCV- alcoholic patients, whereas serum Cu was lower in HCV+ individuals. Serum Zn and Se were related to liver function derangement. MDA levels were higher in alcoholics, but no relation was observed between trace elements and MDA or cytokines, so that our results do not support a relevant role of the analyzed trace elements in the pathogenesis of chronic liver disease. PMID- 19444389 TI - Mannanase transfer into hexane and xylene by liquid-liquid extraction. AB - The formation of noncovalent complexes between glycosidase, endo-1,4-beta-D mannanase, and ionic surfactant di(2-ethylhexyl) sodium sulfosuccinate (AOT) was shown to promote protein transfer into organic solvents such as xylene and hexane. It was found that mannanase can be solubilized in hexane and in xylene with concentration at least 2.5 and 2.0 mg/ml, respectively. The catalytic activity of the enzyme in hexane spontaneously increases with the concentration of AOT and is about 10% of the activity in aqueous system. In xylene, a catalytic activity higher than that in bulk aqueous conditions was found for the samples containing 0.1-0.3 mg/ml of mannanase, while for the samples with a higher concentration of enzyme, the activity was hardly detected. PMID- 19444390 TI - New model for polymerization of oligomeric alcohol dehydrogenases into nanoaggregates. AB - Polymerization and self-assembly of proteins into nanoaggregates of different sizes and morphologies (nanoensembles or nanofilaments) is a phenomenon that involved problems in various neurodegenerative diseases (medicine) and enzyme instability/inactivity (biotechnology). Thermal polymerization of horse liver alcohol dehydrogenase (dimeric) and yeast alcohol dehydrogenase (tetrameric), as biotechnological ADH representative enzymes, was evaluated for the development of a rational strategy to control aggregation. Constructed ADH nuclei, which grew to larger amorphous nanoaggregates, were prevented via high repulsion strain of the net charge values. Good correlation between the variation in scattering and lambda(-2) was related to the amorphousness of the nanoaggregated ADHs, shown by electron microscopic images. Scattering corrections revealed that ADH polymerization was related to the quaternary structural changes, including delocalization of subunits without unfolding, i.e. lacking the 3D conformational and/or secondary-ordered structural changes. The results demonstrated that electrostatic repulsion was not only responsible for disaggregation but also caused a delay in the onset of aggregation temperature, decreasing maximum values of aggregation and amounts of precipitation. Together, our results demonstrate and propose a new model of self-assembly for ADH enzymes based on the construction of nuclei, which grow to formless nanoaggregates with minimal changes in the tertiary and secondary conformations. PMID- 19444391 TI - Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. AB - Saxagliptin is a potent and selective reversible inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. It is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing. Saxagliptin is metabolized in vivo to form an active metabolite, and both parent drug and metabolite are excreted primarily via the kidneys. Saxagliptin reduces the degradation of the incretin hormone glucagon like peptide-1, thereby enhancing its actions, and is associated with improved beta-cell function and suppression of glucagon secretion. Clinical trials of up to 24 weeks duration have shown that saxagliptin improves glycemic control in monotherapy and provides additional efficacy when used in combination with other oral antidiabetic agents (metformin, sulfonylurea, thiazolidinedione). Both fasting and postprandial glucose concentrations are reduce leading to clinically meaningful reductions in glycated hemoglobin, and due to the glucose-dependency of its mechanism of action, there is a low risk of hypoglycemia. Saxagliptin is reported to be well tolerated with a side-effect profile similar to placebo. It has a neutral effect on body weight and dose adjustment because of age, gender, or hepatic impairment is not necessary. Saxagliptin is being co-developed by Bristol-Myers-Squibb (New York, NY, USA) and AstraZeneca (Cheshire, UK), and is currently undergoing regulatory review. PMID- 19444392 TI - Glatiramer acetate and interferon beta-1b: a study of outcomes among patients with multiple sclerosis. AB - INTRODUCTION: To study the medical cost and probability of relapse in patients with multiple sclerosis (MS) treated with either glatiramer acetate (GA) or interferon beta-1b (IFN beta.1b). METHODS: Data were obtained from the i3 InVision Data Mart Database from July 2001 to June 2006. We established an "intent-totreat" (ITT) cohort (n=842) of patients diagnosed with MS who began treatment with either GA or IFN beta-1b and had continuous insurance coverage from 6 months before to 2 years after the date when they began taking the medication. We also created a "continuous use" (CU) cohort (n=418) of individuals who, in addition to the criteria listed above, used either GA or IFN beta-1b within 28 days of the end of the 2-year postperiod. Using multivariate regressions, we examined both the 2-year total average direct medical costs and the likelihood of relapse within this period associated with the use of each of these MS medications. We defined relapse as being either hospitalization with a principal diagnosis of MS or having an outpatient visit with a diagnosis of MS and then prescribed steroids within a 7-day period. All regression analyses controlled for a wide range of factors that may potentially affect outcomes. RESULTS: In the ITT cohort, patients who started treatment with GA had a significantly lower 2-year estimated risk of relapse (13.54% vs. 5.31%; P=0.0006). In the CU cohort, patients who used GA also had a significantly lower 2-year estimated risk of relapse (10.91% vs. 2.09%; P=0.0018), as well as significantly lower average total medical costs ($53,157 vs. $48,130; P=0.0345). CONCLUSIONS: Results from this study indicate that users of GA have a significantly lower probability of 2-year relapse than users of IFN beta-1b. In addition, among continuous users, the 2-year total average direct medical costs are significantly lower for users of GA than for users of IFN beta-1b. PMID- 19444393 TI - The use of novel promotility and prosecretory agents for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. AB - Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (C-IBS) are commonly reported gastrointestinal (GI) disorders that have a major impact on health and quality of life. Patients experience a range of symptoms of which infrequency of bowel movement is but one and report that straining, the production of hard stools, and unproductive urges are more bothersome than stool infrequency. Additionally, in C-IBS, patients report abdominal pain and bloating as particularly troubling. Traditional treatments, such as laxatives, are often ineffective, especially in more severe constipation over the long term. In a population-based survey of constipation sufferers, half were not satisfied with their current treatment, due predominantly to poor efficacy. 5-Hydroxytryptamine receptor 4 (5-HT4) agonists stimulate GI motility and intestinal secretion, and tegaserod has demonstrated efficacy in improving bowel habit. Tegaserod also improves constipation-associated symptoms including bloating, abdominal discomfort, stool consistency, and straining in patients with both CIC and C-IBS. However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects. Further 5-HT(4) receptor agonists, including prucalopride and TD-5108 are in development and show exciting results in clinical studies in CIC patients, suggesting further product approvals are likely. Headache and diarrhea are the most commonly reported adverse event with this class of agent. Recently a novel prosecretory agent has been approved for the treatment of both CIC and C-IBS. Lubiprostone stimulates chloride secretion through activation of type-2 chloride channels, increasing intestinal secretion and transit, and its use has been associated with improvements in bowel habit and symptoms of constipation. Nausea, diarrhea, and headache are the most commonly reported adverse events. Linaclotide also stimulates intestinal chloride secretion, but this molecule achieves this indirectly, through the activation of guanylate cyclase C. Data are emerging, but the efficacy and safety profile of this agent in the treatment of CIC and C-IBS appears encouraging. PMID- 19444394 TI - Cardiovascular risk reduction: what do recent trials with rosuvastatin tell us? AB - Abundant evidence from large-scale clinical trials supports the importance of lowering low-density lipoprotein cholesterol (LDL-C) to decrease the risk of cardiovascular disease (CVD) events. The LDL-C targets in various guidelines remain important treatment goals but, even in trials where statin therapy achieves substantial reduction of LDL-C, a significant number of CVD events still occur and the residual risk remains high. These findings suggest that lipid parameters other than LDL-C, such as high-density lipoprotein cholesterol (HDL C), triglycerides, and LDL particle size, can influence the risk of CVD. On this basis, other strategies that can alter the lipid profile, in particular raising HDL.C, may provide additional benefits. Other factors such as HDL-C functionality and susceptibility to oxidation and inflammatory factors can also influence cardiovascular risk. In addition to the modifications of the lipid profile, statins have cholesterol-independent beneficial pleiotropic effects. The contribution of these effects to event reduction is not yet fully understood. Recently, the body of evidence has expanded to support the use of intensive statin therapy in broader patient populations. The JUPITER trial has shown the benefit of intensive statin treatment in low-risk subjects with high levels of high-sensitivity C-reactive protein and average levels of LDL-C. Unlike the setting of primary and secondary prevention, the results of statin trials in patients with heart failure have shown no clear benefit in terms of survival. The recently published AURORA trial was carried out to investigate the effect of rosuvastatin in patients with end-stage renal disease undergoing chronic hemodialysis. In this trial no benefit on cardiovascular events was shown with statin therapy. In conclusion, large outcomes trials have clearly shown that statin treatments have a favorable benefit/risk profile in a large range of patients at different levels of risk, with the exception of patients with heart failure and those with renal disease undergoing dialysis. Further evidence is needed on the role of therapeutic strategies on the so-called residual risk. PMID- 19444395 TI - [Malignant melanoma]. AB - Malignant melanomas have one of the highest increases in incidence among malignancies. There are four histological types: superficial spreading melanoma, nodular melanoma, acrolentiginous melanoma and lentigo maligna melanoma. The TNM classification considers depth of infiltration (Clark's level), vertical tumor thickness (Breslow's thickness), ulceration of the primary tumor, satellites and in-transit metastases as well as regional lymph node and distant metastases. An adequate margin of clearance is important in primary resection. Sentinel lymph node biopsy is relevant in all melanomas with a Breslow tumor thickness >1 mm without clinically suspicious lymph nodes. In the case of lymph node metastases therapeutic dissection is recommended, in patients with in-transit metastases of the extremities hyperthermic isolated limb perfusion with cytostatic agents may be indicated. Resection of distant metastases can be useful if only one site is affected or a R0 resection is expected to be achieved. Adjuvant, neoadjuvant and palliative procedures, such as radiotherapy, chemotherapy and immunotherapy are additional treatment options. PMID- 19444396 TI - [Epidermal barrier function abnormalities in atopic dermatitis caused by filaggrin mutations]. PMID- 19444397 TI - [Mollusca contagiosa. From paediatric dermatology to sexually transmitted infection]. AB - Molluscum contagiosum (MC) is a common cutaneous infection caused by the molluscipox virus (MCV) and can affect both children and adults. Molluscum contagiosum is relatively frequent in children aged 1-5 years old and can be localized almost anywhere on the body, but in adults it is regarded as a sexually transmitted infection (STI). MCV can be transmitted directly from person to person or by autoinoculation. MC in adults characteristically involves the genital area but extragenital appearance can be more typically seen in patients with immunosuppressive conditions, especially in HIV/AIDS. The onset of MC in HIV positive individuals can be regarded as a part of the immune reconstitution inflammatory syndrome (IRIS). MC probably affects both sexes equally in children, whereas it seems that in adults the incidence is more prevalent in males. Therapy is controversial but may be considerably beneficial in preventing transmission or autoinoculation. At present there is no aetiological treatment of MC and most treatment options are mechanical sometimes causing discomfort or are not sufficiently evidence-based. Attention should be given to the extragenital site of involvement in adults and HIV testing should be recommended. Both children and adults with MC should be educated to avoid scratching and skin contact with others to prevent transmission and autoinoculation. Adult patients with MC should be carefully screened for other STIs and appropriately counseled. PMID- 19444398 TI - [Vitiligo. Diagnosis, differential diagnosis, and current patient management]. AB - Vitiligo is characterized by patches of depigmented skin in a localized to generalized distribution. Up to now, vitiligo is not curable and mostly has a chronic and progressive course. The disorder may be part of a polygenic, multifactorial transmitted disease with an increased disposition to autoimmune disorders, which should be screened for. Depending on the age of the patient, the psychological strain, the location, the body surface area involved, and the disease activity, several conservative as well as surgical therapeutic options may be partially successful. How long the induced repigmentation remains and the effect of the available therapeutic options on the natural history of vitiligo remain to be clarified. PMID- 19444399 TI - A convenient thiazole orange fluorescence assay for the evaluation of DNA duplex hybridization stability. AB - OBJECTIVE: A simple and rapid method for measuring the hybridization stability of duplexes of DNAs and other oligomers in different environments is described. When added to an oligomer duplex, the thiazole orange (TO) dye intercalates and in this state is fluorescent. Therefore, when duplex dissociation occurs, the release of TO results in a detectable change in fluorescence intensity. This assay was developed primarily to screen antisense oligomer duplexes that are stable in serum and in the cytoplasm but unstable in the presence of their target messenger RNA (mRNA). METHODS: The two antisense oligomers of this investigation were both 25 mer phosphorothioate (PS) DNAs, one directed against the RIalpha mRNA and the other directed against the mdr1 mRNA. The former duplex was first used in the solution studies, in most cases duplexed with a 16 mer phosphodiester (PO) complementary DNA (i.e., PS-DNA25/PO-cDNA16). Both duplexes were then tested in a series of cell studies using SK-BR-3 (RIalpha+), KB-G2 (mdr1++), and KB-31 (mdr1+/-) cells. RESULTS: Preliminary measurements in solution showed that maximum fluorescence was achieved when more than ten TO molecules were bound to each duplex. When a 25 mer PO-DNA or PO-RNA with the base sequence of the RIalpha mRNA was added, the dramatic change in fluorescence intensity that followed signified dissociation of the antisense DNA from the study duplex and reassociation with the target DNA. Kinetic measurements showed that this process was completed in about 3 min. Fluorescent measurements of SK-BR-3 (RIalpha+) cells incubated at 37 degrees C with the anti-RIalpha study duplex over time showed a maximum at the point where the loss of fluorescence due to dissociation of the study duplex, probably by an antisense mechanism, began to dominate over the increasing fluorescence due to continuing cellular accumulation. A similar result was observed in the KB-G2 (mdr1+) cells incubated with the anti-mdr1 study duplex. CONCLUSIONS: When study duplexes shown to be stable in serum were incubated with their target cells, the assay successfully detected evidence of dissociation, most likely by an antisense mechanism. Thus, a TO fluorescence assay has been developed that is capable of detecting the dissociation of DNA duplexes. PMID- 19444400 TI - [Cardiac emergencies: new solutions for old problems]. PMID- 19444401 TI - [How useful are the algorithms for the differential diagnosis of the monomorphic tachycardias with broad QRS complex in cardiac emergencies?]. AB - This review gives an integrated summary of the three old and two new ECG algorithms for the differential diagnosis of monomorphic regular tachycardias with broad QRS complex. Several studies have provided evidence that a ventricular tachycardia was diagnosed correctly by doctors on call and emergency physicians only in 35-50% of cases. Whether an algorithm may really improve diagnosis in everyday clinical practice and whether the algorithms are feasible for physicians, has not yet been clarified.The algorithms possess a high sensitivity of 88-95%, but only a satisfactory specificity of 73-80%. The values of all algorithms are similar. In the hands of physicians with little experience, the incidence of correct diagnoses is likely to be markedly lower. The algorithms have considerable limitations, especially with regard to the application of the "morphology criteria". As the nondetection of a ventricular tachycardia can have fatal consequences for the patient, any tachycardia with broad QRS complex should be treated as ventricular tachycardia in emergencies. In hemodynamically stable patients, the administration of adenosine for diagnostic purposes should immediately lead to a correct diagnosis. Based on the study situation, a schematic representation for the differential diagnosis has been created which follows very simple ECG criteria identifiable by any physician. PMID- 19444402 TI - Catheter ablation of ventricular tachycardia. From indication to three dimensional mapping technology. AB - The majority of ventricular tachycardias (VTs) occurs in patients with structural heart disease, predominantly coronary heart disease. Implantable cardioverter defibrillators (ICDs) are first-line therapy in patients with VT and structural heart disease. In patients who receive an ICD after a spontaneous sustained VT, recurrent VT episodes or an electrical storm are major problems. In addition, in patients with an ICD implanted for primary prevention of sudden cardiac death, 20% will experience at least one VT episode within 3-5 years after ICD implantation. Catheter ablation has a high acute success rate in eliminating clinical VT. However, several factors make catheter ablation of VT more difficult than ablation of supraventricular tachyarrhythmias. (1) The infarct region is often large. (2) The induced VT can be unstable or hemodynamically only poorly tolerated and therefore "unmappable". (3) Though most commonly located in the subendocardium, the critical VT zone can occasionally be epicardial or intramural in location. (4) In many cases, several reentrant circuits may coexist making ablation of a single form of VT a palliative procedure which does not obviate the risk of sudden death. Thus, catheter ablation of sustained VT in the setting of structural heart disease can only be considered an adjunctive therapy which, in general, will require ICD therapy. Numerous "modern" mapping technologies have been developed, which have increased success rates of catheter ablation of VT in patients with and without structural heart disease. The aim of the present article is to review current three-dimensional mapping systems in comparison to conventional mapping and to describe a reasonable, tailored approach for the individual patient with VT. PMID- 19444403 TI - [Infective endocarditis: considerations regarding optimal timing for surgical treatment]. AB - BACKGROUND: Treatment of infective endocarditis is primarily conservative. Persistent infection, tissue destruction und hemodynamic instabilities argue - in dependence on the microorganisms involved - for an urgent surgical treatment, even when there is still no control of the local and systemic infection. For timing of the surgical intervention, the following suggestions seem to be valid: TIMING OF THE SURGICAL INTERVENTION: Delayed surgical indication is considered a prognostic factor of extraordinary relevance for surgical treatment of infective endocarditis. Presence of intramyocardial, paravalvular and root abscess or development of a septic cardiomyopathy (in addition to the valve-related disturbed pump and muscular function), systemic sepsis and irreversible extracardiac organ destruction (liver, spleen, kidney, brain, lung, bone, etc.) reduce the surgical prognosis even after successful and complete surgical treatment. Extracardiac foci may determine the postoperative course. After cerebral embolization the cardiac operation should be performed as early as possible (within 24-48 h after embolization). Extreme extent of cardiac and extracardiac tissue destruction due to delayed surgical indication can result in a situation, where adequate surgical treatment of the local focus is not likely to be successful anymore and prognosis becomes infaust. In their own patients, the authors observed: NYHA (New York Heart Association) III-IV > 50%; renal failure (dialysis) > 15%, systemic embolization > 30%, cerebral embolization > 8%, cardiogenic shock > 10%. SURGICAL TREATMENT: The most important aspect is complete debridement of all infected tissue with a safety margin of about 3 mm. This holds true, even if it results in resection of the entire aortic root, mitral ring, aortic wall, and atrial tissue. There is no contraindication to the implantation of prosthetic materials (valves, bovine pericardium, mitral rings) as long as surgical debridement has been prompt and aggressive. Not the type of prosthesis, but the quality of surgical debridement is of prognostic relevance. Reconstructive techniques are suggested whenever possible and are primarily effective for the treatment of mitral and tricuspid valves. Prompt and aggressive eradication of extracardiac foci is important to the patient's postoperative course. POSTOPERATIVE COURSE AND TIMING OF THE OPERATION: After successful surgical treatment of the intracardiac focus, the postoperative course is mainly determined by extracardiac foci, systemic sepsis, and persistent secondary organ destruction. PERSPECTIVE: As the results of conservative treatment of infective endocarditis are still not satisfactory, in some subgroups improved surgical results due to aggressive and radical debridement of infective tissue (with a safety margin of at least 3 mm) will suggest the surgical treatment option even in those patients, that have primarily been considered for conservative treatment. PMID- 19444404 TI - [Decompensated valve failure: the revival of balloon valvuloplasty - percutaneous valve intervention]. AB - Calcified aortic stenosis is the dominating valve disease. Patients affected are most commonly elderly people, who often show associated comorbidities like reduced left ventricular function, impaired renal function, and pulmonary hypertension. The risk of open heart surgery is elevated. Balloon aortic valvuloplasty enables a reduction of symptoms, an increase in physical performance, and, therefore, an improved quality of life. Recent data also demonstrated an improved survival of patients after valvuloplasty. New techniques and improved equipment induced a "revival" of balloon aortic valvuloplasty, which has been introduced more than 20 years ago. In acute emergencies, however, mortality is high. Hemodynamic stabilization in the intensive care unit prior to valvuloplasty is recommended. If restenosis in aortic bioprosthesis has occurred, hemodynamic improvement is very limited. Surgical valve replacement or percutaneous transcatheter valve implantation as valve-in-valve must be considered in the short term. PMID- 19444405 TI - [Acute myocardial infarction: acute coronary intervention at any hospital versus acute coronary intervention at specialized centers only]. AB - The acute coronary syndromes (ACS) are currently divided into those with ST elevation (STE-ACS = ST elevation myocardial infarction [STEMI]) and those without ST elevation (NSTE-ACS). The latter are further divided into NSTE-ACS with risk factors and NSTE-ACS without risk factors. For NSTE-ACS patients with risk factors an invasive strategy within 72 h after presentation is recommended, whereas NSTE-ACS patients without risk factors can be treated conservatively, without a routine invasive diagnosis. In patients with STE-ACS, primary angioplasty is the reperfusion therapy of choice. These recommendations concerning the invasive strategies are valid only under three conditions: (1) primary angioplasty has to be performed within 2 h after diagnosis of an STE-ACS; (2) door-to-balloon times for STE-ACS have to be < 60 min; (3) the invasive procedures have to be performed by experienced investigators at hospitals with a sufficient annual PCI (percutaneous coronary intervention) volume. The last point is based on studies which showed a volume-outcome relationship for PCIs in ACS patients and hospital mortality. In Germany, a nationwide supply with such an invasive strategy for ACS patients is currently possible, even within the recommended time frames. Therefore, local networks have to be established to achieve this goal. However, at least in regions with a high density of invasive centers, such networks should take the investigators' experience and the annual interventional volumes of the participating hospitals into account. PMID- 19444406 TI - [Acute thoracic pain: Chest Pain Unit - the certification campaign of the German Society of Cardiology]. AB - The Chest Pain Unit (CPU) Task Force of the German Society of Cardiology inaugurated elaborated prerequisites for a CPU certification program to evaluate CPUs across the country. For this reason, a consensus document including criteria for CPUs was developed and published in October 2008. Aim of this effort is to ensure a network of elaborated centers which meet or exceed quality-of-care measures in order to improve the standard of care of patients with acute thoracic pain. After application and a formal checkup of the institution, the minimum requirements are assessed by an expert committee of the German Society of Cardiology according to presubmitted documentation of the care processes for patients with acute thoracic pain. Components of certification include characteristic locations, equipment, diagnostic and therapeutic strategies, cooperations, staff education, and organization. Certification specifically implies algorithms for ST segment elevation myocardial infarction, non-ST segment elevation myocardial infarction, unstable angina, stable angina, hypertensive crisis, acute pulmonary embolism, acute aortic syndrome, cardiogenic shock, and resuscitation. Availability of a catheter laboratory ready within the facility is mandatory. The CPU and the cath lab are obliged to be available 24 h per day over 365 days per year. After successful documentation review, a certification audit team reviews the facility's application, infrastructure, patient care, and each of the requirements according to the consensus document on site and makes recommendations to the expert committee. Certification is finally awarded by the expert committee of the German Society of Cardiology to those CPUs which fulfill the dedicated requirements and successfully run through the complete certification process. Within this process, CPUs can plan and organize the delivery of care in a systematic manner, and the differentiation between minimum requirements and best practice allows further developments and innovations. PMID- 19444407 TI - [Ivabradine - a new therapeutic option for cardiogenic shock?]. AB - Documented mortality from acute myocardial infarction (AMI) has significantly decreased from around 30% in the 1960s to currently 6-7%, following the introduction of intensive-care treatment, thrombolysis, effective antithrombotic therapy, and coronary angioplasty. However, the approximate mortality of 70-80% of patients with cardiogenic shock following AMI has hardly improved despite the introduction of modern treatment strategies. The major cause of in-hospital AMI mortality remains myocardial failure with consecutive cardiogenic shock and multiorgan failure. Reduction of heart rate is one of the most important energy saving maneuvers, which can be achieved by administration of beta-receptor blocking agents. In patients with clinical signs of hypotension, however, the guidelines recommend to stabilize the patient before administering an oral beta receptor blocker, mainly because of the hypotensive effects of the substance class. In this situation, selective heart rate reduction, e.g., via administration of ivabradine without side effects of hypotension may be advantageous and better tolerated in patients with cardiogenic shock. The aim of the present review is to briefly summarize the treatment options of cardiogenic shock and the mechanisms of action of ivabradine as well as to present a case report of a patient with cardiogenic shock due to main trunk occlusion, where treatment with ivabradine seemed to beneficially influence the outcome. PMID- 19444408 TI - [Health-economic modeling on the use of drug-eluting stents versus coronary artery bypass graft surgery in coronary heart disease]. AB - BACKGROUND AND PURPOSE: The therapy of coronary heart disease (CHD) leads to an enormous economic burden on health-care systems. Coronary artery bypass grafting (CABG) and percutaneous revascularizations with implantation of drug-eluting stents (DES) are important treatment methods in CHD. The presented evaluation addresses cost efficacy of the use of DES versus CABG in CHD patients. METHODS: A health-economic model considering linear resource use was performed from a restricted societal perspective for time periods of 1 and 3 years. Because of the short time horizon discounting was not applied. The clinical assumptions for event rates at 1 and 3 years were derived from the ARTS-I study for CABG, and from the ARTS-II study for DES (sirolimus-eluting stents). Cost assumptions for the resources used were based on the German Diagnosis Related Groups 2007 (G-DRG 2007). The base case value was assumed to be 2,800 Euros, the average DES price 1,200 Euros, and the average DES use per patient 3.7. The average per-patient daily clopidogrel costs were assumed to be 2.57 Euros, and the duration of the clopidogrel therapy 12 months. Within the scope of sensitivity analyses, different model parameters were varied and the evaluation was tested for its robustness. RESULTS: The average costs for percutaneous coronary intervention (PCI) without DES were found to be 4,420 Euros, for CABG 12,840 Euros, and for DES intervention 8,860 Euros (Table 4). 1-year clopidogrel intake resulted in 938 Euros, the treatment of patients with myocardial infarction during follow-up in 3,989 Euros. The 1-year per-patient total costs after CABG were calculated to be 13,373 Euros and after DES 10,443 Euros, leading to a difference of 2,930 Euros in favor of DES implantation (Table 6). The 3-year per-patient total costs after CABG were estimated to be 13,630 Euros and after DES 10,905 Euros, showing a Rehabilitationsmasscost difference of 2,725 Euros in favor of DES implantation (Table 6). Changes in cost-weights of G-DRG-2007 for CABG and PCI, DES price and DES use per patient as well as in the duration of the clopidogrel therapy influenced the cost differences considerably; however, they did not reach a break even point (Figures 2 and 3). Changes in the clinical follow-up assumptions showed a lower effect on the difference in total costs (Figures 2 and 3). CONCLUSION: The presented data, indicating a possible economic middle-term advantage of DES versus CABG, should be proven with clinical assumptions derived from randomized clinical trials. PMID- 19444409 TI - Image of the month. Recovery of myocardial hibernation after percutaneous coronary intervention. Repetitive assessment by magnetic resonance imaging. PMID- 19444410 TI - [Complication of a complex heart failure: perforation of a sinus Valsalva [corrected] aneurysm]. AB - A 68-year-old woman was admitted to hospital because of chronic heart failure. The cause was a left-right shunt between the left sinus of Valsalva and the right atrium. The patient underwent surgery with shunt closure. Intraoperatively, the ramus circumflexus of the coronary artery was occluded. 2.5 years later the patient was readmitted to hospital. There was acute heart failure caused by an ischemic mitral regurgitation III degrees . A planned mitral valve replacement and operative myocardial revascularization were not performed because the patient developed a drug-induced hepatotoxic failure under phenprocoumon. PMID- 19444412 TI - Low levels of prothrombin time (INR) and platelets do not increase the risk of significant bleeding when placing central venous catheters. AB - BACKGROUND AND PURPOSE: Central venous catheters are frequently placed in intensive care medicine for multiple indications. The risk of severe bleeding after cannulation is considered to be increased in patients with abnormal coagulation, common in critically ill patients. PATIENTS AND METHODS: This open prospective trial, performed at two medical intensive care units and one hematology intermediate care ward, investigated whether insertion of a central venous catheter in patients with coagulopathy (prothrombin time or= 1.5] and/or platelets 10 IU/l, it is possible to predict outcome as early as 6 months after initiation of antithyroid drug therapy. Below a certain threshold, depending on the time point of measurement, no representative risk analyses are available for TRAbs. TRAb measurement is also helpful to determine the course of GO. This may guide the physician through crucial treatment decisions, especially if the patient is at risk of deterioration. PMID- 19444415 TI - [Renal artery stenosis. Pathophysiology--diagnosis--therapy]. AB - Renal artery stenosis (RAS) is both a common and progressive disease and its prevalence in patients > 65 years is 6.8%. In patients with known or suspected atherosclerosis undergoing coronary angiography, a frequency of even 11-23% is reported in the literature. Despite this high prevalence, there is an ongoing discussion about the indications for revascularization and it is currently unclear, whether renal artery revascularization reduces adverse cardiovascular and renal events. Nevertheless, the number of interventions for RAS is rising steadily, although up to 40% of patients do not profit from this intervention. This fact underlines the necessity of a thorough diagnostic work-up before intervention, integrating morphological and functional tests. For morphological evaluation, multislice computed tomography, magnetic resonance tomography or digital subtraction angiography can be done. In experienced centers, Doppler ultrasound can serve as an excellent functional tool, to assess the physiological relevance of an RAS, but also invasive measurements of pressure and flow provide valuable information about the significance of stenoses; however, these methods will have to be assessed with respect to their value to predict long-term outcome. Although percutaneous intervention of RAS is associated with a substantially lower risk of major adverse events as compared to surgery, by using contrast media this procedure holds the risk of deterioration of renal function and of a small number of procedure-dependent complications as well. Thus, a careful consideration of pros and cons of this procedure is mandatory. PMID- 19444416 TI - [Viral hepatitis B und C]. AB - Chronic hepatitis B (HBV) and C virus (HCV) infection can lead to liver cirrhosis, hepatocellular carcinoma and death. Treatment of these worldwide prevalent infectious diseases is subject to intensive research efforts with development of new antiviral substances and optimization of treatment strategies using molecular markers. The goal of HBV and HCV treatment is control and elimination of viral replication, respectively, thereby preventing hepatitis associated complications. While interferon alpha is used less frequently to treat hepatitis B today, it is still (in the pegylated or albumin-fused form) an essential component of hepatitis C therapy. The growing number of targeted therapies such as new nucleus(t)ide analogs, HCV protease and RNA polymerase inhibitors and other new compounds has added complexity to the treatment of viral hepatitis. This update summarizes the current standard of care as well as new developments in chronic hepatitis B and C therapy. PMID- 19444417 TI - [Socioeconomic relevance of the idiopathic restless legs syndrome (RLS) in Germany: cost-of-illness study]. AB - BACKGROUND AND PURPOSE: 1.3% of German adults suffer from clinically relevant restless legs syndrome (RLS). A cost-of-illness study was conducted to evaluate the costs for diagnosis and therapy of the idiopathic RLS. METHODS: A clinical pathway based on expert guidelines was developed. The costs for the 1st year of treatment in idiopathic RLS were calculated with the Markov Model. Relevant published clinical study data were used for the model as well as questioning of physicians. RESULTS: Costs per patient with approved drug treatment are 989.80 Euro for sickness funds and 1,285.26 Euro from the societal perspective. Drug costs are the main cost components for sickness funds and the society with 69% and 61%, respectively. Less than half of the patients continue an L-dopa therapy longer than 1 year. About one quarter of all RLS patients need off-label therapy after the 1st year of treatment. CONCLUSION: The costs for a guideline-oriented therapy for all patients with clinically relevant RLS in Germany are about 1,135 billion Euro, representing 0.5% of all health-related costs in Germany. Further controlled clinical trials are required to provide evidence for the efficacy of different treatment options including drugs without an approval for RLS and long term use. Health services research is required for cost-utility analysis, to evaluate the costs of inadequate treatment, and to obtain additional information to improve the resource allocation in RLS treatment. PMID- 19444418 TI - [Idiopathic thrombocytopenic purpura (Werlhof disease) and differential diagnosis from other thrombocytopenic hemorrhagic diatheses]. PMID- 19444419 TI - [Impaction of a "sausage bread" in the esophagus--first manifestation of an eosinophilic esophagitis in a 17-year-old patient]. AB - A 17-year-old patient was transferred to the emergency room with an impacted food bolus by colleagues from the Department of Otorhinolaryngology. The examination of ear, nose and throat revealed significant amounts of saliva in both recessus piriformis, a radiologic examination of the esophagus showed a foreign body with a diameter of 1.6 cm in the region of the transitional zone of esophagus and stomach with a support level of the contrast medium. Clinical examination and laboratory tests showed no abnormalities. An emergency gastroscopy was performed. The foreign body, already evident in the barium swallow, was found in the distal esophagus. The foreign body was identified as a food bolus and gently advanced into the stomach with the aid of the gastroscope. In the stomach further food residues were detected and the examination was aborted because of increased risk of aspiration. On the next day, an elective gastroscopy was performed. Several biopsies were obtained from the esophagus because eosinophilic esophagitis (EE) was suspected due to clinical symptoms. Histological work-up showed a significant amount of eosinophilic granulocytes (> 15 eosinophils/HPF, 400 x) and reactive changes in the distal esophagus. Therefore, EE was diagnosed. Fluticasone therapy led to amelioration of symptoms and there was no evidence of recurring bolus impaction during follow-up. PMID- 19444420 TI - [Current DRG updates--once again the documentation obsession--exemplified by MRSA]. PMID- 19444421 TI - [Specific diagnosis of cranial sinus thrombosis]. PMID- 19444424 TI - Innate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps. AB - The formation of extracellular traps (ETs) by phagocytic cells has been recognized as a novel and important mechanism of the host innate immune response against infections. ETs are formed by different host immune cells such as neutrophils, mast cells, and eosinophils after stimulation with mitogens, cytokines, or pathogens themselves, in a process dependent upon induction of a reactive-oxygen-species-mediated signaling cascade. ETs consist of nuclear or mitochondrial DNA as a backbone with embedded antimicrobial peptides, histones, and cell-specific proteases and thereby provide a matrix to entrap and kill microbes and to induce the contact system. This review summarizes the latest research on ETs and their role in innate immunity and host innate defense. Attention is also given to mechanisms by which certain leading bacterial pathogens have evolved to avoid entrapment and killing in these specialized structures. PMID- 19444425 TI - Background complexity affects colour preference in bumblebees. AB - Flowers adapted for hummingbird pollination are typically red. This correlation is usually explained by the assertion that nectar- or pollen-stealing bees are "blind" to red flowers. However, laboratory studies have shown that bees are capable of locating artificial red flowers and often show no innate preference for blue over red. We hypothesised that these findings might be artefacts of the simplified laboratory environment. Using bumblebees (Bombus impatiens) that had been trained to visit red and blue artificial flowers, we tested whether colour preference was influenced by complexity of the background on which they were foraging. Many bees were indifferent to flower colour when tested using a uniform green background like those commonly used in laboratory studies, but all bees showed strong colour preferences (usually for blue) when flowers were presented against a photograph of real foliage. Overall, preference for blue flowers was significantly greater on the more realistic, complex background. These results support the notion that the red of "hummingbird syndrome" flowers can function to reduce bee visits despite the ability of bees to detect red and highlight the need to consider context when drawing inferences about pollinator preferences from laboratory data. PMID- 19444426 TI - [Multidetector computed tomography in the diagnosis of non-traumatic vascular emergencies]. AB - Radiological imaging of the vascular system is an essential component in the clinical evaluation of vascular emergencies. Duplex ultrasound is still in use as a basic diagnostic means and enables initial diagnostic information. Digital subtraction angiography (DSA), the longtime gold standard, is now more often used with therapeutic interventions rather than purely diagnostic studies. However, over the past 10 years, there has been a rapid development of new technology that has deeply changed vascular imaging and allows a non-invasive depiction with a robust technique, greater speed and higher resolution. Advanced cross-sectional imaging techniques such as magnetic resonance imaging (MRI) and multidetector computed tomography (MDCT) angiography nowadays enable a dedicated diagnostic evaluation of acute aortic and peripheral arterial pathologies. Due to its enormous innovation and broad and quick availability angiographic multidetector computed tomography (MDCT) could replace catheter-based angiography in the diagnostic assessment. This article summarizes the performance of MDCT angiographic imaging and its diagnostic and therapeutic significance for the diagnostic assessment of non-traumatic aortic and peripheral arterial diseases. PMID- 19444429 TI - Accessory soleus in the athletes: literature review and case report of a massive muscle in a soccer player. AB - Accessory soleus is a rare congenital anatomical variant, which may manifest in the second/third decade of life as an exertional ankle pain and swelling or as an asymptomatic postero-medial mass. The incidence of this condition ranges from 0.7 to 5.5%. Many treatment options have been described in literature, including conservative treatment, excision, fasciotomy, release and closure of blood supply. We report a symptomatic massive accessory soleus (17 x 5 x 4 cm) in an 18 year-old male semi-professional soccer player. Excision of the accessory soleus was performed. The patient went back to the game 3 months after surgery. The literature review stated that either fasciotomy or excision of the muscle produce good results in the athletes. PMID- 19444430 TI - Bilateral double-layered lateral meniscus: a report of two cases. AB - Only a few cases of double-layered meniscus have been described in the English literature. We report two cases of bilateral double-layered lateral meniscus, where an additional semicircular meniscus was observed over the normal lateral meniscus. One of the patients exhibited a bucket-handle tear with a double layered meniscus. To our knowledge, this abnormality is extremely rare and the incidence of double layered meniscus with bucket-handle tear has not been previously reported. PMID- 19444431 TI - Hamstrings co-activation in ACL-deficient subjects during isometric whole-leg extensions. AB - It has been reported that anterior cruciate ligament (ACL)-deficient subjects increase the level of hamstrings activation and this has been interpreted as a means to cope with increased anterior tibial laxity in the knee. This study aimed to establish to what extent co-activation strategies in ACL-deficient subjects are load level and knee angle dependent. Eleven chronic ACL-deficient and 15 control subjects were positioned in a range of postures and asked to exert a feedback controlled vertical ground reaction force (GRF; 30, 60% and maximum), while horizontal forces were not constrained. Surface electromyography of the leg muscles and GRF were measured. In postures with the knee over and in front of the ankle, ACL-deficient subjects generated, respectively, 2.4 and 5.1% MVC more hamstrings activation than control subjects. Enhanced hamstrings co-activation in ACL-deficient subjects was more apparent in extended than in flexed knee angles. For both ACL-deficient and control subjects, hamstrings co-activation was larger in males than in females. It is concluded that ACL-deficient subjects show a task dependent increase in hamstrings co-activation, but its clinical significance remains to be shown. PMID- 19444432 TI - Surface-enhanced Raman scattering in nanoliter droplets: towards high-sensitivity detection of mercury (II) ions. AB - We report a new method for the trace analysis of mercury (II) ions in water. The approach involves the use of droplet-based microfluidics combined with surface enhanced Raman scattering (SERS) detection. This novel combination provides both fast and sensitive detection of mercury (II) ions in water. Specifically, mercury (II) ion detection is performed by using the strong affinity between gold nanoparticles and mercury (II) ions. This interaction causes a change in the SERS signal of the reporter molecule rhodamine B that is a function of mercury (II) ion concentration. To allow both reproducible and quantitative analysis, aqueous samples are encapsulated within nanoliter-sized droplets. Manipulation of such droplets through winding microchannels affords rapid and efficient mixing of the contents. Additionally, memory effects, caused by the precipitation of nanoparticle aggregates on channel walls, are removed since the aqueous droplets are completely isolated by a continuous oil phase. Quantitative analysis of mercury (II) ions was performed by calculating spectral peak area of rhodamine B at 1,647 cm(-1). Using this approach, the calculated concentration limit of detection was estimated to be between 100 and 500 ppt. Compared with fluorescence based methods for the trace analysis of mercury (II) ions, the detection sensitivities were enhanced by approximately one order of magnitude. The proposed analytical method offers a rapid and reproducible trace detection capability for mercury (II) ions in water. PMID- 19444433 TI - Catch the moment: multisensory enhancement of rapid visual events by sound. AB - Repetition blindness (RB) is a visual deficit, wherein observers fail to perceive the second occurrence of a repeated item in a rapid serial visual presentation stream. Chen and Yeh (Psychon Bull Rev 15:404-408, 2008) recently observed a reduction of the RB effect when the repeated items were accompanied by two sounds. The current study further manipulated the pitch of the two sounds (same versus different) in order to examine whether this cross-modal facilitation effect is caused by the multisensory enhancement of the visual event by sound, or multisensory Gestalt (perceptual grouping) of a new representation formed by combining the visual and auditory inputs. The results showed robust facilitatory effects of sound on RB regardless of the pitch of the sounds (Experiment 1), despite an effort to further increase the difference in pitch (Experiment 2). Experiment 3 revealed a close link between participants' awareness of pitch and the effect of pitch on the RB effect. We conclude that the facilitatory effect of sound on RB results from multisensory enhancement of the perception of visual events by auditory signals. PMID- 19444435 TI - Perforation of hollow viscera as a result of lithotripsy caused by shock waves: why does this occur? PMID- 19444434 TI - Genetic polymorphisms of CYP2D6 oxidation in patients with systemic sclerosis. AB - BACKGROUND: Involvement of genetic and environmental factors in the pathogenesis of scleroderma has contributed to a number of studies whose aim is to elucidate the way in which xenobiotics exert effects on the occurrence of autoimmune processes resulting in development of systemic sclerosis (SSc). OBJECTIVE: The study dealt with the evaluation of the genetically determined polymorphism of CYP2D6, one of the phase I drug metabolizing isoenzymes, in patients suffering from SSc. Usefulness of the CYP2D6 genotype examination and prevalence of CYP2D6 gene mutation in light of susceptibility to SSc development were assessed. METHODS: Forty-three patients with SSc and 129 healthy volunteers were included in the study. Of the 43 patients with SSc, 17 fulfilled the criteria of diffuse SSc (dSSc) and 26 of limited SSc (lSSc). The determination of the CYP2D6 oxidative polymorphism was performed with the PCR-RFLP method. RESULTS: Relative risk of SSc development for particular genotype carriers expressed by the odds ratio (OR) was statistically significantly higher for subjects with CYP2D6*1/CYP2D6*4 (OR = 4.8; P < 0.001). A statistically significant correlation between the CYP2D6*4 allele prevalence and the risk for developing SSc was found (OR = 2.6; P = 0.0002). CONCLUSION: Higher prevalence of the CYP2D6*4 mutated alleles in patients with SSc and the obtained OR values suggest that this mutation has the effect of increasing SSc morbidity rate. PMID- 19444436 TI - Studies on the role of calcium phosphate in the process of calcium oxalate crystal formation. AB - Crystals of calcium phosphate (CaP) added to solutions with a composition corresponding to that at different levels of the collecting duct (CD) and with different pH were rapidly dissolved at pH 5.0, 5.25 and 5.5. Only minor or no dissolution was observed at higher pH levels. Despite this effect, CaP crystals induced nucleation or heterogeneous crystallization of CaOx up to a pH of 6.1, whereas CaP was the type of crystalline material that precipitated at higher pH. Accordingly, small crystal volumes were recorded at pH 5.5 and great volumes at pH 6.7 4 h after the addition of CaP crystals to the solutions. Dialyzed urine appeared to counteract the dissolution of CaP and to reduce the rate of secondary crystallization. The CaP induced crystallization of CaOx was confirmed by a reduction of (14)C-labeled oxalate in solution. The AP(CaOx) required for a nucleation or heterogeneous crystallization of CaOx in the presence of CaP was around 1.5 x 10(-8) (mol/l)(2). For CaP crystal formation on CaP, an AP(CaP) ((a)Ca(2+) x (a)PO(4)(3-)) of approximately 50 x 10(-14) (mol/l)(2) appeared to be necessary. The CaOx crystals formed were microscopically found in association with the CaP crystalline material and were most frequently of CaOx dihydrate type. Step-wise crystallization experiments comprising supersaturation with CaP (Step A), supersaturation with CaOx (Step B) and subsequently acidification (Step C) showed that CaOx crystal formation occurred when CaP crystals were dissolved and thereby served as a source of calcium. The ensuing formation of CaOx crystals is most likely the result from high local levels of supersaturation with CaOx caused by the increased concentration of calcium. These experimental studies give support to the hypothesis that crystallization of CaOx at lower nephron levels or in caliceal urine might be induced by dissolution of CaP formed at nephron levels above the CD, and that a low pH is prerequisite for the precipitation of CaOx. The observations accordingly provide additional evidence for the important role of calcium phosphate in the crystallization of calcium oxalate, that might occur both at the surface of Randall's plaques and intratubularly at the papillary tip. PMID- 19444437 TI - Pain relief by extracorporeal shockwave therapy: an update on the current understanding. PMID- 19444438 TI - The emperor has no clothes. PMID- 19444439 TI - PET/CT of fibrodysplasia ossificans progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is an exceedingly rare genetic disorder of connective tissue characterized by extensive and irreversible heterotopic ossification of soft-tissue masses that develop in response to inflammation or trauma. Successful management relies on preventative measures and avoidance of invasive procedures such as intramuscular injections and biopsies. Early diagnosis can prevent extensive heterotopic ossification and is possible with recognition of the classic clinical findings in the feet in association with rapidly evolving soft-tissue masses of the trunk and extremities. Unfortunately, in 87% of the 269 previously reported cases, the diagnosis was not considered initially. Patients are often subjected to biopsy of the soft-tissue masses. The pathology of the fibrodysplasia ossificans progressiva is often confused with sarcoma. These patients might be imaged with PET as part of a standard oncological work-up. We present the first reported PET/CT images of a patient with FOP in order to alert radiologists to this diagnostic pathway. Awareness of the disorder might prevent further unnecessary interventions that can lead to extensive deformity and suffering. PMID- 19444440 TI - A rare case of 'blow-up' fracture of the orbit in a child. AB - We present a case of blow-out fracture of the superomedial orbital wall in a 6 year-old boy. The initial plain radiograph showed an intact orbital margin and opacification of the ethmoid sinus. A fine-cut CT scan of the facial bones revealed a complex fracture of the medial orbital wall extending into the orbital roof, with migration of fracture fragments into the anterior cranial fossa. Suspicion for unusual orbital fractures is crucial when assessing a child for orbital trauma, especially when plain radiographs do not display the typical signs. PMID- 19444441 TI - Physiological characterisation of acuB deletion in Aspergillus niger. AB - The acuB gene of Aspergillus niger is an ortholog of facB in Aspergillus nidulans. Under carbon-repression conditions, facB is repressed, thereby preventing acetate metabolism when the repressing carbon source is present. Even though facB is reported to be repressed directly by CreA, it is believed that a basal level of FacB activity exists under glucose-repressive conditions. In the present study, the effect of deletion of acuB on the physiology of A. niger was assessed. Differences in organic acid and acetate production, enzyme activities and extracellular amino and non-amino organic acid production were determined under glucose-repressing and -derepressing conditions. Furthermore, consumption of alternative carbon sources (e.g. xylose, citrate, lactate and succinate) was investigated. It was shown that AcuB has pleiotropic effects on the physiology of A. niger. The results indicate that metabolic pathways that are not directly involved in acetate metabolism are influenced by acuB deletion. Clear differences in organic acid consumption and production were detected between the acuB and reference strain. However, the hypothesis that AcuB is responsible for basal AcuA activity necessary for activation of acetate metabolic pathways, even during growth on glucose, could not be confirmed. The experiments demonstrated that also when acuB was deleted, no acetate was formed. Therefore, AcuB cannot be the only activator of AcuA, and another control mechanism has to be available for activating AcuA. PMID- 19444442 TI - Bioproduction of lauryl lactone and 4-vinyl guaiacol as value-added chemicals in two-phase biotransformation systems. AB - Recombinant Escherichia coli whole-cell biocatalysts harboring either a Baeyer Villiger monooxygenase or ferulic acid decarboxylase were employed in organic aqueous two-phase bioreactor systems. The feasibility of the bioproduction of water-insoluble products, viz., lauryl lactone from cyclododecanone and 4-vinyl guaiacol from ferulic acid were examined. Using hexadecane as the organic phase, 10 approximately 16 g of lauryl lactone were produced in a 3-l bioreactor that operated in a semicontinuous mode compared to 2.4 g of product in a batch mode. For the decarboxylation of ferulic acid, a new recombinant biocatalyst, ferulic acid decarboxylase derived from Bacillus pumilus, was constructed. Selected solvents as well as other parameters for in situ recovery of vinyl guaiacol were investigated. Up to 13.8 g vinyl guaiacol (purity of 98.4%) were obtained from 25 g of ferulic acid in a 2-l working volume bioreactor by using octane as organic phase. These selected examples highlight the superiority of the two-phase biotransformations systems over the conventional batch mode. PMID- 19444443 TI - Effects of Lactobacillus plantarum MA2 isolated from Tibet kefir on lipid metabolism and intestinal microflora of rats fed on high-cholesterol diet. AB - The objective of this study was to evaluate the effects of Lactobacillus plantarum MA2, an isolate from Chinese traditional Tibet kefir, on cholesterol lowering and microflora of rat in vivo. Rats were fed on cholesterol-enriched experimental diet, supplemented with lyophilized L. plantarum MA2 powder, with a dose of 10(11) cells/day per mice. The results showed that L. plantarum MA2 feeding significantly lowered serum total cholesterol, low-density lipoprotein cholesterol, and triglycerides level, while there was no change in high-density lipoprotein cholesterol. In addition, liver total cholesterol and triglycerides was also decreased. However, fecal cholesterol and triglycerides was increased significantly (P < 0.05) in comparison with the control. Also, L. plantarum MA2 increased the population of lactic acid bacteria and bifidobacteria in the fecal, but it did not change the number of Escherichia coli as compared to control. Moreover, pH, moisture, and organic acids in the fecal were also measured. The present results indicate the probiotic potential of the L. plantarum MA2 strain in hypocholesterolemic effect and also increasing the probiotic count in the intestine. PMID- 19444444 TI - Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged. AB - Multiple investigators have reported the presence of defects in the immune response of the elderly [Castle In: Clin Infect Dis 31:578, 2000; Ortqvist et al. In: Eur Respir J 30:414-422, 2007; Saurwein-Teissl et al. In: J Immunol 168:5893, 2002; Haynes et al. In: Proc Natl Acad Sci USA 100:15053-15058, 2003]. These defects reduce the magnitude of the immune response to infection and to vaccination. In individuals greater than 55 years of age, the probability of developing a fully protective neutralizing antibody response to the yearly multivalent particle inactivated influenza vaccine is less than 20% [Jefferson et al. In: Lancet 264:1165-1174, 2005; Goodwin et al. In: Vaccine 24:1159-1169, 2006; Jackson et al. In: Lancet 372:398-405, 2008; Simonsen and Taylor In: Lancet 7:658-666, 2007]. The defects in the aged immune system that are responsible for this limited response to vaccination in the older age groups include functional defects of the antigen presenting cells, functional defects in CD4 helper CD4 T cells and monocytes, and an altered microenvironment [Eaton et al. In: J Exp Med 200:1613-1622, 2004; Dong et al. In: J Gen Virol 84:1623-1628, 2003; Deng et al. In: Immunology 172:3437-3446, 2004; Cella et al. In: J Exp Med 184:747-752, 1996]. Starting at puberty, the involution of the thymus and the consequent reduction of the export of naive T cells specific to neo-antigens leads to the reduction of the ratio of antigen naive to memory cells as chronological age advances [Prelog In: Autoimmun Rev 5:136-139, 2006; McElhaney et al. In: J Immunology 176:6333-6339, 2006]. Changes in glycosylation of T cells and target antigens acquired during the aging process and the antibodies to these new glycopeptides and glycoproteins may also contribute to a reduction in the functioning of the adaptive immune response [Ishii et al. In: J Clin Neurosci 14:110-115, 2007; Shirai et al. In: Clin Exp Immunol 12:455-464, 1972; Adkins and Riley In: Mech Ageing Dev 103:147-164, 1998; Ben-Yehuda and Weksler In: Cancer Investigation 10:525-531, 1992]. One of the more interesting examples of the functional defects in the cells of the adaptive immune response is a reduced level of expression in the surface cytoadhesion and activation receptor molecules on CD4 helper T cells undergoing activation during vaccination. Upon infection or vaccination, CD40L is typically increased on the surface of CD4 helper T cells during activation, and this increased expression is absolutely essential to the CD40L promotion of expansion of antigen-specific B cells and CD 8 effector T cells in response to infection or vaccination [Singh et al. In: Protein Sci 7:1124-1135, 1998; Grewal and Flavell In: Immunol Res 16: 59-70, 1997; Kornbluth In: J Hematother Stem Cell Res 11:787-801, 2002; Garcia de Vinuesa et al. In: Eur J Immunol 29:3216-3224, 1999]. In aged human beings and mice, the reduced levels of expression of CD40 ligand (CD40L) in activated CD4 helper T cells is dramatically reduced [Eaton et al. In: J Exp Med 200:1613-1622, 2004; Dong et al. In: J Gen Virol 84:1623-1628, 2003]. To circumvent the reduction in CD40L expression and the subsequent reduction in immune response in the elderly, we have developed a chimeric vaccine comprised of the CD40L linked to the target antigen, in a replication incompetent adenoviral vector and in booster protein. This review will discuss the implementation the potential use of this approach for the vaccination of the older populations for cancer and infection. PMID- 19444446 TI - Isoderivative of deleted chromosome 20 in primary myelofibrosis (PMF) characterized by molecular cytogenetics and array CGH. PMID- 19444447 TI - Behcet's disease associated with celiac disease: a very rare association. AB - There are common findings between Behcet's disease (BD) and celiac disease (CD); however, association in the same patient is a rarity. We relate the third case in the literature of this overlap in a 40-year-old woman with history of obstipation since her childhood. She also presented asymmetric polyarthralgia, loss of weight, anemia, oral recurrent aphthas (>3/year) and genital ulcerations, inflammatory lower back pain, bowel bleeding and abdominal colic. Afterwards, she presented episodes of erythema nodosum, superficial thrombophlebitis, pseudofolliculitis and aseptic meningitis, thus fulfilling criteria for BD. Due to persistence of the digestive complaints, a gastrointestinal endoscopy was performed. The biopsy showed chronic duodenitis with intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy. Endomysial antibody was positive. She fulfilled the diagnosis criteria for CD; a gluten-free diet was applied with clinical improvement. Ascertaining whether pathogenic mechanisms are common in these two conditions requires further investigation. PMID- 19444448 TI - Autoimmune hypothyroidism and lupus-like syndrome. AB - The frequency of thyroid disorders, particularly Hashimoto's thyroiditis, may be increased in patients with connective tissue diseases. Both hypothyroidism and connective tissue diseases often cause muscle and joint aches, pains and stiffness. Skin, renal and cardiovascular involvement seen in the course of autoimmune hypothyroidism (AIH) may simulate connective tissue diseases such as systemic lupus erythematosus (SLE). We herein report a case of AIH who presented with massive proteinuria, haematuria, pleural fluid and arthritis simulating SLE. PMID- 19444449 TI - Altered T-cell subtypes in spondyloarthritis, rheumatoid arthritis and polymyalgia rheumatica. AB - The objective of the present study was to assess the prevalences of naive, memory, memory/effector, regulatory and activated T-cells in peripheral blood (PB) and synovial fluid (SF) of patients with spondyloarthritis (SpA), rheumatoid arthritis (RA), polymyalgia rheumatica/giant cell arteritis (PMR/GCA) and healthy controls (HC). Twenty-two patients with SpA, 15 patients with RA, 38 patients with PMR/GCA and 17 HC were prospectively enrolled. The expression of differentiation and activation markers (CD3, CD4, CD8, CD25, CD28, CD45RA, CD45RO) characterizing T-cell subsets were analyzed by flow cytometry. The frequency of CD3(+)CD4(+)CD28(-) memory/effector T-cells was increased in PB of patients with SpA (median 1.1%, range 0.1-69.6), RA (2.5%, 0-42.9) and PMR/GCA (2.7%, 0-49.5) when compared with HC (0.7%, 0-38.0) and tended to be higher in SF of SpA patients (4.5%, 0.2-7.2, P = 0.084). CD28(+)CD45RA(+)CD4(+) (9.6%, 4.1 10.3) and CD28(+)CD45RA(+)CD8(+) naive T-cells (15.0%, 12.9-26.2) were reduced and CD28(+)CD45RO(+)CD4(+) (93.5%, 51.0-99.0), CD28(+)CD45RO(+)CD8(+) memory (81.2%, 38.9-83.5), CD8(+)CD25(+) activated T-cells (10.9%, 2.7-13.8) and CD4(+)CD25(hi) TREGs (10.2%, 7.0-13.3) were increased in SF compared to PB (P < 0.05 each). These findings demonstrate altered T-cell subsets in patients with immune-mediated disease, particularly at sites of inflammation. PMID- 19444450 TI - Thrombocytopenia as a presenting feature of Kawasaki disease: a case series from North India. AB - Thrombocytosis is well described in children with Kawasaki disease (KD). We describe six children with KD who had thrombocytopenia at disease onset. This is an unusual finding and has clinical implications in the diagnosis of this condition. PMID- 19444451 TI - Changes of manifestations of 122 patients with rheumatic fever in South China during last decade. AB - The main objective of this study is to investigate changes of features of rheumatic fever (RF) in recent 10 years. A total of 315 patients with RF during 1985-1995 (group 1) and 1997-2007(group 2) were selected. Their manifestations were compared. Results show that the female/male ratio was 2.0. Group 2 had higher rate of low-grade fever and carditis, and lower rate of heart failure, lower positive rate of C-reactive protein and antistreptolycin o than group 1. In group 2, 61.4% patients fulfilled the updated Jones criteria, however, 76.2% fulfilled 2002-2003 WHO criteria. Diagnosing rheumatic carditis, sensibility and specificity of lymphocyte procoagulant activity (PCA) were 79.1 and 71.4%, respectively, and those of antibody to streptococcal polysaccharide (ASP) were 70.3 and 70%, respectively. Follow-up data of 35 cases were available. Recurrent rate of RF was 62.8%. Only 1/3 cases received regular secondary prevention. In conclusion, mild carditis was increasing. PCA and ASP were valuable tests for diagnosing rheumatic carditis. Atypical cases and secondary prevention need more attention. PMID- 19444452 TI - Pitfalls in diagnostics of hip pain: osteoid osteoma and osteoblastoma. AB - Osteoid osteoma and osteoblastoma are benign bone tumors that occur most often in adolescents and predominantly in males. Typical clinical symptoms, such as reduced range of motion of adjacent joints, nocturnal bone pain and relief of pain using non-steroidal anti-inflammatory drug therapy especially in osteoid osteoma may lead to the correct diagnosis. However, these symptoms are not always apparent and specific. In radiographic examinations, the initial changes are often uncharacteristic causing further delay in diagnosis. Magnetic resonance imaging is increasingly used for screening, but early findings in the course of disease might not lead to the definite diagnosis. Both entities (especially osteoid osteoma) occur frequently in the area of the hip. To demonstrate pitfalls in the diagnostic pathway of hip pain caused by benign bone tumors, we present two cases with osteoid osteoma and one with osteoblastoma. PMID- 19444453 TI - Association of anti-CCP positivity with serum ferritin and DAS-28. AB - Antibodies to cyclic citrullinated peptides (anti-CCP) are highly specific for the diagnosis of rheumatoid arthritis (RA) with a marginal increased prediction of the disease. In this study, we aimed to investigate the relation of the presence of anti-CCP with clinical manifestations and disease activity in a cohort of RA patients. A total of 61 RA patients were included in this study. Data of disease-related parameters such as duration of disease, medications, degree of pain (visual analog scale, VAS), disease activity score 28 (DAS-28) and health assessment questionnaire (HAQ) were recorded. Laboratory workup included erythrocyte sedimentation rate (ESR), plasma C-reactive protein (CRP), rheumatoid factor (RF), anti-CCP, complete blood count and anemia parameters. Anti-CCP positivity was associated with higher scores of DAS-28, longer duration of morning stiffness, serum RF positivity and low levels of serum ferritin, while it was not associated with disease duration, VAS, HAQ, ESR, CRP and hemoglobin. PMID- 19444454 TI - Combined dynamic contrast-enhancement and serial 3D-subtraction analysis in magnetic resonance imaging of osteoid osteomas. AB - The purpose of this study was to retrospectively correlate the results of dynamic contrast-enhanced magnetic resonance imaging (MRI) with histological and clinical diagnoses in patients with osteoid osteomas. Fifty-four patients with the MR diagnosis of osteoid osteoma were studied. MRI (1.5 Tesla) consisted of thin section STIR sequences, dynamic 3D T1 gradient echo sequences during application of contrast material, and high-resolution postcontrast T1 spin echo sequences with fat saturation (maximum voxel size 0.6 x 0.6 x 3.0 mm). Evaluation was focused on serial image subtraction during the early phase after contrast injection and on time-intensity curves. The surrounding edema was helpful in finding the nidus in each lesion. In 49 of 54 patients (90.7%), the diagnosis of osteoid osteoma was certain or highly probable (sensitivity 1.0, positive predictive value 0.91). A total of 38 of 54 osteoid osteomas were histologically proven. Five MRI diagnoses were regarded as false positives. A similar proportion has been reported for computed tomography. Tailored high-resolution MR examinations with dynamic contrast enhancement can reliably diagnose osteoid osteomas and exactly localize the nidus without radiation exposure. We propose a stepwise approach with STIR sequences, dynamic contrast-enhanced scanning, and high-resolution postcontrast T1 spin echo sequences with fat saturation. PMID- 19444456 TI - Perforation of the upper and lower segments of atretic esophagus (type C) secondary to nasogastric tube insertion. AB - We report an unusual case of nasogastric tube, during insertion, perforating the upper and lower segments of atretic esophagus (type C) and ending up in the stomach. Symptoms and imaging of the newborn are presented and the causative factors of the incident discussed. PMID- 19444455 TI - Medulloblastomas: a correlative study of MIB-1 proliferation index along with expression of c-Myc, ERBB2, and anti-apoptotic proteins along with histological typing and clinical outcome. AB - BACKGROUND: Medulloblastoma (MB) is the most common pediatric brain tumor. It is however rare in adults. The genetic and protein expression profile of medulloblastoma is complex, which is worthwhile in terms of prognostication and development or selection of targeted therapy. AIMS AND OBJECTIVES: The aims and objectives to correlate the MIB-1 proliferation index and protein expression profiles of c-Myc, ERBB2, and anti-apoptotic proteins (Bcl2 and Bcl-xL) in tumor cells with histological subtypes and clinical outcome. METHODS AND MATERIAL: In 50 cases, histopathological subtyping was done, and protein expression profiling by immunohistochemical technique was performed by stains for MIB-1, Bcl2, Bcl-xL, c-Myc, and ERBB2 in 30 cases. The findings were correlated with histological types and patient's average follow-up data. RESULTS: Histological subtypes were similar to that described in literatures. The average expression of Bcl2, Bcl-xL, MIB-1, c-Myc, and ERBB2 were as follows: 50.38%, 38.18%, 59.03%, 46.16%, and 59.62%, respectively. Bcl2 expression showed statistically significant correlation with progress-free survival (PFS) [p = 0.046], while ERBB2 and MIB-1 showed a trend of higher expression in progressive disease. The protein expression pattern did not correlate with histological subtypes. CONCLUSION: Though Bcl-2, ERBB2, and MIB-1 LI came out to be potential markers of aggressive behavior, c-Myc did not correlate with PFS in MB. PMID- 19444457 TI - Mesalamine enema-induced exacerbation of ulcerative colitis. PMID- 19444458 TI - [Hypophosphatemic diabetes and knee pain: does treatment with total knee arthroplasty promise success?]. AB - Hypophosphatemic diabetes, a rare metabolic disease, presents in children, young adults as well as in elderly patients. In this report we describe the case of a 43-year-old woman with known hypophosphatemic diabetes who complained of severe knee pain after several osteotomies of the lower extremities. The patient was treated with bilateral total knee arthroplasty. The immediate post-operative outcome was good but showed deterioration at 12-month follow-up with decreased range of motion due to ligament stiffness. Knee arthroplasty in patients with hypophosphatemic diabetes remains a challenge for the orthopaedic surgeon. Arthroplasty can be recommended in severe knee pain; however, pre-operative interventions should be considered to prevent post-operative complications. PMID- 19444459 TI - [How much do we know about human brucellosis?]. AB - Human brucellosis manifests as an acute or persistent febrile disease with a wide variety of symptoms. To our knowledge this is the first case report of brucellar monoarthritis of the hip in Croatia, with difficulties regarding its diagnosis and protracted clinical course. PMID- 19444460 TI - Intracytoplasmic sperm injection outcome of women over 39: an analysis of 668 cycles. AB - PURPOSE: To evaluate intracytoplasmic sperm injection (ICSI) outcome of women over age 39 and to determine when to discourage such couples to undergo IVF using their own oocytes. METHODS: Four hundred ninety-five consecutive women (n=668 cycles) over age 39 were evaluated by year-by-year age increments to discriminate the independent prognostic factors for the achievement of pregnancy. RESULTS: Although the ovarian hyperstimulation performance (COH) and embryological data were not too diverse, the clinical pregnancy rates per embryo transfer decreased from 26 to 13% from age 40 to 44. According to logistic regression, the female age seems to be the only variable in order to predict an ongoing pregnancy. The miscarriage rate increased with advancing female age. It was 33% at age 40 but increased to 100% by age 45. CONCLUSIONS: The performance of COH and embryological data is not discouraging among women over 39 years in ICSI cycles. However, increased miscarriages as well as decreased implantation rate are mainly responsible for the poor performance of patients with advanced female age. Irrespective of the ovarian reserve testing, ICSI may be refused at age 45 and thereafter. PMID- 19444461 TI - Five commonly used markers (p53, TTF1, CK7, CK20, and CK34betaE12) are of no use in distinguishing between primary endocervical and endometrial adenocarcinomas in a tissue microarray extension study. AB - BACKGROUND: The choice of appropriate therapeutic plans for primary endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) depends on the tumor's site of origin. Some panels of antibodies help to distinguish primary ECA from EMA. However, unexpected expressions of those markers often exist, which causes this diagnostic dilemma to be still unresolved. In this study, we investigate five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34betaE12) to evaluate their potential use in distinguishing between these two gynecologic malignancies. METHODS: A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. Utilizing the avidin-biotin (ABC) technique, tissue array sections were immunostained with the five aforementioned commercially available antibodies. RESULTS: Immunohistochemical (IHC) expressions of p53, TTF1, CK7, CK20, and CK34betaE12 were all nonsignificant (P>0.05) in frequency differences between the immunostaining results (positive vs. negative) in tumors from both the two primary adenocarcinomas (ECA vs. EMA). CONCLUSION: It is still uncertain which markers or panels would be the most appropriate for making diagnoses; hence, exploration of other useful markers, which make a definitive distinction between ECA and EMA merits further studies. This study, however, uncovered that the five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34betaE12) are of no beneficial value in distinguishing between primary ECA and EMA. PMID- 19444462 TI - Isotretinoin exposure and pregnancy outcome: an observational study of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. AB - OBJECTIVE: Apart from thalidomide, retinoids like isotretinoin are the strongest teratogens in humans known today. The overall risk of birth defects is estimated as up to 30% after exposure during embryogenesis. In spite of well established pregnancy prevention programs, pregnancies still occur during isotretinoin therapy in many countries including Germany. A detailed investigation of the incidence and outcome of these pregnancies would fill an important gap. METHODOLOGY: The Berlin Institute for Clinical Teratology documents prospectively the course of drug-exposed pregnancies when contacted for individual drug risk assessment. Datasets of isotretinoin exposed pregnancies recorded between 1993 and 2008 were evaluated as to the outcome of pregnancy. RESULTS: A total of 108 pregnancies exposed to systemic isotretinoin (median dosage 20 mg/day) during the contraindicated period were registered. 76% (69/91) of the pregnancies with known outcome were electively terminated-mainly for fear of medication risk. No terminations due to abnormal prenatal ultrasound findings were reported. Spontaneous abortions occurred in five pregnancies. Of 18 live births including 1 pair of twins 1 major birth defect (small ventricular septal defect) was observed. None of the infants showed symptoms of retinoid embryopathy. 70% (48/69) of the patients with data on contraception did not use any method, in 30% contraception failed. There was no evidence that poor maternal education was a major cause for the omission of contraception documented in 48 women. CONCLUSION: Inadvertent isotretinoin exposure during the first 2 weeks post conception does not necessarily require discussion of termination of pregnancy, as the risk of major birth defects appears to be much lower than it becomes beyond this period. Nevertheless, additional efforts are required to improve the effectiveness of contraception while on isotretinoin treatment considering psycho-social aspects such as improved self-confidence, unexpected new partnership and sexual activity and incorrect perception of infertility. PMID- 19444463 TI - Cerebrospinal fluid pressure and glaucomatous optic disc cupping. PMID- 19444464 TI - Defense-related gene expression and enzyme activities in transgenic cotton plants expressing an endochitinase gene from Trichoderma virens in response to interaction with Rhizoctonia solani. AB - There are many reports on obtaining disease-resistance trait in plants by overexpressing genes from diverse organisms that encode chitinolytic enzymes. Current study represents an attempt to dissect the mechanism underlying the resistance to Rhizoctonia solani in cotton plants expressing an endochitinase gene from Trichoderma virens. Several assays were developed that provided a powerful demonstration of the disease protection obtained in the transgenic cotton plants. Transgene-dependent endochitinase activity was confirmed in various tissues and in the medium surrounding the roots of transformants. Biochemical and molecular analyses conducted on the transgenic plants showed rapid/greater induction of ROS, expression of several defense-related genes, and activation of some PR enzymes and the terpenoid pathway. Interestingly, even in the absence of a challenge from the pathogen, the basal activities of some of the defense-related genes and enzymes were higher in the endochitinase-expressing cotton plants. This elevated defensive state of the transformants may act synergistically with the potent, transgene-encoded endochitinase activity to confer a strong resistance to R. solani infection. PMID- 19444465 TI - Nuclear thymidylate synthase expression in sporadic colorectal cancer depends on the site of the tumor. AB - Colorectal carcinoma (CRC) is a heterogeneous disease with specific epidemiological, pathological, molecular, and clinical characteristics that depend on the location of the tumor relative to the splenic flexure. Thymidylate synthase (TS) is a major target of 5-fluorouracil-based chemotherapy for CRC and high expression of this enzyme in tumor cells can influence the effect of therapy. We examined differences in TS protein expression in nuclei of tumor cells between CRCs located proximal and distal to the splenic flexure. Nuclear TS was detected by immunohistochemistry with a TS 106 monoclonal antibody on tissue microarrays constructed from 269 CRCs. The median histological score of nuclear TS expression of all proximal tumors was two times higher (p = 0.0003) and in men three times higher (p = 0.00023) than that found in distal tumors. In multivariate analysis which included age, sex, Astler-Coller stage, histological grade, and site, only proximal location of the tumor was identified as an independent factor associated with higher TS expression (odds ratio 2.46, 95% confidence interval = 1.29-4.70, p = 0.0062). These results demonstrate significant differences in nuclear TS expression between proximal and distal cancers and suggest the potential importance of the site of the tumor for proper stratification of patients for chemotherapy. PMID- 19444466 TI - APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations. AB - INTRODUCTION: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease caused by mutations in the adenomatous polyposis coli (APC) gene. Massive formation of colorectal adenomas, of which some will inevitably develop into adenocarcinomas, is the hallmark of the disease. Characterization of causative APC mutations allows presymptomatic diagnosis, close follow-up and prophylactic intervention in families. To date more than 900 different germline mutations have been characterized worldwide demonstrating allelic heterogeneity. PURPOSE: The germline mutation spectrum of APC identified in 69 apparently unrelated Norwegian FAP families are presented and discussed with reference to clinical phenotype and novel mutation rate. METHODS: Different methods have been used over the years. However, all mutations were confirmed detectable by an implemented denaturing high-performance liquid chromatography screening approach. Multiplex ligation-dependent probe amplification analysis was employed for potential gross rearrangements. RESULTS: Fifty-three distinctive mutations were detected, of which 22 have been detected in Norway exclusively. Except for two major deletion mutations encompassing the entire APC, all mutations resulted in premature truncation of translation caused by non-sense (31%) or change in reading frame (69%). CONCLUSION: A high ratio of novel APC mutations continues to contribute to APC mutation heterogeneity causing FAP. This is the first comprehensive report of APC germline mutation spectrum in Norway. PMID- 19444467 TI - Differentially expressed genes between female and male adult Anopheles anthropophagus. AB - The aim of the present study was to identify sex-specific genes in adult Anopheles anthropophagus. As the major malaria vector and Brugia malayi vector in the Asian continent, female Anopheles mosquitoes take blood meals and transmit pathogens through this pathway, while males are nectar feeders. This complex behavior is controlled at several levels, but is probably initiated by the genetic background difference between these two groups. In our study, a subtractive cDNA library for female A. anthropophagus was constructed using the suppression subtractive hybridization (SSH) technique and then 3,074 clones from the female SSH library were analyzed using a microarray-based survey. Genes that were expressed differentially according to sex in A. anthropophagus were screened using real-time polymerase chain reaction and reverse transcription polymerase chain reaction. In our results, we report a series of genes which may be involved in female-specific mosquito behavior, including an inorganic phosphate transporter, a serine protease, the salivary protein GP35-2, and the D7 cluster salivary protein. These findings will provide clues to the nature of insect vectors and open up unprecedented opportunities to develop novel strategies for the control of mosquito-borne diseases. PMID- 19444468 TI - Flubendazole and ivermectin in vitro combination therapy produces a marked effect on Echinococcus granulosus protoscoleces and metacestodes. AB - The aim of the present work was to evaluate the in vitro efficacy of the flubendazole (FLBZ) and ivermectin (IVM) combination against Echinococcus granulosus protoscoleces and metacestodes. Protoscoleces and groups of ten peritoneal cysts obtained from BALB/c mice were incubated with the two drugs, either separately or in combination, at the following final concentrations: 10 microg/mL FLBZ, 1 microg/mL FLBZ, 1 microg/mL IVM, 10 microg/mL FLBZ + 1 microg/mL IVM, and 1 microg/mL FLBZ + 1 microg/mL IVM. The maximum protoscolicidal effect was found with the combination 10 microg/mL FLBZ + 1 microg/mL IMV. After 1 day of incubation, the presence of numerous blebs in the tegument of protoscoleces was observed. Ultrastructural studies revealed that the primary site of damage was the tegument of the parasite. The effect of the two drugs on hydatid cysts obtained from mice was more rapidly detected in cysts treated with the combination of FLBZ + IVM than when drugs were used separately. Ultrastructural studies revealed that the germinal layer of treated cysts lost the multicellular structure feature and underwent considerable degenerative changes after in vitro treatment. The outcomes obtained demonstrated the favorable effect of the combination of FLBZ and IVM against E. granulosus. PMID- 19444469 TI - A case of Diphyllobothrium nihonkaiense infection possibly linked to salmon consumption in New Zealand. AB - Global increases in salmon consumption and changes in fish-eating habits have meant that Diphyllobothrium infections now occur in regions where they were previously absent. In the present paper, a case of diphyllobothriasis through the likely ingestion of raw salmon in New Zealand in a Japanese patient is reported. The causative tapeworm species was identified as Diphyllobothrium nihonkaiense based on mitochondrial DNA analysis of proglottid expelled from the patient. PMID- 19444470 TI - Isolation of a Latimeria menadoensis heat shock protein 70 (Lmhsp70) that has all the features of an inducible gene and encodes a functional molecular chaperone. AB - Molecular chaperones facilitate the correct folding of other proteins, and heat shock proteins form one of the major classes of molecular chaperones. Heat shock protein 70 (Hsp70) has been extensively studied, and shown to be critically important for cellular protein homeostasis in almost all prokaryotic and eukaryotic systems studied to date. Since there have been very limited studies conducted on coelacanth chaperones, the main objective of this study was to genetically and biochemically characterize a coelacanth Hsp70. We have successfully isolated an Indonesian coelacanth (L. menadoensis) hsp70 gene, Lmhsp70, and found that it contained an intronless coding region and a potential upstream regulatory region. Lmhsp70 encoded a typical Hsp70 based on conserved structural and functional features, and the predicted upstream regulatory region was found to contain six potential promoter elements, and three potential heat shock elements (HSEs). The intronless nature of the coding region and the presence of HSEs suggested that Lmhsp70 was stress-inducible. Phylogenetic analyses provided further evidence that Lmhsp70 was probably inducible, and that it branched as a clade intermediate between bony fish and tetrapods. Recombinant LmHsp70 was successfully overproduced, purified and found to be functional using ATPase activity assays. Taken together, these data provide evidence for the first time that the coelacanth encodes a functional molecular chaperone system. PMID- 19444472 TI - Dynamics of cell proliferation and apoptosis reflect different life strategies in hydrothermal vent and cold seep vestimentiferan tubeworms. AB - Deep-sea vestimentiferan tubeworms, which live in symbiosis with bacteria, exhibit different life strategies according to their habitat. At unstable and relatively short-lived hydrothermal vents, they grow extremely fast, whereas their close relatives at stable and long-persisting cold seeps grow slowly and live up to 300 years. Growth and age differences are thought to occur because of ecological and physiological adaptations. However, the underlying mechanisms of cell proliferation and death, which are closely linked to homeostasis, growth, and longevity, are unknown. Here, we show by immunohistochemical and ultrastructural cell cycle analyses that cell proliferation activities of the two species studied are higher than in any other characterized invertebrate, being only comparable with tumor and wound-healing processes. The slow growth in Lamellibrachia luymesi from cold seeps results from balanced activities of proliferation and apoptosis in the epidermis. In contrast, Riftia pachyptila from hydrothermal vents grows fast because apoptosis is down-regulated in this tissue. The symbiont-housing organ, the trophosome, exhibits a complex cell cycle and terminal differentiation pattern in both species, and growth is regulated by proliferation. These mechanisms have similarities to the up- and down-regulation of proliferation or apoptosis in various types of tumor, although they occur in healthy animals in this study, thus providing significant insights into the underlying mechanisms of growth and longevity. PMID- 19444471 TI - Evidence that TGFA influences risk to cleft lip with/without cleft palate through unconventional genetic mechanisms. AB - This study examined the association between markers in transforming growth factor alpha (TGFA) and isolated, non-syndromic cleft lip with/without palate (CL/P) using a case-parent trio design, considering parent-of-origin effects. We also tested for gene-environmental interaction with common maternal exposures, and for gene-gene interaction using markers in TGFA and another recognized causal gene, IRF6. CL/P case-parent trios from four populations (76 from Maryland, 146 from Taiwan, 35 from Singapore, and 40 from Korea) were genotyped for 17 single nucleotide polymorphisms (SNPs) in TGFA. The transmission disequilibrium test was used to test individual SNPs, and the parent-of-origin likelihood ratio test (PO LRT) was used to assess parent-of-origin effects. We also screened for possible gene-environment interaction using PBAT, and tested for gene-gene interaction using conditional logistic regression models. When all trios were combined, four SNPs showed significant excess maternal transmission, two of which gave significant PO-LRT values [rs3821261: P = 0.004 and OR(imprinting) = 4.17; and rs3771475: P = 0.027 and OR(imprinting) = 2.44]. Haplotype analysis of these two SNPS also supported excess maternal transmission. We saw intriguing but suggestive evidence of G x E interaction for several SNPs in TGFA when either individual SNPs or haplotypes of adjacent SNPs were considered. Thus, TGFA appears to influence risk of CL/P through unconventional means with an apparent parent-of-origin effect (excess maternal transmission) and possible interaction with maternal exposures. PMID- 19444473 TI - Early identification of inner pillar cells during rat cochlear development. AB - Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Here, we examine its spatio-temporal development in rats from embryonic day 16 (E16) to E19 by using cytochemical and immunocytochemical methods at the light- and electron-microscope levels. We demonstrate that the organ of Corti develops from a non-proliferating cell zone that is located in the junctional region between two edges of the dorsal epithelium of the cochlear duct. We also reveal that the first cells to develop in this zone are the inner pillar cells, a particular type of non-sensory supporting cell, which arise in the base of the cochlear duct at the boundary between the two ridges at E16. Cell differentiation in this prosensory region continues according to a base-to-apex gradient; the inner hair cells appear in the greater epithelial ridge at E17 and the outer hair cells in the lesser epithelial ridge at E18. At E19, the various cell types of the organ of Corti are in place. Finally, we show that unlike the development of all the supporting cell types of the organ of Corti, the development of inner pillar cells within the prosensory domain seems not to involve Notch1 activation. These results highlight the central role that the inner pillar cells probably play in the development of the organ of Corti. PMID- 19444474 TI - Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase. AB - Etoposide is a chemotherapeutic agent that induces cell death by blocking topoisomerase II catalytic function. Although etoposide is effective in the treatment of cancer, it also causes the death of normal proliferating cells, including male germ cells. Administration of etoposide during the prepubertal phase causes diturbances in several testicular morphometric parameters and in Sertoli cells. Cytoprotection of the seminiferous epithelium is the only means of preserving potential male reproduction in prepubertal cancer patients. Carnitine, an amino acid naturally present in normal cells, is a promising cryoprotectant as it is concentrated in the epididymis and promotes sperm maturation. We have therefore investigated whether carnitine protects rat testes against etoposide and, thus, improves fertility in adulthood. Our results suggest that carnitine partially protects the testis against damage caused by etoposide, although the mechanism by which it happens remains unknown. PMID- 19444475 TI - Herbivory and population dynamics of invasive and native Lespedeza. AB - Some exotic plants are able to invade habitats and attain higher fitness than native species, even when the native species are closely related. One explanation for successful plant invasion is that exotic invasive plant species receive less herbivory or other enemy damage than native species, and this allows them to achieve rapid population growth. Despite many studies comparing herbivory and fitness of native and invasive congeners, none have quantified population growth rates. Here, we examined the contribution of herbivory to the population dynamics of the invasive species, Lespedeza cuneata, and its native congener, L. virginica, using an herbivory reduction experiment. We found that invasive L. cuneata experienced less herbivory than L. virginica. Further, in ambient conditions, the population growth rate of L. cuneata (lambda = 20.4) was dramatically larger than L. virginica (lambda = 1.7). Reducing herbivory significantly increased fitness of only the largest L. virginica plants, and this resulted in a small but significant increase in its population growth rate. Elasticity analysis showed that the growth rate of these species is most sensitive to changes in the seed production of small plants, a vital rate that is relatively unaffected by herbivory. In all, these species show dramatic differences in their population growth rates, and only 2% of that difference can be explained by their differences in herbivory incidence. Our results demonstrate that to understand the importance of consumers in explaining the relative success of invasive and native species, studies must determine how consumer effects on fitness components translate into population-level consequences. PMID- 19444477 TI - Urinary tract infections: to prophylaxis or not to prophylaxis? AB - Urinary tract infections, with or without reflux, are the most frequent reason for long-term antibacterial prophylaxis in infants and children. When one is considering the use of prophylaxis in these children, what is clear from existing published data? Up to 2006 there were a small number of poor quality studies, with no reliable evidence of the effectiveness of antibiotics in preventing recurrent symptomatic urinary tract infections (UTIs). Since then, four randomised controlled studies, to assess the benefits, or lack thereof, of antibiotic prophylaxis, have been published. None has demonstrated a clear benefit. The following conclusions can be drawn: antibiotic prophylaxis is not indicated for children following a first febrile UTI if no or mild grade I or II reflux is present; for higher grade reflux there is no definite conclusion. PMID- 19444478 TI - Retarded hand growth due to a hemodialysis fistula in a young girl. AB - Long-term presence of an arteriovenous hemodialysis fistula (AVF) may lead to alterations in hand perfusion. In the case reported here, a 14-year-old girl developed pain associated with hand ischemia 5 years after a successful kidney transplantation. At age 8 years, she required a period of hemodialysis using an autogenous left upper arm AVF. Compared to the healthy right hand, a smaller ischemic left hand was observed in the presence of a patent AVF. Access flow was 1400 ml/min. Seldinger angiography demonstrated a stenotic brachial artery, and duplex measurements indicated a reversed blood flow in the radial artery. AVF ligation abolished the ischemic symptoms. Distal hypotension due to an impaired arterial inflow combined with a low resistance elbow AVF may result in chronic hypoperfusion of acral portions of the extremity and growth retardation. Access ligation is advised in children with an optimal renal transplant function and a patent elbow AVF suffering from lowered distal tissue perfusion. PMID- 19444479 TI - Changes in behavior as an early symptom of renovascular hypertension in children. AB - Renovascular hypertension in children is usually asymptomatic and diagnosed incidentally. Behavioral changes have not yet been well recognized as a part of the clinical spectrum of renovascular disease in children. We surveyed all children diagnosed with renovascular hypertension in our institute over a 15-year period. Eleven children were identified, of whom five (45%) had abnormal behavior, which had preceded the diagnosis of hypertension by 3-12 months. The symptoms included restlessness, sleep disturbances, temper tantrums, hyperactivity, aggressive behavior and attention deficit. In three children all behavioral symptoms disappeared following blood pressure normalization, and, in the other two a significant improvement was noted. It was concluded that behavioral symptoms may be a common and early manifestation of renovascular hypertension. Awareness of this association may bring about earlier diagnosis of the disease and prevent end-organ damage as well as unnecessary investigations for behavioral abnormalities. PMID- 19444481 TI - Imaging studies for first urinary tract infection in infants less than 6 months old: can they be more selective? AB - This retrospective study aimed to evaluate the applicability of the selective approach of imaging infants < 6 months old with urinary tract infection (UTI) according to the UTI guidelines of the National Institute for Health and Clinical Excellence (NICE) 2007. Infants < 6 months old with their first UTI from January 2001 to December 2006 having undergone an ultrasound examination of the urinary tract, a micturating cystourethrogram, and a late di-mercaptosuccinic acid (DMSA) scan, were included. Their condition was evaluated against a set of risk features according to the UTI guidelines. Those having any one of these were classified as atypical and those having none as typical. There were 134 infants reviewed, with a typical (98 infants) to atypical (36 infants) ratio of 2.7 to 1. Girls were found to be relatively more represented in the atypical group [male (M):female (F) = 1.3:1] than in the typical group (M:F = 4.4:1) (P < 0.004). There were significantly more infants with abnormal micturating voiding cystourethrograms (MCUGs) (P = 0.007), more refluxing ureters (P < 0.001) and more significant vesico-ureteral reflux (VUR) (>/= grade III) (P = 0.013) in the atypical group than in the typical group; while there was no significant difference in ultrasound (US) and DMSA scan findings between the two groups. In the atypical group there was no difference in imaging studies (and, thus, the results) between the conventional practice and the NICE UTI recommendation. In the typical group, if the recommendations of the guidelines had been followed (i.e. only those with abnormal US would have been further investigated), 25 refluxing ureters and 22 scarred kidneys would have been left undiagnosed. In conclusion, application of the suggested selective imaging approach would leave a significant number of VUR and renal scars undiagnosed, and it may not be an optimal practice for infants less than 6 months old with their first UTI. The best approach remains to be clarified. PMID- 19444480 TI - Contrast-induced nephropathy: pathogenesis and prevention. AB - Contrast-induced nephropathy (CIN) is the third most common cause of acute kidney injury in hospitalized patients. Diagnostic and interventional cardiovascular procedures generate nearly half the cases. Elderly patients and those with chronic kidney disease, diabetes, and cardiovascular disease are at greatest risk. Procedure-related risk factors include large volumes of contrast and agents with a high osmolality. Renal medullary ischemia arising from an imbalance of local vasoconstrictive and vasodilatory influences coupled with increased demand for oxygen-driven sodium transport may be the key to its pathogenesis. Contrast agents may also have a direct cytotoxic effect that operates through the generation of reactive oxygen species. Pre- and post-procedure administration of normal saline, isotonic sodium bicarbonate, N-acetylcysteine, and a variety of other pharmacologic agents have been used to prevent or mitigate CIN. While normal saline is generally accepted as protective against CIN, uncertainty still surrounds the role of sodium bicarbonate and N-acetylcysteine. Dialytic therapies before, during, and after exposure to contrast have been tested with mixed results. Logistical and economic disincentives argue against these modalities. PMID- 19444483 TI - Vitamin A responsive night blindness in Dent's disease. AB - Dent's disease is an X-linked renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis or nephrolithiasis. The disease is caused by mutations in a renal chloride channel gene, CLCN5. We report on three boys, of Indian origin, with Dent's disease that presented at an early age (1-4 years), with polyuria, polydipsia, salt craving, recurrent vitamin A-responsive night blindness, hypophosphataemic rickets, hypercalciuria and low molecular weight proteinuria. All these patients were found to have novel mutations in the CLCN5 gene. PMID- 19444482 TI - Inappropriate left ventricular mass in children and young adults with chronic renal insufficiency. AB - Increased left ventricular (LV) mass (M) in children with chronic renal insufficiency (CRI) might represent an adaptive mechanism to compensate for increased workload. We hypothesized that in children with CRI, pre-dialysis, values of left ventricular mass (LVM) exceed compensatory values for individual cardiac load. Complete anthropometric characteristics, biochemical profile and echocardiograms were obtained for 33 children with CRI, pre-dialysis (age 1-23 years, mean 12.2 +/- 5.0 years), and 33 age- and gender-matched healthy controls. LV dimensions, wall thicknesses and volume were measured. Endocardial and midwall shortening, ejection fraction, LVM, LVM index, relative wall thickness, circumferential wall stress and excess LVM (as ratio of observed LVM to value predicted from body size, gender and cardiac workload) were analysed. Patients with CRI showed higher values of LVM index, resulting in higher prevalence of LV hypertrophy (36.3% vs 9%, P < 0.05). The ratio of excess LVM was greater in patients with CRI than in healthy controls (126 +/- 19% and 103 +/- 13%, respectively, P < 0.001). LV ejection fraction, midwall fractional shortening and stress-corrected midwall shortening were lower in patients with CRI than in controls. We concluded that, in children with CRI, the values of LVM are higher than those needed to sustain individual cardiac load than in healthy controls, a condition associated with LV hypertrophy and reduced systolic performance. PMID- 19444484 TI - Fluid and electrolyte therapy: a primer. AB - The prescription of fluid therapy in pediatrics is a common clinical event. The foundations that underpin such therapy should be understood by all clinicians involved in the short-term care of children. This article describes some important basic principles of fluid management. PMID- 19444485 TI - Array-CGH in unclear syndromic nephropathies identifies a microdeletion in Xq22.3 q23. AB - To investigate whether submicroscopic chromosomal deletions or duplications can be causative of unclear syndromic nephropathies, we analyzed ten patients with congenital abnormalities of the kidney and urinary tract or glomerulopathies combined with important extrarenal anomalies by whole-genome array-based comparative genomic hybridization. In a 14-year-old girl presenting with hematuria, proteinuria, mental retardation (MR), sensorineural hearing loss, dysmorphisms, and epilepsy, we detected a microdeletion in chromosome Xq22.3-q23. This deletion was verified and characterized by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analyses, found to be de novo, uniallelic and 3.3 Mb in size. Electron microscopy of a kidney biopsy showed glomerular basement membrane thinning and segmental splitting of the lamina densa compatible with Alport syndrome. Cranial magnetic resonance and diffusion tensor imaging detected a severe neuronal migration disorder with double cortex formation and pronounced reduction of the fronto occipital tract system. Thus, in one of ten patients with unclear syndromic nephropathies we identified a previously undescribed contiguous gene syndrome at Xq22.3-q23. The microdeletion contains the X-linked Alport syndrome gene COL4A5, the MR genes FACL4 and PAK3, and parts of the X-chromosomal lissencephaly gene DCX associated with double cortex formation in girls, MR, and epilepsy. The phenotype in our patient combines features of the Alport-MR contiguous gene syndrome with lissencephaly. PMID- 19444486 TI - Left ventricular mass in normotensive, prehypertensive and hypertensive children and adolescents. AB - The purpose of this study was to investigate differences in left ventricular mass index (LVMI) and the prevalence of left ventricular hypertrophy (LVH) in children and adolescents classified as normotensives, prehypertensives and hypertensives by ambulatory blood pressure (BP) levels. A total of 124 consecutive children and adolescents aged 5 to 18 years were analysed. Patients underwent 24 h ambulatory blood pressure monitoring (ABPM) and echocardiography. Hypertensive and prehypertensive subjects had significantly higher LVMI than normotensives (36.8 +/- 8.4 g/m(2.7) and 34.1 +/- 3.4 g/m(2.7) vs. 29.5 +/- 8.3 g/m(2.7), P < 0.01 and P < 0.05, respectively). In multivariate analysis predictors for LVMI were body mass index (BMI) z score and hypertension (R-squared = 0.31). LVMI values in hypertensive subjects were significantly higher than those of normotensives even after adjustment for age, sex and BMI z score. The prevalence of LVH was significantly higher in the prehypertensive compared to normotensive subjects, and was equal to that of the hypertensive subjects. Hypertension and prehypertension in children and adolescents were associated with pathologically elevated LVMI values. If confirmed in a larger group prehypertensive children may be at risk for target organ damage similar to the condition of established hypertension. PMID- 19444487 TI - Duration of vitamin D synthesis from weather model data for use in prospective epidemiological studies. AB - In order to investigate the influence of solar radiation on vitamin D status and its association with different health outcomes in population based studies, appropriate estimates of the subjects' UV radiation exposure are needed. This unique study describes a method that estimates the daily number of vitamin D effective hours (VD-hours) at arbitrary ground locations throughout the period 1957-2002. The method is particularly suited for large-scale prospective epidemiological studies with questionnaire-based information on sun exposure, and where blood measures of vitamin D status are not available. The model takes total cloud cover fraction and total ozone column at noon as input from the ERA-40 data series (i.e. the 40 + year European Centre for Medium-Range Weather Forecasts Re Analysis archive). By comparing the model results against high accuracy measurements at two different locations in Norway, we found the method for estimating the number of VD-hours to be accurate within 2.5 +/- 7% or better for moderate solar zenith angles (< 65 degrees). For higher solar zenith angles (> 65 degrees) the results are more variable, but the contribution to a population's vitamin D level from solar radiation when the sun is this low in the sky is rather small. The program code to compute VD-hours from ERA-40 files is written in Perl (v 5.8.7) and may be obtained free of charge by contacting corresponding author. PMID- 19444488 TI - Differential growth response to arbuscular mycorrhizal fungi and plant density in two wild plants belonging to contrasting functional types. AB - The effect of arbuscular mycorrhizal fungi (AMF) on plant growth was examined in two wild plant species belonging to contrasting functional types: an annual forb (Bidens pilosa, Asteraceae) and a deciduous shrub (Acacia caven, Fabaceae) at three contrasting plant densities (one, two, and three individuals per pot). AMF had a slightly negative effect on B. pilosa when the species grew in isolation while they positively affected A. caven. Positive effects of AMF on shoot mass of A. caven decreased at higher plant densities, while shoot mass of individuals of B. pilosa showed less marked differences between plant densities. When considering total biomass per pot, AMF positively affected A. caven growth while negatively affecting B. pilosa, at all three plant densities. Root/shoot ratio per pot was negatively affected by AMF but not plant density in both species. These findings highlight the importance of including plants belonging to different life forms and/or traits in research regarding the interaction between AMF and intraspecific plant competition. PMID- 19444489 TI - Isolation and sequence analysis of a beta-tubulin gene from arbuscular mycorrhizal fungi. AB - A full-length beta-tubulin gene has been cloned and sequenced from Gigaspora gigantea and Glomus clarum, two arbuscular mycorrhizal fungi (AMF) species in the phylum Glomeromyota. The gene in both species is organized into five exons and four introns. Both genes are 94.9% similar and encode a 447 amino acid protein. In comparison with other fungal groups, the amino acid sequence is most similar to that of fungi in the Chytridiomycota. The codon usage of the gene in both AMF species is broad and biased in favor of an A or a T in the third position. The four introns varied in length from 87 to 168 bp for G. gigantea and from 90 to 136 bp for G. clarum. Of all fungi in which full-length sequences have been published, only AMF do not have an intron before codon 174. The introns positioned at codons 174 and 257 in AMF match the position of different introns in beta-tubulin genes of some Zygomycete, Basidiomycete, and Ascomycete fungi. The 5' and 3' splice site consensus sequences are similar to those found in introns of most fungi. Sequence analysis from single-strand conformation polymorphism analysis confirmed the presence of two beta-tubulin gene copies in G. clarum, but only one copy was evident in G. gigantea based on Southern hybridization analysis. PMID- 19444490 TI - Long-term results of pediculo-body fixation and posterolateral fusion for lumbar spondylolisthesis. AB - Grob et al. (Eur Spine J 5:281-285, 1996) illustrated a new fixation technique in inveterate cases of grade 2-3 spondylolisthesis (degenerative or spondylolytic): a fusion without reduction of the spondylolisthesis. Fixation of the segment was achieved by two cancellous bone screws inserted bilaterally through the pedicles of the lower vertebra into the body of the upper slipped vertebra. Since 1998 we have been using this technique according to the authors' indications: symptomatic spondylolisthesis with at least 25% anterior slippage and advanced disc degeneration. Afterwards this technique was used also in spondylolisthesis with low reduction of the disc height and slippage less than 25%. In every case we performed postero-lateral fusion and fixation with two AO 6.5 O thread 16 mm cancellous screws. From 1998 to 2002 we performed 62 fusions for spondylolisthesis with this technique: 28 males (45.16%) and 34 females (54.84%), mean age 45 years (14-72 years). The slipped vertebra was L5 in 57 cases (92%), L4 in 2 cases (3.2%), L3 in 1 case (1.6%), combined L4 and L5 in 2 cases (3.2%). In all cases there was an ontogenetic spondylolisthesis with lysis. Lumbar pain was present in 22 patients and lumbar-radicular pain was present in 40 patients. The mean preoperative VAS was 6.2 (range 5-8) for lumbar pain, and 5.5 (range 4 7) for leg pain. The fusion area was L5-S1 in 53 cases (85.5%), L3-L4 in 1 case (1.6%), L4-S1 in 8 cases (12.9%). A decompression of the spinal canal by laminectomy was performed in 33 procedures (53%). When possible a bone graft was done from the removed neural arc, and from the posterior iliac crest in the other cases. The mean blood loss was about 254 ml (100-1,000). The mean operative time was 75 min (range 60-90). The results obtained by computerized analysis at follow up at least 5 years after surgery showed a significant improvement in preoperative symptoms. The patients were asymptomatic in 52 cases (83.9%); strained-back pain was present in 8 cases (12.9%), and there was persistent lumbar-radicular pain in 2 cases (3.2%). The mean ODI score was 2.6%, the mean VAS back pain was 1.3, the mean VAS leg pain 0.7. Some complications were observed: a nerve root compression by a screw invasion of intervertebral foramen, resolved by screw removal; an iliac artery compression by a lateral exit screw from pediculo, resolved by screw removal; a deep iliac vein phlebitis with thrombosis caused by external compression due to a wrong intraoperative position, treated by medicine. Two cases of synthesis mobilization and two cases of broken screws was detected. No cases of pseudoarthrosis and immediate or late superficial or deep infection were observed. The analysis of the long-term results of the spondylolisthesis surgical treatment with direct pediculo-body screw fixation and postero-lateral fusion gave a very satisfactory response. The technique is reliable in allowing an optimal primary stability, creating the best biomechanical conditions to obtain a solid fusion. PMID- 19444491 TI - Dual-rhodamine urea derivative, a novel chemidosimeter for Hg(II) and its application in imaging Hg(II) in living cells. AB - The synthesis and spectral properties of a chemidosimeter 1,4-di[2-(6-ethylamino 3-ethylimino-2,7-dimethyl-3H-xanthen-9-yl) benzoic acid (aminomethyl)-3 phenylthiourea] benzene (1) for Hg(II) ions are reported, and it has been demonstrated that 1 can be used as a fluorescent probe for monitoring Hg(II) ions in living cells. PMID- 19444492 TI - Detection of Salmonella enterica serovar Typhimurium with pUO-StVR2-like virulence-resistance hybrid plasmids in the United Kingdom. AB - The aim of this study was to investigate the presence in the United Kingdom (UK) of Salmonella enterica serovar Typhimurium isolates carrying pUO-StVR2-like virulence-resistance hybrid plasmids that originated from pSLT. One hundred and fifty ampicillin-resistant isolates of S. Typhimurium, collected in different regions of the UK during 2006, were screened for the presence of bla (OXA-1) carried by an InH-like integron (2000 bp/bla (OXA-1)-aadA1) characteristic of pUO StVR2. Positive isolates were tested for the presence of a large plasmid that hybridised with probes specific for the bla (OXA-1) and spvC genes, used as resistance and virulence markers of the hybrid plasmid, respectively. Eleven out of the 150 isolates fulfilled both criteria and were assigned to the S. Typhimurium pUO-StVR2 group. Nine were resistant to ampicillin, chloramphenicol, streptomycin/spectinomycin, sulfonamides and tetracycline, encoded by bla (OXA 1), catA1, aadA1-like, sul1 and tet(B), respectively, and carried a pUO-StVR2 like plasmid of ca. 130 kb. Two contained hybrid plasmids of smaller size and lacked resistance(s) to chloramphenicol or chloramphenicol and tetracycline. The eleven isolates, which showed five and six closely related XbaI and BlnI profiles, respectively, were resistant to nitrofurantoin. In conclusion, multidrug-resistant S. Typhimurium isolates of the pUO-StVR2 group, which are endemic in Spain, were also detected in the UK, albeit with a low frequency (7.3%). PMID- 19444493 TI - Morbidity and mortality associated with influenza exposure in long-term care facilities for dependent elderly people. AB - The purpose of this paper is to describe the impact of exposure to influenza on hospitalizations and deaths in the elderly residents of long-term care facilities (LTCFs). An observational, longitudinal, prospective, multicenter, cohort study collected influenza and influenza-like cases, diseases, hospitalizations, and deaths of dependent elderly residents of French LTCFs during the 2004-2005 seasonal influenza epidemic. A total of 8,041 residents of 98 participating LTCFs were included. The mean age was 85 +/- 9 years; 93% were vaccinated against influenza and 64% of the residents were exposed to influenza during the epidemic. Exposure to influenza increased both the all-cause risk of hospitalization (9.2% of the residents exposed vs. 7.4% of the residents not exposed) (relative risk, RR [95% confidence interval, CI] = 1.24 [1.05; 1.47]) and the all-cause risk of death (5.8% vs. 4.3%) (RR [95% CI] = 1.36 [1.10; 1.70]). Exposure to influenza increased the risks of death and hospitalization. Additional measures should be taken to avoid influenza exposure and apply recommendations more thoroughly in the particularly susceptible population of elderly LTCF residents. PMID- 19444494 TI - Musculoskeletal: what is different in children? Pushed into ditch; left forearm pain. PMID- 19444495 TI - Impact of microarousal associated with increased negative esophageal pressure in sleep-disordered breathing. AB - PURPOSE: "Microarousals" during sleep have not been analyzed systematically. We investigated the importance of "microarousals" (lasting 1.5-3 s). METHODS: Standard polysomnography including esophageal pressure (Pes) assessment was performed on ten patients (aged 54.0 +/- 5.0 years) with respiratory effort related arousal > or =5/h. We measured the number of arousals per hour (American Sleep Disorders Association (ASDA) arousal index) and the number of microarousals lasting 1.5-3 s per hour (mASDA arousal index). On the night after the baseline sleep study, we performed overnight continuous positive airway pressure (CPAP) titration. RESULTS: mASDA arousals, characterized by lower Pes values, were observed more frequently in patients with sleep-disordered breathing. The Pes results did not differ significantly between ASDA and mASDA arousals (-15.6 +/- 5.0 vs -15.0 +/- -4.4 cmH(2)O). mASDA arousals were significantly improved by CPAP treatment (mASDA arousals, 82.6 +/- 60.1 vs 6.0 +/- 1.4/h). CONCLUSIONS: mASDA arousals were characterized by an increase in Pes. mASDA arousals are thus key to our understanding of clinical manifestations in patients with sleep disordered breathing. PMID- 19444496 TI - Genetic diversity of eukaryotic plankton assemblages in Eastern Tibetan Lakes differing by their salinity and altitude. AB - Eukaryotic plankton assemblages in 11 high-mountain lakes located at altitudes of 2,817 to 5,134 m and over a total area of ca. one million square kilometers on the Eastern Tibet Plateau, spanning a salinity gradient from 0.2 (freshwater) to 187.1 g l(-1) (hypersaline), were investigated by cultivation independent methods. Two 18S rRNA gene-based fingerprint approaches, i.e., the terminal restriction fragment length polymorphism and denaturing gradient gel electrophoresis (DGGE) with subsequent band sequencing were applied. Samples of the same lake type (e.g., freshwater) generally shared more of the same bands or T-RFs than samples of different types (e.g., freshwater versus saline). However, a certain number of bands or T-RFs among the samples within each lake were distinct, indicating the potential presence of significant genetic diversity within each lake. PCA indicated that the most significant environmental gradient among the investigated lakes was salinity. The observed molecular profiles could be further explained (17-24%) by ion percentage of chloride, carbonate and bicarbonate, and sulfate, which were also covaried with change of altitude and latitude. Sequence analysis of selected major DGGE bands revealed many sequences (largely protist) that are not related to any known cultures but to uncultured eukaryotic picoplankton and unidentified eukaryotes. One fourth of the retrieved sequences showed < or =97% similarity to the closest sequences in the GenBank. Sequences related to well-known heterotrophic nanoflagellates were not retrieved from the DGGE gels. Several groups of eukaryotic plankton, which were found worldwide and detected in low land lakes, were also detected in habitats located above 4,400 m, suggesting a cosmopolitan distribution of these phylotypes. Collectively, our study suggests that there was a high beta-diversity of eukaryotic plankton assemblages in the investigated Tibetan lakes shaped by multiple geographic and environmental factors. PMID- 19444497 TI - Influence of dissolved organic matter and invertebrates on the function of microbial films in groundwater. AB - Microbial films play a central role in mediating energy flux in groundwater ecosystems. The activity of these microbes is likely to be influenced by the availability of resources, especially dissolved organic matter (DOM), and also by consumers, such as invertebrates that feed on microbial films. We used microcosm experiments to examine how bacterial production and extracellular enzyme activity on rocks and fine sediments from cave streams responded to amendments of DOM of varying form and to cave amphipods (Gammarus minus) that feed on microbial films. Glucose and mixtures of DOM extracted from soils and leaves stimulated bacterial production on rocks by 89-166% relative to unamended controls. In contrast, tannic acid amendment did not influence production. Microbial films on fine sediment were not consistently responsive to DOM amendment. Glucose amendment led to increased activity of enzymes associated with C acquisition, but other forms of DOM generally did not alter enzyme activity. DOM amendment led to removal of nitrate and this was correlated with bacterial production, suggesting microbes can link carbon and nitrogen cycling in groundwater as is the case in surface systems. Amphipods reduced bacterial production on rocks, but not fine sediments. The reduction caused by amphipods offset the stimulatory effect of glucose amendment, but there was no interactive effect of DOM and grazing on bacterial production or enzyme activity. Both resources and consumers play important roles in regulating microbial activity in groundwater with important implications for higher trophic levels that use microbes for food. PMID- 19444498 TI - Fungi vectored by the bark beetle Ips typographus following hibernation under the bark of standing trees and in the forest litter. AB - The bark beetle Ips typographus has different hibernation environments, under the bark of standing trees or in the forest litter, which is likely to affect the beetle-associated fungal flora. We isolated fungi from beetles, standing I. typographus-attacked trees, and forest litter below the attacked trees. Fungal identification was done using cultural and molecular methods. The results of the two methods in detecting fungal species were compared. Fungal communities associated with I. typographus differed considerably depending on the hibernation environment. In addition to seven taxa of known ophiostomoid I. typographus associated fungi, we detected 18 ascomycetes and anamorphic fungi, five wood decaying basidomycetes, 11 yeasts, and four zygomycetes. Of those, 14 fungal taxa were detected exclusively from beetles that hibernated under bark, and six taxa were detected exclusively from beetles hibernating in forest litter. The spruce pathogen, Ceratocystis polonica, was detected occasionally in bark, while another spruce pathogen, Grosmannia europhioides, was detected more often from beetles hibernating under the bark as compared to litter. The identification method had a significant impact on which taxa were detected. Rapidly growing fungal taxa, e.g. Penicillium, Trichoderma, and Ophiostoma, dominated pure culture isolations; while yeasts dominated the communities detected using molecular methods. The study also demonstrated low frequencies of tree pathogenic fungi carried by I. typographus during its outbreaks and that the beetle does not require them to successfully attack and kill trees. PMID- 19444499 TI - Tumor detection and serosal invasion of bladder cancer: role of three-dimensional volumetric reconstructed US. AB - BACKGROUND: Accurate evaluation of local extent in bladder cancer is important to determine the optimal therapeutic strategy and to predict the outcome of treatment. The purpose of this study is to evaluate the accuracy of 3D volumetric reconstructed US in the assessment of tumor detection and serosal invasion in patients with bladder cancer. METHODS: A total of 14 patients with findings of bladder cancer determined with the use of cystoscopy was examined with the use of bladder two-dimensional (2D) US and subsequent 3D US. US findings were compared with cystoscopy findings and the pathological stage after a TURB or a radical cystectomy in a double-blinded manner. RESULTS: The sensitivity of preoperative tumor staging was 67.9% for 2D US and sensitivity was 78.6% for 3D US. 3D US was superior sensitivity than 2D US (P < 0.05). The accuracy for serosal invasion in staging of bladder cancer was demonstrated for 88.9% in 2D US and for 100% in 3D US. CONCLUSIONS: The accuracy for serosal invasion (T3b) in the staging of bladder cancer was demonstrated for 88.9% in 2D US and for 100% in 3D US. 3D volumetric reconstructed US is a non-invasive and accurate technique for tumor detection of bladder cancer. PMID- 19444500 TI - Endoleaks after endovascular repair of abdominal aortic aneurysm: value of CEUS. AB - Endovascular repair (EVAR) is playing an increasingly role in the treatment of abdominal aortic aneurysm. A successful procedure depends on the complete sealing of the aneurysm sac from blood flow to achieve general pressure relief and avoid aneurysm rupture, with a shrinkage of the aneurysm sac. The most common complication of EVAR is endoleak that is the persistence of perigraft flow within the aneurysm sac, which has to be considered the major cause of enlargement and rupture of the aneurysm, and the main indication for surgical late conversion. For this reason, strict surveillance of these patients is mandatory for the early detection of endoleaks and the preferred method of follow-up is represented by CT angiography. However, CTA has limitations. The investigation is repeated several times, making radiation exposure a necessary concern. Therefore, it would be useful to have another reliable diagnostic examination during follow-up. Color duplex ultrasound is non-invasive, does not use radiation or contrast medium, is less expensive, easy to perform and widely available. However, this technique obtained poor results in terms of sensitivity in the detection of endoleaks. In the last years, the introduction of ultrasound contrast agents and contrast specific imaging has, however, rekindled interest in this modality and its potential for replacing of CTA in routine surveillance. The purpose of this review is to highlight the diagnostic value of CEUS in the post-EVAR endoleaks detection. PMID- 19444501 TI - Multi-detector row CT of patients with acute intestinal bleeding: a new perspective using multiplanar and MIP reformations from submillimeter isotropic voxels. AB - Acute intestinal bleeding is a severe condition, with a mortality rate of up to 40% in case of associated hemodynamic instability. The diagnosis of acute intestinal bleeding is often challenging and to date, there is no definite consensus upon the most appropriate technique for this specific diagnosis. This pictorial essay illustrates our preliminary use of multiplanar (MPR) and maximum intensity projection (MIP) reformations using MDCT scanner with submillimeter and isotropic voxels as an adjunct to axial images in patients with acute intestinal bleeding. MDCT examinations were routinely performed with 64-slice helical CT scanner and images were reconstructed 0.6-mm thickness at 0.5-mm intervals. Multiplanar reconstructions and MIP views were created with a commercially available workstation. Reformatted images from submillimeter isotropic voxels enhanced the depiction of subtle vascular abnormalities and served as a useful adjunct to the axial plane images to improve diagnostic capabilities. Although we are aware that reformatted images should not replace careful analysis of the axial images in patients with acute gastrointestinal bleeding, reformatted images from submillimeter isotropic voxels may clarify the cause of the bleeding, add confidence to image analysis and help interventional radiologists or surgeons improving planning approach. PMID- 19444502 TI - Treatment of venous aortorenal bypass graft aneurysm using a stent-graft. AB - We present the case of a 77-year-old male patient who had undergone a bilateral venous aortorenal bypass graft 30 years previously. Thirteen years previously, the patient was shown to have a decrease in renal function, with mild shrinking of both kidneys; additionally, a stenosis was found in the left proximal anastomosis. At the most recent follow-up visit (1 year previously), ultrasound revealed an aneurysm (42 mm in diameter) of the left renal bypass graft; the finding was confirmed by CT angiography. A significant ostial stenosis of the left renal bypass graft was also confirmed. It was decided to place a self expandable stent-graft into the aneurysm while also attempting to dilate the stenosis. Proximal endoleak after stent-graft placement necessitated the implantation of another, balloon-expandable stent-graft into the bypass graft ostium. Postprocedural angiography and follow-up by CT angiography at 3 months confirmed good patency of the stent-grafts and complete thrombosis of the aneurysmal sac, with preserved kidney perfusion. Renal function remained unaltered, while the hypertension is better controlled. PMID- 19444503 TI - Transarterial infusion chemotherapy using cisplatin-lipiodol suspension with or without embolization for unresectable hepatocellular carcinoma. AB - We evaluate the long-term prognosis and prognostic factors in patients treated with transarterial infusion chemotherapy using cisplatin-lipiodol (CDDP/LPD) suspension with or without embolization for unresectable hepatocellular carcinoma (HCC). Study subjects were 107 patients with HCC treated with repeated transarterial infusion chemotherapy alone using CDDP/LPD (adjusted as CDDP 10 mg/LPD 1 ml). The median number of transarterial infusion procedures was two (range, one to nine), the mean dose of CDDP per transarterial infusion chemotherapy session was 30 mg (range, 5.0-67.5 mg), and the median total dose of transarterial infusion chemotherapy per patient was 60 mg (range, 10-390 mg). Survival rates were 86% at 1 year, 40% at 3 years, 20% at 5 years, and 16% at 7 years. For patients with >90% LPD accumulation after the first transarterial infusion chemotherapy, rates were 98% at 1 year, 60% at 3 years, and 22% at 5 years. Multivariate analysis identified >90% LPD accumulation after the first transarterial infusion chemotherapy (p = 0.001), absence of portal vein tumor thrombosis (PVTT; p < 0.001), and Child-Pugh class A (p = 0.012) as independent determinants of survival. Anaphylactic shock was observed in two patients, at the fifth transarterial infusion chemotherapy session in one and the ninth in the other. In conclusion, transarterial infusion chemotherapy with CDDP/LPD appears to be a useful treatment option for patients with unresectable HCC without PVTT and in Child-Pugh class A. LPD accumulation after the first transarterial infusion chemotherapy is an important prognostic factor. Careful consideration should be given to the possibility of anaphylactic shock upon repeat infusion with CDDP/LPD. PMID- 19444505 TI - Spontaneous dissection of the renal arteries: a misdiagnosed but not infrequent disease! PMID- 19444506 TI - Diversification of TOLLIP isoforms in mouse and man. AB - The Toll-interacting protein TOLLIP is an ubiquitin-binding protein that interacts with several components of the Toll-like receptor signaling cascade. The canonical protein consists of three annotated domains: an N-terminal TBD-loop coil domain that mediates protein-protein interactions, a C2 domain that targets TOLLIP to the endosome, and a CUE domain at the C-terminus that binds monoubiquitin. TOLLIP has been described primarily in trafficking of the interleukin-1 receptor (IL1R) and turnover of the interleukin-1 receptor associated kinase (IRAK), so it is an essential regulator of inflammatory signaling. Here we describe the expression of numerous alternate transcripts from mouse and human TOLLIP, which are predicted to generate at least five variant proteins between the two species. Most of the variant proteins are predicted to have altered N-terminal domains, altered TBD-loop-coil domains, or a truncated C2 domain. A mouse-specific variant arises from an alternate termination exon, and the resulting protein lacks the CUE domain. Two transcripts arising from alternate initiating exons are highly conserved between mouse and human but exhibit different patterns of expression. The consequent protein isoforms retain (TOLLIP.A) or lack (TOLLIP.D) the protein-binding TBD, so are predicted to traffic monoubiquitinated proteins to alternate protein complexes within the endosomal compartment. In summary, the widespread and inducible expression of Tollip isoforms predicts diversification of its function in rodent and human immune systems. Alternate splicing of critical signaling molecules such as Tollip may provide one mechanism behind the broad repertoire of responses generated by cells of the innate immune system in response to infection. PMID- 19444508 TI - RandoMate: a program for the generation of random mating schemes for small laboratory animals. AB - Advanced intercross lines (AIL) have proven to be a powerful tool in genetic research to map complex genetic traits. The advantage of AIL is the high enrichment of visible recombination events to fine map the position of the target gene. Therefore, AIL are generated under the avoidance of inbreeding. We developed an online software tool, RandoMate, that generates random mating schemes such that only animals from different families are paired. When animals have to be selected randomly for mating, RandoMate optimizes the mating scheme such that all families contribute equally to the next generation. RandoMate uses a divide-and-conquer algorithm to define a mating scheme without brother-sister matings for all animals of a generation. If not all animals can be considered for the next generation, the mating scheme maximizes the randomness of the occurrences of animals from their families to make the family contributions as equal as possible. RandoMate is freely available at http://www2.hu berlin.de/RandoMate . PMID- 19444507 TI - Murine models of colorectal cancer. AB - Colorectal cancer is one of the most prevalent cancers of humans. To experimentally investigate this common disease, numerous murine models have been established. These models accurately recapitulate the molecular and pathologic characteristics of human colorectal cancers, including activation of the myelocytomatosis oncogene (MYC), which has recently been suggested to be a key mediator of colorectal cancer development. This review focuses on the variety of murine models of human colorectal cancer that are available to the research community and on their use to identify common and distinct characteristics of colorectal cancer. PMID- 19444509 TI - Laparoscopic gastrectomy for organ-confined cancer: a reality in the West? PMID- 19444510 TI - Laparoscopic cholecystectomy in 427 adults with sickle cell disease: a single center experience. AB - BACKGROUND: Sickle cell disease (SCD) is common in the Eastern Province of Saudi Arabia. Patients with this disease have an increased risk for gallstones. Cholecystectomy is the most common general surgical procedure performed in patients with SCD. Laparoscopic cholecystectomy (LC) is the standard treatment for symptomatic gallstones. To date, only small series of LC in adults with SCD have been reported. We report a large series of LC in these patients. METHODS: A retrospective study included all adults with SCD who underwent LC for symptomatic gallstones at King Fahad Hospital, Hofuf, Saudi Arabia, during a 13-year period. Data analyzed were patient demographics, preoperative blood transfusion, duration of operation, rates of conversion and morbidity, and length of hospital stay. RESULTS: There were 427 patients; 56% were women with a mean age of 21 years. Blood transfusion was used in 393 patients (92%). Nineteen patients (4.5%) had endoscopic extraction of common bile duct (CBD) stones before LC. Overall, conversion to open surgery was necessary in 21 patients (5%). However, the conversion rate significantly decreased from 9% in the first half of the study to 2% during the second half (p < 0.001). The mean operation time was 76 min. There were 31 complications (7%), mostly related to SCD. There was no mortality, and the mean hospital stay was 2.6 days. CONCLUSION: Provided that standard perioperative care is ensured and the procedure is performed by experienced surgeons, LC in adults with SCD results in low rates of conversion and morbidity, no mortality, and a short hospital stay. PMID- 19444511 TI - Computed tomographic measurements of mesh shrinkage after laparoscopic ventral incisional hernia repair with an expanded polytetrafluoroethylene mesh. AB - BACKGROUND: The potential for shrinkage of intraperitoneally implanted meshes for laparoscopic repair of ventral and incisional hernia (LRVIH) remains a concern. Numerous experimental studies on this issue reported very inconsistent results. Expanded polytetrafluoroethylene (ePTFE) mesh has the unique property of being revealed by computed tomography (CT). We therefore conducted an analysis of CT findings in patients who had previously undergone LRVIH with an ePTFE mesh (DualMesh, WL Gore, Flagstaff, AZ, USA) in order to evaluate the shrinkage of implanted meshes. PATIENTS AND METHODS: Of 656 LRVIH patients with DualMesh, all patients who subsequently underwent CT scanning were identified and only those with precisely known transverse diameter of implanted mesh and with CT scans made more than 3 months postoperatively were selected (n = 40). Two radiologists who were blinded to the size of the implanted mesh measured in consensus the maximal transverse diameter of the meshes by using the AquariusNET program (TeraRecon Inc., San Mateo, CA, USA). Mesh shrinkage was defined as the relative loss of transverse diameter as compared with the original transverse diameter of the mesh. RESULTS: The mean time from LRVIH to CT scan was 17.9 months (range 3-59 months). The mean shrinkage of the mesh was 7.5% (range 0-23.7%). For 11 patients (28%) there was no shrinkage at all. Shrinkage of 1-10% was found in 16 patients (40%), of 10-20% in 10 patients (25%), and of 20-24% in 3 patients (7.5%). No correlation was found regarding the elapsed time between LRVIH and CT, and shrinkage. There were two recurrences, one possibly related to shrinkage. CONCLUSION: Our observations indicate that shrinkage of DualMesh is remarkably lower than has been reported in experimental studies (8-51%). This study is the first to address the problem of shrinkage after intraperitoneal implantation of synthetic mesh in a clinical material. PMID- 19444512 TI - How much do we need experts during laparoscopic suturing training? AB - INTRODUCTION: Because of the complex nature of laparoscopic suturing, numerous curricula have been developed to overcome the steep learning curve in a patient free environment. Distributed training leads to better acquisition and retention of skill compared with massed training. However, this requires considerable time commitment of experts that supervise these training sessions. This study investigates the possibility of replacing expert supervision by structured training with video demonstrations and peer feedback. MATERIALS AND METHODS: The study population consisted of two balanced groups of ten senior medical students with minimal experience in laparoscopy. The control group trained with continuous expert feedback while for the experimental group only video demonstrations and external feedback from peers were available. Training was completed when a previously determined expert level was achieved on two consecutive attempts (proficiency criterion). Students were tested on their suturing skills 1 week after the training as well as after 4 months. A composite score assessing quality and quantity of suturing performance was used. Data are shown as median (interquartile range, IQR). RESULTS: Students' performance improved more than 200% after training. Learning curves did not differ between groups (p = 0.28). One week after training, scores were 192 s (IQR 65 s) for the control and 190 s (IQR 27 s) for the experimental group (p = 0.63). After 4 months this was 223 s (IQR 88 s) and 220 s (IQR 37 s), respectively (p = 0.60). CONCLUSIONS: Both training methods are very efficient at improving laparoscopic suturing skills and provide excellent skill retention. We therefore conclude that structured training with video demonstrations and peer feedback can replace expert supervision to teach laparoscopic suturing skills to novices. This will facilitate practical organization of skills training. PMID- 19444513 TI - Robotic D2 surgery for gastric cancer. PMID- 19444514 TI - Lugol chromoendoscopy combined with brush cytology in patients at risk for esophageal squamous cell carcinoma. AB - BACKGROUND AND STUDY AIMS: Patients with achalasia or malignancies of the head and neck are at increased risk for esophageal squamous cell carcinoma. The discussion of a screening and surveillance program is controversial. The aim of the present study was to determine the diagnostic potential of Lugol chromoendoscopy combined with brush cytology to diagnose esophageal squamous cell carcinoma and high-grade dysplasia. Secondly, the benefit of additional biomarkers was investigated. PATIENTS AND METHODS: A total of 61 patients (21 patients with achalasia and 40 patients with malignancies of the head and neck) were included. Chromoendoscopy with 1.2% Lugol iodine solution with targeted biopsies and brush cytology processed by digital image cytometry (DICM) and fluorescence in situ hybridization (FISH) from unstained lesions (USLs) and stained mucosa were performed. RESULTS: Six of the 61 patients had USLs >=2 cm. Four patients had high-grade dysplasia (HGD) or carcinoma in situ (CIS). One patient with HGD and one patient with CIS were detected only after Lugol chromoendoscopy. The sensitivity and specificity for detected HGD or CIS in USLs >=2 cm were 100% and 96.5%. No dysplasia was found in USLs <2 cm. DNA ploidy by DNA cytometry and p53 loss of heterozygosity (LOH) by fluorescence in situ hybridization showed no additional impact on diagnostic accuracy. CONCLUSIONS: Lugol chromoendoscopy enhances the detection rate of high-risk lesions with dysplasia or carcinoma in situ in large unstained lesions. Biomarkers such as aneuploidy and p53 LOH from brush cytology were not of additional benefit in this setting. PMID- 19444515 TI - Randomized controlled trial on sterile fluid collections management in acute pancreatitis: should they be removed? AB - OBJECTIVE: To evaluate if percutaneous drainage of sterile fluid collections recurring after initial aspiration in acute pancreatitis yields better results than their conservative management. METHODS: Fifty-eight patients with fluid collections in acute pancreatitis were followed up prospectively. Forty of them with sterile fluid collections that recurred after initial aspiration were randomly assigned to two groups of 20 in each. One group was initially treated with conservative management and the other group with prolonged catheter drainage. Patients with unsuccessful initial treatment were converted to more aggressive procedure. Outcome measure was conversion rate to more aggressive procedure. RESULTS: Conversion to more aggressive procedure was done in 11 and 3 patients treated conservatively and with catheter drainage, respectively (p = 0.02). Four and 11 patients had bacterial colonization of their fluid collections in conservative management and drainage group, respectively (p = 0.048). Conservative treatment was successful in all six patients with sterile liquid collections < 30 ml. However, this treatment was unsuccessful in all seven patients with multiloculated and liquid collections >100 ml. CONCLUSIONS: Prolonged catheter drainage is more efficient for management of recurrent sterile fluid collections in acute pancreatitis than is conservative treatment. Conservative treatment is successful for patients with small fluid collections. PMID- 19444517 TI - Preoperative bariatric screening and treatment of Helicobacter pylori. AB - BACKGROUND: A preoperative screening and treatment program for pre-existing H. pylori infections was hypothesized to reduce postoperative bariatric complications and associated morbidity as the role of H. pylori in gastrointestinal symptomatology and peptic ulcer disease is well established. METHODS: A single-institution, single-surgeon, IRB-approved, retrospective chart review was performed. It included 183 consecutive patients who underwent an initial laparoscopic gastric bypass over a 40-month period from December 2003 to April 2006. The patients were divided into a H. pylori untested group (125 patients) and a tested and treated if indicated group (58 patients). Patient demographics and incidence of hospital re-admissions, GI ulceration and bleeding, perforated viscus, esophagogastroduodenoscopy (EGD), and foregut symptoms were documented at routine follow-up and emergency room visits. Results were subjected to analysis with Fisher's exact test. RESULTS: Seven patients (12%) in the tested group were positive for H. pylori and treated. The number of GI ulcers and bleeding, EGDs, ER visits, and hospital re-admissions were not statistically different between groups; however, in the untested group, six patients (5%) presented with viscus perforation compared with none in the tested and treated group (p = 0.09). Demographics for both groups were similar and both had a large number of nonspecific foregut symptoms. CONCLUSION: Preoperative H. pylori screening should continue, especially in geographically high-prevalence areas, as data suggest that the incidence of viscus perforation may be reduced with preoperative treatment if indicated. PMID- 19444516 TI - Fibrinolytic and coagulation pathways after laparoscopic and open surgery: a prospective randomized trial. AB - BACKGROUND: Tissue injury poses increased risk for postoperative thromboembolic complications. Laparoscopic surgery, by causing limited tissue injury, is associated with lower risk for thromboembolism than is open surgery. We conducted a prospective randomized study in order to detect potentially existing differences in activation of coagulation and fibrinolytic pathways between open and laparoscopic surgery. METHODS: Forty patients with chronic cholelithiasis were randomly assigned to undergo open (group A) or laparoscopic cholecystectomy (group B). Blood samples were taken preoperatively, at the end of the procedure, and at 24 and 72 h postoperatively. Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), platelets (PLT), soluble fibrin monomer complexes (F.S. test), fibrin degradation products (FDP), D-dimers (D-D), and fibrinogen (FIB) were measured and compared within each group and between groups: Thrombin-antithrombin complexes (TAT) and prothrombin fragments (F1 + 2) were measured at 24 and 72 h postoperatively. RESULTS: Demographics were comparable between groups. Immediately postoperatively, TAT and F1 + 2 were significantly higher in group A (p < 0.05). They also increased significantly postoperatively as compared with preoperative levels within each group (p < 0.05). D-dimers were significantly higher in group A (p < 0.01) immediately postoperatively. D-dimers also increased significantly postoperatively in group B as compared with preoperative levels (p < 0.001). FIB decreased slightly in both groups at 24 h postoperatively but there was a significant increase in group A (p < 0.01). Soluble fibrin monomer complexes (SFMC) were detected twice in group A and only once in group B. FDP levels over 5 MUg/ml were detected more often in group A (p < 0.05). There was not any case of thromboembolism or abnormal bleeding. CONCLUSIONS: Open surgery leads to higher activation of the clotting system than do laparoscopic procedures. Although of a lower degree, hypercoagulability is still observed in patients undergoing laparoscopic surgery and therefore routine thromboembolic prophylaxis should be considered. PMID- 19444518 TI - Effects of Ca and Mg on growth and calcification of the coccolithophorid Pleurochrysis haptonemofera: Ca requirement for cell division in coccolith bearing cells and for normal coccolith formation with acidic polysaccharides. AB - The effects of Ca2+ and Mg2+ on cellular growth and calcification in Pleurochrysis haptonemofera were investigated. In the presence of a normal concentration of Mg2+, coccolith-bearing cells (C-cells) required more than 0.5 mM Ca2+ for growth, while naked cells could grow even with 0.5 mM Ca2+. The calcification rate of C-cells, which was determined using decalcified cells, was significantly repressed with less than or equal to 0.5 mM Ca2+. Although the calcification rate did not change so much with 5-30 mM Ca2+, it decreased with higher concentrations of Ca2+, as well as C-cell-specific growth repression. Under these conditions, Ca2+ affected the rate of coccolith formation, but neither the coccolith morphology nor total amounts and ratios of divalent cations and acidic polysaccharides (Ph-PS-1, -2, and -3) were included in coccoliths. These findings suggest that sufficient calcification is required for the division of C-cells. Under low Ca2+ and high Mg2+ conditions, coccoliths with an abnormal morphology, having immature shield elements, were synthesized. Composition analysis of the coccoliths revealed high Mg/Ca and low Ph-PS-2/(Ph-PS-1 and -3) ratios, as compared with those under low Ca2+ and normal Mg2+ conditions, suggesting that the abnormal morphology is due to a change in the crystal type and/or acidic polysaccharide composition. PMID- 19444519 TI - Comparison of the bacterial communities of wild and captive sponge Clathria prolifera from the Chesapeake Bay. AB - The red-beard sponge Clathria prolifera, which is widely distributed in the USA, has been widely used as a model system in cell biology and has been proposed as a suitable teaching tool on biology and environmental sciences. We undertook the first detailed microbiological study of this sponge on samples collected from the Chesapeake Bay. A combination of culture-based studies, denaturing gradient gel electrophoresis, and bacterial community characterization based on 16S rRNA gene sequencing revealed that C. prolifera contains a diverse assemblage of bacteria that is different from that in the surrounding water. C. prolifera individuals were successfully maintained in a flow-through or recirculation aquaculture system for over 6 months and shifts in the bacterial assemblages of sponges in aquaculture compared with wild sponges were examined. The proteobacteria, bacteroidetes, actinobacteria, and cyanobacteria represented over 90% of the species diversity present in the total bacterial community of the wild C. prolifera. Actinobacteria, cyanobacteria, and spirochetes were not represented in clones obtained from C. prolifera maintained in the aquaculture system although these three groups comprised ca. 20% of the clones from wild C. prolifera, showing a significant effect of aquaculture on the bacterial community composition. This is the first systematic characterization of the bacterial community from a sponge found in the Chesapeake Bay. Changes in sponge bacterial composition were observed in sponges maintained in aquaculture and demonstrate the importance of monitoring microbial communities when cultivating sponges in aquaculture systems. PMID- 19444520 TI - Association between habitat size, brushtail possum density, and the mosquito fauna of native forests in the Auckland region, New Zealand. AB - Human activities have been causing dramatic and unprecedented changes to the Earth's ecosystems, and are a primary factor associated with biological invasions. Disturbed and fragmented habitats allow some vector mosquitoes to thrive. The New Zealand landscape has been extensively modified since the arrival of humans, and there is accumulating evidence that the distribution of mosquitoes is being altered as a result of anthropogenic environmental changes. This study aimed to assess whether forest habitat size affected the community composition of mosquitoes, and whether the density of the introduced brushtail possum would benefit exotic mosquito species that feed primarily on mammal hosts. Extensive sampling of the mosquito community was carried out using dry ice-baited light traps, oviposition traps, and larval surveys. The results provided the first experimental evidence in New Zealand that changes in forest habitat size affect the indigenous and introduced mosquito fauna differently. The proportion of native species making up the mosquito community appears to be steadily reduced as native forest habitats become smaller. In contrast, the opposite pattern appears to occur for the introduced vector Aedes notoscriptus. Although there was a trend indicating that possums may have a negative impact on a native species (Culex pervigilans), the impact of these animals on the mosquito fauna remains unclear. The evidence suggests that the conservation of large pristine forest ecosystems in New Zealand could have human health implications. PMID- 19444521 TI - Male-produced aggregation pheromones of the cerambycid beetles Xylotrechus colonus and Sarosesthes fulminans. AB - Adults of both sexes of the cerambycid beetles Xylotrechus colonus (F.) and Sarosesthes fulminans (F.) were attracted to odors produced by male conspecifics in olfactometer bioassays. Analyses of headspace volatiles from adults revealed that male X. colonus produced a blend of (R)- and (S)-3-hydroxyhexan-2-one and (2 S,3 S)- and (2R,3R)-2,3-hexanediol, whereas male S. fulminans produced (R)-3 hydroxyhexan-2-one and (2 S,3R)-2,3-hexanediol. All of these compounds were absent in the headspace of females. Two field bioassays were conducted to confirm the biological activity of the synthesized pheromones: (1) enantiomerically enriched pheromone components were tested singly and in species-specific blends and (2) four-component mixture of racemic 3-hydroxyhexan-2-one plus racemic 2 hydroxyhexan-3-one and the four-component blend of the stereoisomers of 2,3 hexanediols were tested separately and as a combined eight-component blend. In these experiments, adult male and female X. colonus were captured in greatest numbers in traps baited with the reconstructed blend of components produced by males, although significant numbers were also captured in traps baited with (R)-3 hydroxyhexan-2-one alone or in blends with other compounds. Too few adult S. fulminans were captured for a statistical comparison among treatments, but all were caught in traps baited with lures containing (R)-3-hydroxyhexan-2-one. In addition to these two species, adults of two other species of cerambycid beetles, for which pheromones had previously been identified, were caught: Neoclytus a. acuminatus (F.) and its congener Neoclytus m. mucronatus (F.). Cross-attraction of beetles to pheromone blends of other species, and to individual pheromone components that are shared by two or more sympatric species, may facilitate location of larval hosts by species that compete for the same host species. PMID- 19444522 TI - Attraction of New Zealand flower thrips, Thrips obscuratus, to cis-jasmone, a volatile identified from Japanese honeysuckle flowers. AB - This work was undertaken to identify floral compound(s) produced by honeysuckle flowers, Lonicera japonica (Thunberg), that mediate the attraction of New Zealand flower thrips Thrips obscuratus (Crawford). Volatiles were collected during the day and night and analyzed by gas chromatography-mass spectrometry (GC-MS) to determine their emission over these two periods. Nine compounds were identified in the headspace; the main compound was linalool, and the other compounds were germacrene D, E,E-alpha-farnesene, nerolidol, cis-jasmone, cis-3-hexenyl acetate, hexyl acetate, cis-hexenyl tiglate, and indole. There was a quantitative difference between day and night volatiles, with cis-3-hexenyl acetate, hexyl acetate, cis-hexenyl tiglate, and cis-jasmone emitted in higher amounts during the day compared to the night. When the compounds were tested individually in field trapping experiments, only cis-jasmone attracted New Zealand flower thrips in a significant number. In another field trapping experiment, cis-jasmone caught similar numbers of New Zealand flower thrips compared to a floral blend formulated to mimic the ratios of the compounds emitted during the day, while catch with the night-emitted floral blend was not significantly different from the control. Subsequently, two field trapping experiments were conducted to determine the optimal attraction dose for cis-jasmone, a range of 1-100 mg loaded onto a red rubber stopper was tested, and the highest catches were in traps baited with 100 mg loading. A higher range of 100-1000 mg loaded into polyethylene vials was tested, and the highest catch was in traps baited with 500 mg. In another experiment aimed at comparing the attraction efficacy of cis jasmone with the two other known thrips attractants (ethyl nicotinate and p anisaldehyde), ethyl nicotinate showed the highest trap catch followed by cis jasmone. A smaller number of Thrips tabaci (Lindeman) was attracted to traps baited with cis-jasmone. These results suggest that cis-jasmone might act as a kairomone that mediates the attraction of New Zealand flower thrips to the flowers of the Japanese honeysuckle. PMID- 19444523 TI - Totally laparoscopic gastric resection with extended lymphadenectomy for gastric adenocarcinoma. AB - BACKGROUND: Laparoscopic gastric resection with extended lymphadenectomy is being evaluated in North America for the surgical treatment of gastric cancer. The aim of this study is to compare short-term postoperative and oncologic outcomes of laparoscopic and open resection for gastric cancer at a single cancer center. METHODS: The study population consisted of patients with gastric adenocarcinoma who underwent a completely abdominal intervention with curative intent. Laparoscopic and open gastric resections were compared. A totally laparoscopic technique was employed with a robotic extended lymphadenectomy in a subset of patients. RESULTS: A total of 78 consecutive patients were evaluated, including 30 laparoscopic and 48 open procedures. An extended lymphadenectomy was performed in 58 patients and was executed robotically in 16 of these. There was no difference in the mean number of lymph nodes retrieved by laparoscopic or open approach (24 +/- 8 vs. 26 +/- 15, P = .66). Laparoscopic procedures were associated with decreased blood loss (200 vs. 383 mL, P = .0009) and length of stay (7 vs. 10 days, P = .0009), but increased operative time (399 vs. 298 minutes, P < .0001). CONCLUSION: Completely laparoscopic gastric resection yields similar lymph node numbers compared with open surgery for gastric cancer. It was found to be advantageous in terms of operative blood loss and length of stay. Minimally invasive techniques represent an oncologically adequate alternative for the surgical treatment of gastric adenocarcinoma. PMID- 19444524 TI - Effect of surgeon training, specialization, and experience on outcomes for cancer surgery: a systematic review of the literature. AB - BACKGROUND: Outcomes after cancer resections have been shown to be better for high-volume surgeons compared with low-volume surgeons; however, reasons for this relationship have been difficult to identify. The objective of this study was to assess studies examining the effect of surgeon training and experience on outcomes in surgical oncology. METHODS: A systematic review of the literature was performed to assess articles examining the impact of surgeon training, certification, and experience on outcomes. Studies were included if they examined cancer resections and performed multivariable analyses adjusting for relevant confounding variables. RESULTS: An extensive literature search identified 29 studies: 27 examined surgeon training/specialization, 1 assessed surgeon certification, and 4 evaluated surgeon experience. Of the 27 studies examining training/specialization, 25 found that specialized surgeons had better outcomes than nonspecialized surgeons. One study found that American Board of Surgery (ABS)-certified surgeons had better outcomes than noncertified surgeons. Of the two studies examining time since ABS certification, both found that increasing time was associated with better outcomes. Of the four studies that examined experience, three studies found that increasing surgeon experience was associated with improved outcomes. CONCLUSIONS: Although numerous studies have examined the impact of surgeon factors on outcomes, only a few cancers have been examined, and outcome measures are inconsistent. Most studies do not appear robust enough to support major policy decisions. There is a need for better data sources and consistent analyses which assess the impact of surgeon factors on a broad range of cancers and help to uncover the underlying reasons for the volume-outcome association. PMID- 19444525 TI - Severe metallosis after total elbow arthroplasty-a case report. AB - We present a case of severe metallosis after total elbow arthroplasty in a female patient presenting with manifestations resembling a septic loosening. We discuss the clinical and the operative findings as well as the outcome of this uncommon complication. A review of the literature regarding the pathogenesis, radiographic appearance, and management of metallosis in prosthetic joints is presented. PMID- 19444526 TI - Activation and perceived expectancies: correlations with health outcomes among veterans with inflammatory bowel disease. AB - OBJECTIVE: Inflammatory bowel disease imposes psychosocial stress on the patient. Patients' adaptive capacities may predict quality of life. We examined two adaptive capacity measures and their association with quality of life. DESIGN: Cross-sectional mail survey of patients with inflammatory bowel disease. The Patient Activation Measure (PAM) assesses knowledge, skill, and confidence in self-health management. The Perceived Expectancies Index (PEI) measures perceived competence and dispositional optimism. SETTING/PATIENTS: Four hundred and seventy seven veterans at VA-Tennessee Valley Healthcare System. MAIN OUTCOME MEASURE: Primary outcome was health-related quality of life (measured by the Short Inflammatory Bowel Disease Questionnaire). Bivariate analysis assessed unadjusted correlations. Sequential multivariate linear regression tested theoretical model relationships by calculating the variation in each dependent variable accounted for by independent variables (R-squared statistic). RESULTS: Two hundred and sixty surveys were returned with usable data (54.5%). Median age was 63 years (range 19-91); 90.8% were men and 86.9% self-identified as white. Fifty percent reported having ulcerative colitis, 36.5% Crohn's disease, and 12.3% uncertain type. Unadjusted bivariate analysis revealed positive correlations between the PAM and PEI and the Short Inflammatory Bowel Disease Questionnaire (correlation coefficient = 0.35 and 0.60, respectively; p < 0.0001). Multivariate model including the PAM accounted for 26% of the variation in Short Inflammatory Bowel Disease Questionnaire scores, while the model including the PEI accounted for 50% (p < 0.0001). CONCLUSIONS: There are positive, highly significant correlations between adaptive capacities and health-related quality of life in patients with inflammatory bowel disease. PMID- 19444527 TI - Digital templating and preoperative deformity analysis with standard imaging software. AB - Analysis of deformity and subsequent correction are the basis for many orthopaedic surgical procedures. In advanced cases of joint degeneration, arthroplasty may be the only available treatment option. Until recently, these analyses and preoperative surgical plans have been performed using standard radiographs, tracing paper, and/or plastic overlays. Numerous customized, commercially available, computer-based preoperative planning software programs have been introduced. The purposes of this study were to describe (1) the techniques used in deformity analysis and preoperative surgical planning using standard radiographs for joint arthroplasty and corrective osteotomies of the extremities, (2) the use of computed tomography (CT) scans to analyze rotational deformities in the presence and absence of joint prostheses and in planning corrective rotational osteotomies or revision joint replacement, and (3) the techniques for analyzing angular deformities of the spine. All these applications were performed with a widely available image analysis software. PMID- 19444528 TI - Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies. AB - The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10-15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Straussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD. PMID- 19444529 TI - The spectrum of nervous system involvement in Behcet's syndrome and its differential diagnosis. AB - Behcet's Syndrome (BS) is a multi-system, vascular-inflammatory disease of unknown origin, involving the nervous system in a subgroup of patients. The growing clinical and imaging evidence suggests that primary neurological involvement in BS may be subclassified into two major forms: the first one, which is seen in the majority of patients, may be characterized as a vascular inflammatory central nervous system (CNS) disease, with focal or multifocal parenchymal involvement mostly presenting with a subacute brainstem syndrome and hemiparesis; the other, which has few symptoms and a better neurological prognosis, may be caused by isolated cerebral venous sinus thrombosis and intracranial hypertension. These two types rarely occur in the same individual, and their pathogenesis is likely to be different. Isolated behavioral syndromes and peripheral nervous system involvement are rare, whereas a nonstructural vascular type headache is relatively common and independent from neurological involvement. Neurologic complications secondary to systemic involvement of BS such as cerebral emboli from cardiac complications of BS and increased intracranial pressure due to superior vena cava syndrome, as well as neurologic complications related to BS treatments such as CNS neurotoxicity with cyclosporine and peripheral neuropathy with the use of thalidomide or colchisin are considered as secondary neurological complications of this syndrome. As the neurological involvement in this syndrome is so heterogeneous, it is difficult to predict its course and prognosis, and response to treatment. Currently, treatment options are limited to attack and symptomatic therapies with no evidence for the efficacy of any long term preventive treatment. PMID- 19444530 TI - Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. AB - Knowledge of restless legs syndrome (RLS) has greatly increased in recent years due to the many advances that have been made in diagnosis, management and genetics. Tools have been developed that facilitate the diagnosis and treatment of RLS, in particular the essential diagnostic criteria for RLS have been refined, severity scales (IRLS, RLS-6, JHSS) have been developed, as have instruments that improve diagnostic accuracy and assess for specific aspects of RLS such as augmentation. These newly developed tools have been used in recent population-based studies, which have provided a greater understanding of the epidemiology of RLS, and also within patient-based trials. As far as the genetics of RLS is concerned, linkage studies in RLS families have revealed eight loci but no causally related sequence variant has yet been identified using this approach. Recent genome-wide association studies have identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBXCOR1, and PTPRD, raising new pathological hypotheses for RLS. An overview on therapeutic options and recent trials is given based on evidence-based management strategies for this common disorder. PMID- 19444531 TI - Multiple sclerosis patients' benefit-risk preferences: serious adverse event risks versus treatment efficacy. AB - OBJECTIVE: The aim of this study is to estimate the willingness of multiple sclerosis (MS) patients to accept life-threatening adverse event risks in exchange for improvements in their MS related health outcomes. METHODS: MS patients completed a survey questionnaire that included a series of choice-format conjoint tradeoff tasks. Patients chose hypothetical treatments from pairs of treatment alternatives with varying levels of clinical efficacy and associated risks. RESULTS: Among the 651 patients who completed the survey, delay in years to disability progression was the most important factor in treatment preferences. In return for decreases in relapse rates from 4 to 1 and increases in delay in progression from 3 to 5 years, patients were willing to accept a 0.38% annual risk of death or disability from PML, a 0.39% annual risk of death from liver failure or a 0.48% annual risk of death from leukemia. CONCLUSIONS: Medical interventions carry risks of adverse outcomes that must be evaluated against their clinical benefits. Most MS patients indicated they are willing to accept risks in exchange for clinical efficacy. Patient preferences for potential benefits and risks can assist in decision-making. PMID- 19444532 TI - Factors that influence adherence with disease-modifying therapy in MS. AB - BACKGROUND: The complexity and cost of injection treatment can represent a formidable challenge for patients affected by a chronic illness, particularly those whose treatment is primarily preventative and only modestly effective on the more conspicuous symptomatic aspects of the disease process. The aim of this investigation was to identify which factors most influenced nonadherent behavior with the available disease-modifying injection therapies for multiple sclerosis (MS). METHODS: A multicenter, observational (three-wave) study using surveys was developed and administered to patients with MS through the World Wide Web. Healthcare providers at 17 neurology clinics recruited patients for the study. RESULTS: A total of 798 patients responded to the baseline wave of the study (708 responded to all three waves). The nonadherence rates for all patients (missing one or more injections) across these waves remained relatively stable at 39%, 37%, and 36%, respectively. The most common reason participants listed for missing injections was that they simply forgot to administer the medication (58%). Other factors including injection-site reactions, quality of life, patients' perceptions on the injectable medications, hope, depression, and support were also assessed in relation to adherence. CONCLUSIONS: This study characterizes factors that are associated with failure to fully adhere with disease modifying injection therapy for MS and underscores the principles associated with optimizing adherence and its implications for effective treatment of the disease process in MS. PMID- 19444534 TI - Serum free hemoglobin as a novel potential biomarker for acute ischemic stroke. AB - OBJECTIVE: Currently, no practical biomarker is available for the diagnosis of acute ischemic stroke. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has being applied extensively to analyze large biomolecules such as proteins. The technique is likely to be of remarkable value as indicators of systemic processes such as atherosclerosis and stroke. The aim of this study is to identify potential protein biomarkers for ischemic stroke diagnosis utilizing MALDI-TOF MS. METHODS: Serum samples obtained from acute ischemic stroke patients (n = 47) and controls (n = 34) were analyzed by MALDI TOF MS. Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS), subtype by the Trial of Org 10172 in Acute Stroke Treatment (TOAST), functional outcome by the modified Rankin Scale (mRS) and infarct volume by the diffusion-weighted images. Risk factors and routine laboratory data of the stroke patients were registered prospectively. RESULTS: The peaks of hemoglobin (Hb) alpha-chain and beta-chain were differentially expressed between stroke patients and controls (p < 0.0001). Hb ions were detected in the samples collected from 33 (70.2%) stroke patients and 5 (14.7%) controls. The sensitivity is 70.2% and the specificity is 85.3%. Among stroke patients, there is no significant correlation (p > 0.05) between Hb peaks and the NIHSS, TOAST, mRS, stroke risk factors, infarct volume, infarct location and laboratory data. CONCLUSIONS: Serum free Hb may serve as a novel potential biomarker for the diagnosis of acute ischemic stroke. The clinical value of this potential biomarker may be clarified by further studies quantifying serum free Hb levels. PMID- 19444533 TI - Clinical determinants of infarct pattern subtypes in large vessel atherosclerotic stroke. AB - BACKGROUND: Although stroke from large vessel atherothromboembolism has a common pathogenesis, its topographic presentation is variable. Given the impact of cerebral infarct size and location on incident stroke magnitude and subsequent prognosis, we evaluated the determinants of cerebral infarct topography among patients with atherosclerotic stroke. METHODS: We analyzed data on 148 consecutive patients admitted over a 4-year period to a university medical center with acute ischemic stroke within the MCA distribution on DWI, presumed due to atherosclerosis. Based on the DWI data, we divided the patients into three stroke phenotypes: large cortical, small (< 1 cm in diameter) cortical, and deep pattern. Independent factors for each stroke phenotype were evaluated using logistic regression. RESULTS: After adjusting for covariates, premorbid statin use (OR, 3.05; 95% CI, 1.40-6.65) and older age (OR, 1.05 per 1 year increase; 95% CI, 1.02-1.08) were independently associated with the small cortical phenotypic pattern. In contrast, younger age (OR, 0.95 per 1 year increase; 95% CI, 0.92-0.98), premorbid statin non-use (OR, 0.40; 95% CI, 0.17-0.99), and higher levels of fasting s-glucose (OR, 1.01 per 1 mg/dl increase; 95% CI, 1.00 1.02) and admission peripheral WBC counts (OR, 1.13 per 1 x 10(9) cells/L; 95% CI, 1.00-1.27) were independently associated with the large cortical pattern. There was no relation between DWI patterns and LDL-cholesterol levels. CONCLUSIONS: Age, premorbid statin use, s-glucose and WBC count predict atherosclerotic stroke phenotype. Further studies should examine whether modifying some of these factors may result in more favorable phenotypic patterns. PMID- 19444536 TI - Erectile dysfunction in myotonic dystrophy type 1 (DM1). PMID- 19444535 TI - Course of matrix metalloproteinase-9 isoforms after the administration of uric acid in patients with acute stroke: a proof-of-concept study. AB - Oxidative stress as well as expression and activity of matrix metalloproteinase 9 (MMP-9) are rapidly enhanced after cerebral ischemia. The magnitude of these effects is related to stroke outcome. In human stroke, the extent of oxidative stress correlates well with increased MMP-9 expression. The aim of this study was to evaluate whether treatment with the antioxidant molecule uric acid (UA) decreased the levels of MMP-9 in stroke patients treated with rtPA. The patients were part of a pilot, double-blind, randomized, vehicle-controlled study of patients with acute stroke treated with rtPA (< 3 h) and randomized to receive an intravenous infusion of UA (n = 16) or vehicle (n = 8). Total matrix metalloproteinase (tMMP)-9 and active (aMMP-9) levels were measured in serum at baseline (< 3 h), at the end of study treatment infusion (< 5.5 h), and at 48 hours. Total MMP-9 and aMMP-9 increased very early after stroke onset in patients allocated vehicle after rtPA therapy. Lower increments of aMMP-9 were associated with better outcome at 3 months. UA treatment was associated with reduced levels of aMMP-9 at T1 (p < 0.02) in multivariate models adjusted for age, NIHSS score, and baseline aMMP-9 levels. The decline of aMMP-9 attained after UA administration supports further clinical assessment of UA therapy in patients with acute stroke. PMID- 19444537 TI - Tolosa-Hunt syndrome responsive to infliximab therapy. PMID- 19444538 TI - Restless legs syndrome induced by topiramate: two more cases. PMID- 19444539 TI - Monocular ophthalmoplegia and partial supranuclear vertical gaze palsy due to unilateral paramedian rostral midbrain infarction. PMID- 19444540 TI - Secondary SUNCT syndrome caused by viral meningitis. PMID- 19444541 TI - A novel mutation as a cause of L-2-hydroxyglutaric aciduria. PMID- 19444542 TI - Amyloid myopathy with external ophthalmoparesis. PMID- 19444543 TI - An infantile case of Alexander disease unusual for its MRI features and a GFAP allele carrying both the p.Arg79His mutation and the p.Glu223Gln coding variant. PMID- 19444546 TI - The alpha2C-adrenoceptor deletion322-325 variant and cold-induced vasoconstriction. AB - OBJECTIVES: Cold-induced vasoconstriction is mediated in part by selective enhancement of local alpha(2C)-adrenoceptor (alpha(2C)-AR) activity. A common insertion-deletion variant in the alpha(2C)-AR gene (ADRA2C del322-325) results in an approximately 85% reduction of agonist-mediated function in vitro. We tested the hypothesis that individuals with the ADRA2C del322-325 variant have attenuated vasoconstriction in response to cold. METHODS: Cutaneous digital blood flow (flux) was measured by laser Doppler flowmetry in a controlled environment at room temperature and during two cycles of graduated local heat and cold exposure in 31 subjects. Temperature-response curves were analyzed to estimate the following measures: E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50 and 90%, respectively). RESULTS: We found no significant genotypic differences in E(min) (24.3 +/- 19.5, 30.0 +/- 20.5, and 21.5 +/- 25.9 AU for ins/ins, ins/del, and del/del genotypes, respectively; P = 0.48), ET(50) (25.5 +/- 6.0, 25.1 +/- 6.7, and 25.1 +/- 7.1 degrees C; P = 0.99), or ET(90) (20.5 +/- 4.7, 22.1 +/- 4.0, and 20.8 +/- 6.7 degrees C; P = 0.77) in either the first or second heating and cooling cycle (cycle 1 values presented). INTERPRETATION: The ADRA2C del322-325 variant did not affect vascular sensitivity to local cold exposure. PMID- 19444547 TI - Development of a real-time reverse-transcription PCR for the detection and simultaneous pathotyping of Newcastle disease virus isolates using a novel probe. AB - A real-time reverse-transcription PCR (RRT-PCR) was developed to detect and pathotype avian paramyxovirus type 1 (APMV-1), also known as Newcastle disease virus (NDV), which had been grown in embryonated fowls' eggs. Two pairs of probes, VRP1 with ARP1 and VRP2 with ARP2, each with either the 'universal base' 2' deoxyinosine incorporated or both inosines and locked nucleic acids (LNAs) incorporated, were designed to detect, respectively, a diverse range of virulent and avirulent viral templates that included the region coding for the fusion protein cleavage site. Oligonucleotide VRP1 hybridised with 76 of the 84 virulent isolates tested, while VRP2 detected 82, including 17 isolates with five or six template-probe mismatches. An alternative conventional probe, VRP3, with no inosine bases or LNAs, failed to hybridise 7 of 13 isolates, all of which tested positive with VRP2. Real-time assays with ARP1 showed that it detected 21 of the 28 avirulent isolates tested, and ARP2 detected 22/28, including one present in a mixture with virulent NDV. Neither probe was able to detect those isolates that were classified in genogroup six. All probes were specific for detecting either virulent or avirulent NDV. A specific PCR fragment of the predicted size was obtained, using the primer set designed for this study, with the 112 NDV isolates tested, including those in genogroup six. This assay demonstrates a rapid means for simultaneous detection and pathotyping of notifiable avian disease due to NDV. PMID- 19444548 TI - Heart rate as a risk factor for developing chronic kidney disease: longitudinal analysis of a screened cohort. AB - BACKGROUND: High heart rate and chronic kidney disease (CKD) are both risk factors for cardiovascular morbidity and mortality. The relationship between heart rate and the risk of developing CKD, however, has not been studied in a large screened cohort. METHODS AND RESULTS: We examined the relationship between heart rate and the risk of developing CKD in participants in a health evaluation program. CKD was diagnosed as glomerular filtration rate of less than 60 mL/min/1.73 m(2), calculated using the Modification of Diet in Renal Disease (MDRD) study equation or dipstick proteinuria. Among 7,958 subjects, 1,199 subjects diagnosed with CKD or with arrhythmia at baseline examination were excluded. A total of 6,759 subjects (4,268 men, 2,491 women, 20-84 years of age) were evaluated. The subjects were quadrisected according to baseline heart rate. The subjects were followed up for a mean of 47 +/- 16 months (range 7-71 months). Seven hundred and thirty-four subjects developed CKD over the 5-year follow-up period. Subjects with a high heart rate had greater magnitude of decreasing glomerular filtration rate (eGFR) and higher odds ratio of developing proteinuria. Cox analysis indicated that each heart rate category increment led to approximately 1.1 times increase in the risk of developing CKD, eGFR less than 60 mL/min/1.73 m(2), and 1.2 times increase of the risk of developing proteinuria in middle-aged or older subjects. CONCLUSIONS: High heart rate is a risk factor for developing CKD in middle-aged or older subjects. PMID- 19444549 TI - Altered peptide ligands regulate type II collagen-induced arthritis in mice. AB - We reported that peripheral blood mononuclear cells from HLA-DRB1*0101 Japanese patients with rheumatoid arthritis (RA) were highly reactive to 256-271 peptide of type II collagen (CII). Similar to RA, T cells reactive to CII (AA256-271) play a crucial role in the generation of arthritis in CII-induced arthritis mouse (I-A(q)). In the present study, we regulated the CII reactivity of T cells from CIA mouse with I-A(q) by altered peptide ligand (APL). Eight different APLs were designed and screened for their antagonistic activity using CII reactive cytokine production assay. Four APLs of CII 256-271 exhibited antagonistic activity in CII reactive T cells. Moreover, intraperitoneally injected APL-5 (G262A) significantly suppressed CII-induced arthritis in mice, whereas the other three APLs did not. Compared with the control, APL-5 suppressed interleukin (IL)-17 production by T cells from CII-induced arthritis mice. These results suggest that CII APL is a potentially suitable therapeutic strategy for the control of RA. PMID- 19444550 TI - Differential diagnosis between (18)F-FDG-avid metastatic lymph nodes in non-small cell lung cancer and benign nodes on dual-time point PET/CT scan. AB - OBJECTIVE: To clarify the difference of (18)F-FDG uptake kinetics between FDG avid metastatic lymph nodes (LNs) in patients with non-small-cell lung cancer (NSCLC) and FDG-avid benign LNs associated with various etiologies on dual-time point PET/CT scan, and to determine the optimal parameter for differentiation. METHODS: The subjects were 134 FDG-avid metastatic LNs in 67 patients with NSCLC and 62 FDG-avid benign LNs in 61 patients with various lung disorders including NSCLC. PET/CT scan was performed at 2 time points (at 60 min and at 120 min) after intravenous injection of 4.4 MBq/kg (18)F-FDG. The maximum standardized uptake value (SUVmax) on early and delayed scans and the percent change of SUVmax (%DeltaSUVmax) were measured at each FDG-avid LN. The optimal parameter for differentiation was determined by the receiver-operating characteristic analysis. RESULTS: Delayed SUVmax was increased compared with early SUVmax in 114 (85.0%) FDG-avid metastatic LNs and 42 (67.7%) FDG-avid benign LNs, with significant higher delayed SUVmax than early values (7.0 +/- 5.0 vs. 5.9 +/- 3.4; P < 0.0001, and 3.0 +/- 1.3 vs. 2.8 +/- 1.0; P < 0.05, respectively). Early and delayed SUVmax and %DeltaSUVmax in metastatic LNs were significantly higher than those in benign LNs (P < 0.0001). The optimal parameter for the differentiation was the combined use of early SUVmax > 3.0 or delayed SUVmax > 4.0, yielding sensitivity of 88.8%, specificity of 80.6%, accuracy of 86.2%, negative predictive value of 76.9%, and positive predictive value of 90.6%. It provided better results than the use of early SUVmax > 3.0 alone (P = 0.019) or the optimal parameter for %DeltaSUVmax (>5%) (P = 0.012). However, 12 (19.3%) benign LNs were indistinguishable from metastatic LNs. CONCLUSIONS: Although dual-time point PET/CT scan enhances the difference of FDG uptake between FDG-avid metastatic and benign LNs and improves the differentiation when compared with a single scan, biopsy procedure may be still required for accurate assessment of LN status in patients with NSCLC and possible etiologies showing intensive FDG uptake in benign LNs. PMID- 19444551 TI - Variation in FDG uptake on PET in patients with radiation-induced pelvic insufficiency fractures: a review of 10 cases. AB - INTRODUCTION: The information available on (18)F-fluorodeoxyglucose (FDG) uptake on PET in radiation-induced pelvic insufficiency fracture (PIF) is limited. In this study, we reviewed the findings of FDG-PET in 10 cases with PIF. MATERIALS AND METHODS: We diagnosed 83 cases of PIF in patients who received pelvic radiotherapy between Jan 1995 and Aug 2005. Among these patients, we selected 10 patients who performed FDG-PET and reviewed the FDG uptake. RESULTS: Mild FDG uptake was still present at 6-months after the diagnosis of PIF in two patients. Eight patients had mild and diffuse FDG uptake and two patients had intense and heterogeneous uptake. All patients had vertical uptake parallel to the sacroiliac joints and one patient had the typical 'H' sign associated with PIF. The maximum of standardized uptake values was variable and ranged from 2.4 to 7.2. In three patients, follow-up PET images were obtained. All patients had FDG uptake that decreased with time. CONCLUSION: The FDG-PET demonstrated a variable degree of uptake in patients with a PIF. The pattern of uptake was diffuse and vertical, parallel to the sacroiliac joints. Therefore, clinicians should be careful with the interpretation of FDG uptake around the sacroiliac joints, and keep in mind false-positive lesions such as PIFs. PMID- 19444552 TI - Influence of N-butylscopolamine on SUV in FDG PET of the bowel. AB - OBJECTIVES: Peristalsis can lead to confusing FDG PET bowel uptake artefacts and potential for recording inaccurate mean standardised uptake value (SUV) measurements in PET-CT scans. Accordingly, we investigate the influence of different SUV normalisations on FDG PET uptake of the bowel and assess which one(s) have least dependence on body size factors in patients with and without the introduction of the anti-peristalsis agent N-butylscopolamine (Buscopan). METHODS: This study consisted of 92 prospective oncology patients, each having a whole body (18)F-FDG PET scan. Correlations were investigated between height, weight, glucose, body mass index (bmi), lean body mass (lbm) and body surface area (bsa) with maximum and mean SUV recorded for bowel normalised to weight (SUV(w)), lbm (SUV(lbm)), bsa (SUV(bsa)) and blood glucose corrected versions (SUV(wg), SUV(lbmg), SUV(bsag)). RESULTS: Standardised uptake value normalisations were significantly different between control and Buscopan groups with less variability experienced within individual SUV normalisations by the administration of Buscopan. Mean SUV normalisations accounted for 80% of correlations in the control group and 100% in the Buscopan group. Further, >86% of all correlations across both groups were dominated by mean SUV normalisations of which, about 69% were accounted for by SUV(bsa) and SUV(bsag). CONCLUSIONS: We recommend avoiding mean SUV(bsa) and individual glucose normalisations especially, mean SUV(bsag) as these dominated albeit relatively weak correlations with body size factors in control and Buscopan groups. Mean and maximum SUV(w) and SUV(lbm) were shown to be independent of any body size parameters investigated in both groups and therefore considered suitable for monitoring FDG PET uptake in the normal bowel for our patient cohort. PMID- 19444553 TI - Evaluation of the applicability of sevoflurane during post-tetanic myogenic motor evoked potential monitoring in patients undergoing spinal surgery. AB - PURPOSE: Recent evidence has indicated that post-tetanic motor evoked potentials (p-MEPs) can be used to improve the reliability of the monitoring of motor function during spinal surgery. However, data on p-MEP monitoring are limited to those in subjects under propofol anesthesia. The present study was conducted to assess the applicability of sevoflurane during p-MEP monitoring in patients undergoing spinal surgery. METHODS: Thirty-five patients undergoing spinal surgery under sevoflurane anesthesia were enrolled in the study and classified as being without preoperative motor deficits (n = 25) or with preoperative motor deficits (n = 10). For conventional MEP (c-MEP), transcranial train-pulse stimulation was delivered and the compound muscle action potentials were bilaterally recorded from the abductor pollicis brevis, abductor hallucis, tibialis anterior, and soleus muscles. For p-MEP, tetanic stimulation (50 Hz, 50 mA stimulus intensity) for 5 s was applied to the bilateral median and left tibial nerves 1 s prior to transcranial stimulation. RESULTS: The amplitudes of p MEP were significantly higher in all muscle recording sites than those of c-MEP in patients without motor deficits, whereas these amplitudes were significantly higher in only four of the eight muscles in patients with motor deficits (P < 0.05). The success rates of c-MEP and p-MEP recording were 48% and 64%, respectively, in patients without motor deficits and 30% and 60%, respectively, in patients with motor deficits. There were no statistically significant differences in success rates between c-MEP and p-MEP recording. CONCLUSION: Although the application of tetanic stimulation prior to transcranial stimulation did not significantly increase the success rates of MEP recording, it significantly enlarged MEP amplitude under sevoflurane anesthesia in patients without preoperative motor deficits. PMID- 19444554 TI - Low bispectral index values following electroconvulsive therapy associated with memory impairment. AB - PURPOSE: It has been reported some patients have opened eyes with low bispectral index (BIS) values immediately following electroconvulsive therapy (ECT). We investigated the time course of the recovery from amnesia and BIS values. METHODS: Five patients with depression requiring repeated ECT procedures were enrolled. The patients were asked to recall an object presented prior to anesthesia at four specific points (prior to induction, upon regaining consciousness following ECT, when they returned to their ward, and when their BIS values had returned to pre-anesthetic levels). BIS data were recorded continuously until BIS values returned to the pre-anesthetic levels at their ward. The area under a receiver-operating characteristic (ROC) curve was used to detect associations between the BIS values and disturbance of memory function. RESULTS: A total of 41 ECT stimuli were administered. After returning to their ward, patients generally fell asleep, with BIS values of between 50 and 70, and they woke up 1-2 h later. All the patients could recall the presented object prior to anesthesia and when the BIS values had returned to pre-anesthetic levels. The area under the ROC curve for the detection of memory disturbance was 0.902. CONCLUSION: The present study demonstrated a high frequency of patients falling asleep and the frequent occurrence of prolonged periods of low BIS values following ECT. The results of memory testing showed that ECT procedures resulted in amnesia. The ROC curve findings suggest a strong association of memory disturbance with BIS values. In conclusion, patients generally fell asleep, with low BIS values, for 1-2 h after ECT, and a prolonged period of impairment of memory formation was associated with low BIS values. PMID- 19444555 TI - Effect of landiolol hydrochloride on suxamethonium-induced neuromuscular block. AB - PURPOSE: The aim of this study was to examine the effect of landiolol hydrochloride, an ultrashort-acting beta(1)-blocker, on suxamethonium-induced neuromuscular block. METHODS: Thirty patients were randomly allocated to receive a loading dose of landiolol, 0.125 mg x kg(-1) x min(-1) for 1 min, followed by an infusion at 0.04 mg x kg(-1) x min(-1), or placebo. Twenty minutes after the infusion of landiolol or placebo, suxamethonium 1 mg x kg(-1) was administered during propofolfentanyl-nitrous oxide anesthesia. Neuromuscular block was monitored by train-of-four (TOF) responses of the adductor pollicis muscle, applying acceleromyographic stimuli to the ulnar nerve. RESULTS: The onset of neuromuscular block did not differ between the groups. The time from administration of suxamethonium to spontaneous recovery to the first twitch of TOF (T1) of control was significantly longer in the landiolol group (mean [SD]; 12.2 [2.5] min), when compared with the control group (9.8 [2.6] min). However, the TOF ratios measured when the T1 had spontaneously recovered to 10%, 25%, 50%, 75%, 90%, and 100% of control was comparable between the groups. CONCLUSION: Landiolol delayed recovery from suxamethonium-induced paralysis. However, the interaction between the drugs seemed to be small in the clinical setting. PMID- 19444556 TI - Gradient of bronchial end-tidal CO2 during two-lung ventilation in lateral decubitus position is predictive of oxygenation disorder during subsequent one lung ventilation. AB - PURPOSE: Hypoxemia is one of the major problems during one-lung ventilation (OLV). During two-lung ventilation (TLV) using a double-lumen bronchial tube, bronchial endtidal carbon dioxide partial pressure (ETbr(CO2)) can be determined on both sides, independently. The ETbr(CO2) is mainly dependent on the pulmonary perfusion to each lung. If the degree of oxygenation disorder during OLV were to be predictable before starting OLV, this could provide time to prepare for any subsequent hypoxemia. The aim of this study was to investigate whether the difference of ETbr(CO2) (D-ETbr(CO2)) between the dependent and the nondependent lungs during TLV in the lateral decubitus position (LP) could be a predictive factor for the severity of oxygenation disorder under subsequent OLV. METHODS: Eighteen patients undergoing lung surgery were enrolled in this study. Anesthesia was induced with intravenous thiopental and fentanyl, supplemented by the inhalation of sevoflurane. A left-sided double-lumen bronchial tube was placed. The ETbr(CO2) was independently determined on each side during TLV in the supine position (SP) and at 10 min after changing the position from SP to LP. PaO2/inspiratory fraction of oxygen (FIO2) was taken at 15 min after switching from TLV to OLV in LP. RESULTS: The decrease of PaO2/FIO2 at 15 min during OLV in LP correlated with the reduction of the D-ETbr(CO2) predetermined during TLV in LP (r = 0.698; P < 0.01). CONCLUSION: The D-ETbr(CO2) predetermined during TLV in LP could be a predictive factor for the severity of oxygenation disorder after starting OLV in LP. PMID- 19444557 TI - Transcutaneous PCO2 monitors are more accurate than end-tidal PCO2 monitors. AB - PURPOSE: The accuracy of monitors for measuring transcutaneous PCO2 (TcPCO2), end tidal PCO2 (EtPCO2), and nasal EtPCO2 was evaluated. METHODS: The measuring devices included a TcPCO2 monitor (TCM3; Radiometer Trading), an EtPCO2 monitor (Ultima; Datex-Ohmeda), and a nasal EtPCO2 monitor (TG-920P; Nihon Kohden). The sensor electrode of the TCM3 TcPCO2 monitor was applied to the skin of the subject's upper arm. A sampling tube attached to the proximal end of the tracheal tube was connected to the Ultima EtPCO2 monitor. The miniature sensor of the TG 920P nasal EtPCO2 monitor was attached to the nostril. The values obtained were compared with direct measurements of arterial PCO2 (PaCO2) obtained by means of an ABL700 blood gas analyzer (Radiometer Trading) in surgically treated patients. The means +/- 2 SD of the differences between variables were calculated. RESULTS: The TcPCO2 monitor (0.19 +/- 4.8 mmHg, mean +/- 2-SD) was more accurate than the EtPCO2 monitor (-4.4 +/- 6.5 mmHg, mean +/- 2-SD) in patients receiving artificial ventilation via an endotracheal tube and the TcPCO2 monitor was also more accurate than the nasal EtPCO2 monitor (-6.3 +/- 9.8 mmHg, bias +/- 2-SD) in patients breathing spontaneously. CONCLUSION: We found that the TcPCO2 monitor was more accurate than the EtPCO2 or nasal EtPCO2 monitor in surgically treated patients. PMID- 19444558 TI - Low dose of fentanyl reduces predicted effect-site concentration of propofol for flexible laryngeal mask airway insertion. AB - PURPOSE: In contrast to reports on the classical laryngeal mask airway (classical LMA; CLMA), no report has calculated the 50% and 95% effect-site concentrations (EC(50) and EC(95), respectively) of propofol required for flexible LMA (FLMA) insertion. This study was designed to determine the EC(50) and EC(95) of propofol for FLMA insertion, using probit analysis, and to investigate whether supplemental 0.25 microg x kg(-1) fentanyl decreased these concentrations. METHODS: Fifty-nine unpremedicated patients who were scheduled for elective minor oral surgery were randomly allocated to a saline-propofol group (S-P group; n = 30) or a fentanyl-propofol group (F-P group; n = 29). Each group was further divided into four subgroups, in which the propofol EC for FLMA insertion was set at 2.5, 3.0, 3.5, and 4.0 microg x ml(-1), respectively, in the S-P group and 1.8, 2.0, 2.5, and 3.0 microg x ml(-1), respectively, in the F-P group. The experiment was assessed as "successful" when FLMA insertion within 1 min was possible. RESULTS: The EC(50) and EC(95) in the S-P group were 3.29 (95% confidence interval [CI], 2.83-3.93) and 4.73 (95% CI, 3.94-12.22) microg x ml( 1), and those in the F-P group were 2.13 (95% CI, 1.42-2.60) and 3.54 95% CI, (2.78-34.78) microg x ml(-1), respectively. The EC(50) in the F-P group was significantly lower than that in the S-P group. There were no significant differences in bispectral index (BIS), hemodynamic variables, respiratory rate, and arterial oxygen saturation (SpO2) between the S-P and F-P groups. CONCLUSION: The propofol EC(50) for FLMA insertion was decreased by supplemental 0.25 microg x kg(-1) fentanyl without BIS, hemodynamic, or respiratory depression. PMID- 19444559 TI - Desflurane requirements for laryngeal mask airway insertion during inhalation induction. AB - PURPOSE: We hypothesized that the simultaneous use of low concentrations (<6%) of desflurane, nitrous oxide (N(2)O), and fentanyl would allow a laryngeal mask airway (LMA) to be inserted safely with inhalation induction of desflurane, even in nonparalyzed patients. This prospective, observational study was performed to determine the 50% effective concentration (EC(50)) of desflurane for LMA insertion in such patients. METHODS: Twenty-two adult patients undergoing ambulatory surgical procedures under general anesthesia using an LMA were included in the study. Fentanyl was administered intravenously at 1.5 microg x kg(-1), and anesthesia was induced with desflurane in 50% N(2)O and oxygen, using a normal tidal volume breathing technique. Subsequently, a preselected steady state end-tidal desflurane concentration was maintained for 10 min before insertion of the LMA. Successful LMA insertion was defined as the absence of adverse airway responses until cuff inflation. Target concentrations of desflurane for LMA insertion were determined using a modified Dixon's up-and-down method (starting dose, 5%; step size, 0.5%). RESULTS: All 22 patients completed the study without adverse events related to airway irritation. The EC(50) of desflurane for insertion of the LMA was determined to be 3.61 +/- 0.31%, and the 95% confidence interval (CI) of the EC(50) obtained using probit analysis was 3.13-3.90. CONCLUSION: We demonstrated that N(2)O-desflurane inhalation induction with a normal tidal breathing technique after premedication with fentanyl can be used safely without any adverse airway events in nonparalyzed patients. In such patients, the EC(50) of desflurane for successful LMA insertion was 3.61 +/- 0.31% (95% CI, 3.13-3.90). PMID- 19444560 TI - A randomized study of the effects of perioperative i.v. lidocaine on hemodynamic and hormonal responses for cesarean section. AB - PURPOSE: Intravenous infusion of lidocaine attenuates the stress response to surgery. We aimed to evaluate the effects of perioperative lidocaine on the hemodynamic and hormonal responses for cesarean delivery. METHODS: After the gaining of ethical approval, 90 patients scheduled for elective cesarean delivery were randomly allocated to receive either lidocaine 1.5 mg x kg(-1) i.v. bolus 30 min before induction, followed by an infusion of 1.5 mg x kg(-1) x h(-1) until 1 h after surgery (n = 45), or saline placebo (n = 45). Anesthesia was maintained with 50% nitrous oxide in oxygen with 0.7% isoflurane. Hemodynamic variables, plasma cortisol, maternal and neonatal lidocaine concentrations, Apgar scores at 1 and 5 min, neonatal acid-base status, and the neurologic and adaptive capacity score (NACS) were recorded. RESULTS: After induction, patients receiving lidocaine had a smaller increase in heart rate and mean arterial blood pressure (P < 0.02) and lower plasma cortisol concentrations (31.1 +/- 9.91 vs 45.6 +/- 8.43 microg x dL(-1); P < 0.001). There were no differences between the two groups in Apgar scores, NACS, or neonatal acid-base status. After delivery, maternal and umbilical venous concentrations and umbilical vein-to-maternal vein ratios of lidocaine were 2.05 +/- 0.42 microg x mL(-) and 1.06 +/- 0.31 microg x mL(-1), and 0.52 +/- 0.07, respectively. CONCLUSION: Perioperative lidocaine is safe and effective in attenuating the maternal stress response to surgery for cesarean delivery. PMID- 19444561 TI - Preoperative fluid and electrolyte management with oral rehydration therapy. AB - PURPOSE: We hypothesized that oral rehydration therapy using an oral rehydration solution may be effective for preoperative fluid and electrolyte management in surgical patients before the induction of general anesthesia, and we investigated the safety and effectiveness of oral rehydration therapy as compared with intravenous therapy. METHODS: Fifty female patients who underwent breast surgery were randomly allocated to two groups. Before entry to the operation room and the induction of general anesthesia, 25 patients drank 1000 ml of an oral rehydration solution ("oral group") and 25 patients were infused with 1000 ml of an intravenous electrolyte solution ("intravenous group"). Parameters such as electrolyte concentrations in serum and urine, urine volume, vital signs, vomiting and aspiration, volumes of esophageal-pharyngeal fluid and gastric fluid (EPGF), and patient satisfaction with the therapy (as surveyed by a questionnaire) were assessed. RESULTS: After treatment, the serum sodium concentration and the hematocrit value, which both declined within the normal limits, were significantly higher in the oral group than in the intravenous group (sodium, 140.8 +/- 2.9 mEq x l(-1) in the oral group and 138.7 +/- 1.9 mEq x l( 1) in the intravenous group; P = 0.005; hematocrit, 39.03 +/- 4.16% in the oral group and 36.15 +/- 3.41% in the intravenous group; P = 0.01). No significant difference was observed in serum glucose values. Urine volume was significantly larger in the oral group (864.9 +/- 211.5 ml) than in the intravenous group (561.5 +/- 216.0 ml; P < 0.001). The fractional excretion of sodium (FENa), as an index of renal blood flow, was increased in both groups following treatment (0.8 +/- 0.5 in the oral group and 0.8 +/- 0.3 in the intravenous group). Patient satisfaction with the therapy favored the oral rehydration therapy, as judged by factors such as "feeling of hunger", "occurrence of dry mouth", and "less restriction in physical activity". The volume of EPGF collected following the induction of anesthesia was significantly smaller in the oral group than in the intravenous group (6.03 +/- 9.14 ml in the oral group and 21.76 +/- 30.56 ml in the intravenous group; P < 0.001). No adverse events or adverse reactions were observed in either group. CONCLUSION: The results suggest that the oral rehydration therapy with an oral rehydration solution before surgery is superior to the current preoperative intravenous therapy for the provision of water, electrolytes, and carbohydrates, and this therapy should be considered as an alternative to the intravenous therapy for preoperative fluid and electrolyte management in selected surgical patients in whom there is no reason to suspect delayed gastric emptying. PMID- 19444562 TI - Time progression from the patient's operating room entrance to incision: factors affecting anesthetic setup and surgical preparation times. AB - PURPOSE: Owing to recent advances in surgical technology, substantial time is required for preparing surgical equipment before incision. The purpose of this study was to demonstrate the time progression from a patient's operating room entrance to incision and to evaluate the duration of each anesthetic procedure and surgical preparation. METHODS: We marked the following seven points on the anesthetic chart: (1) entrance; (2) i.v. line placement; (3) preoxygenation; (4) intubation; (5) completion of patient positioning (Anesth-Set); (6) applying antiseptic solution; and (7) incision. Afterward, we analyzed the event time periods according to anesthetic procedure, patient position, surgical service, and surgical procedure (such as the utilization of endoscopy, navigation systems, and sentinel lymph node biopsy). RESULTS: On average, it took approximately 3 min to start i.v. placement, 7 min until preoxygenation, 15 min until intubation, and 30 min until Anesth-Set. Epidural, arterial, and central venous catheterization required 15, 9, and 13 min, respectively. It took 20 min from Anesth-Set to incision, on average; 22, 4, and 5 min were required to prepare the navigation system, endoscope, and sentinel lymph node biopsy, respectively. In total, it took an average of 49.8 +/- 17.1 min from entrance to incision, which was significantly longer (30.4 +/- 8.8 min) than it took in 1985-1986. CONCLUSION: The mean time taken from the patient's operating room entrance to incision is now significantly longer than before. This may be attributed, at least in part, to the preparation of equipment associated with new surgical technologies. PMID- 19444563 TI - Work stress and workload of full-time anesthesiologists in acute care hospitals in Japan. AB - PURPOSE: The number of anesthesiologists per population in Japan is small compared with that in Europe and North America. While there is a growing concern that hard work causes anesthesiologists' fatigue and may compromise patient safety, the workload and physical stress, as well as the impact of staff support on physicians' stress have not been assessed in detail. The goal of this study was to evaluate the working environment, anesthesia workload, and occupational stress of anesthesiologists in Japan. METHODS: A questionnaire survey was performed targeting 1010 members of the Japanese Society of Anesthesiologists working as anesthesiologists affiliated with acute care hospitals in Japan. Data on background information, working environment, operation anesthesia duties, and stress were collected, and the relationship of work stress with background, environment, and anesthesia duties was evaluated by linear regression analysis. RESULTS: Responses were obtained from 383 full-time anesthesiologists (response rate, 43.9%). The total anesthesia time per week was 23.6 h on average. The work stress score was 114.3 +/- 30.2 (mean +/- SD) when the average workers' work stress score in Japan was 100. The work stress score was significantly associated with "years of experience" (with experience < 10 years considered as the reference; 10-19 years: beta = -0.18, P = 0.02, > or = 20 years: beta = -0.15, P = 0.04), "hospital with > or = 500 beds" (with a hospital with < or = 299 beds considered as the reference; beta = 0.15, P = 0.04), "total time of anesthesia per week" (beta = 0.18, P.02), "estimated annual cases managed by an anesthesiologist" (beta = 0.12, P = 0.04) and "no-support stress" (beta = 0.21, P < 0.01) on linear regression analysis (R(2) = 0.12). CONCLUSION: Our results provide a quantitative assessment of the duties of anesthesiologists and show that work stress among anesthesiologists is related to workload and other factors. PMID- 19444564 TI - Does high-dose opioid anesthesia exacerbate ischemic spinal cord injury in rabbits? AB - PURPOSE: Intrathecal morphine given during a post-ischemic period has been reported to have the potential to exacerbate ischemic spinal cord injury. However, it remains unknown whether synthetic opioids administered systemically exacerbate ischemic injury. We sought to compare the damage of the spinal cord after transient spinal cord ischemia in rabbits anesthetized with three different regimens; isoflurane, fentanyl with isoflurane, and remifentanil with isoflurane. METHODS: We assigned rabbits to three groups (n = 9 in each); an isoflurane group (isoflurane 1 minimum alveolar concentration [MAC]), a fentanyl group (isoflurane 0.5 MAC + 100 microg x kg(-1) i.v. fentanyl given over 30 min before aortic occlusion), and a remifentanil group (isoflurane 0.5 MAC + 1 microg x kg(-1) x min(-1) i.v. remifentanil started 30 min before aortic occlusion and maintained until 1 h after reperfusion). Spinal cord ischemia was produced by occluding the abdominal aorta for 13 min. Hindlimb motor function (score range: 4, normal to 0, paraplegia) was assessed daily for 7 days, and then the number of normal neurons in the anterior spinal cord was counted. RESULTS: Severe motor dysfunction (score < or = 1) was observed in seven, four, and five animals in the isoflurane, fentanyl, and remifentanil groups, respectively. There were no significant intergroup differences in neurological scores. There were no differences in the numbers of normal neurons among the three groups (22 +/- 22, 42 +/- 30, 33 +/- 28, respectively). CONCLUSION: Our results suggest that neither i.v. fentanyl nor i.v. remifentanil added to 0.5 MAC isoflurane exacerbated ischemic spinal cord injury in rabbits when compared to 1 MAC isoflurane. PMID- 19444565 TI - Interaction between midazolam and serotonin in spinally mediated antinociception in rats. AB - PURPOSE: Intrathecal administration of serotonin (5-HT) is antinociceptive through the involvement of spinal cord gamma-aminobutyric acid (GABA) receptors. Therefore, 5-HT would interact with the GABA agonist, midazolam, which is well known to exert spinally mediated antinociception in the spinal cord. The present study investigated the antinociceptive interaction between spinally administered 5-HT and midazolam, using two different rat nociceptive models. METHODS: Sprague Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and paw flinches induced by formalin injection after the intrathecal administration of midazolam or 5-HT, or the midazolam/ HT combination. The effects of the combination were tested by isobolographic analysis, using the combination of each 1, 1/2, 1/4, 1/8, and 1/16 of the 50% effective dose (ED50). The total fractional dose was calculated. Behavioral side effects were also examined. RESULTS: 5-HT alone and midazolam alone both showed dose-dependent antinociception in both the tail flick test and the formalin test. The ED50 of the combination was not different from the calculated additive value either in the tail flick test or in phase 2 of the formalin test, but it was significantly smaller than the calculated additive value in phase 1 of the formalin test. The total fractional dose value was 0.90 in the tail flick test, 0.093 in phase 1 of the formalin test, and 1.38 in phase 2 of the formalin test. The agitation, allodynia, or motor disturbance observed with either agent alone was not seen with the combination treatment. CONCLUSION: The antinociceptive effects of intrathecal midazolam and 5-HT were additive on thermal acute and inflammatory facilitated stimuli, and synergistic on inflammatory acute stimulation. PMID- 19444566 TI - Postoperative cognitive decline. AB - Memory loss and lack of concentration are symptoms that frequently occur in patients who have undergone a surgical procedure. Although cognitive function can be assessed using neuropsychological tests, reliable diagnosis of postoperative cognitive decline (POCD) appears to be difficult. Therefore, the true incidence of POCD is unknown. Severe POCD, which is apparent even without neuropsychological testing, is reported most frequently after cardiac and hip replacement surgery. In these cases, POCD probably reflects microembolic brain injury. Apart from the nature of the surgical procedure, advanced age is the most important risk factor for POCD. The anesthetic technique is not a determinant of POCD: the risk of POCD appears to be similar after both general and regional anesthesia. PMID- 19444567 TI - Three-dimensional CT image analysis of a tracheal bronchus in a patient undergoing cardiac surgery with one-lung ventilation. AB - The incidence of a tracheal bronchus--that is, a congenitally abnormal bronchus originating from the trachea or main bronchi--is 0.1%-2%. Serious hypoxia and atelectasis can develop in such patients with intubation and one-lung ventilation. We experienced a remarkable decrease in peripheral oxygen saturation (SpO2) and a rise in airway pressure during placement of a double-lumen endobronchial tube in a patient with patent ductus arteriosus and tracheal bronchus. Substitution of the double-lumen tube with a bronchial blocker tube provided secure isolation of the lung intraoperatively. A type I tracheal bronchus and segmental tracheal stenosis were identified on postoperative three dimensional (3D) computed tomographic (CT) images. Preoperative examination of chest X-rays, CT images, and preoperative tracheal 3D images should preempt such complications and assist in securing safe and optimal one-lung ventilation. PMID- 19444568 TI - Successful treatment with hydrocortisone for heat stroke with critical illness related corticosteroid insufficiency: transitional changes in serum cytokine and cortisol concentrations. AB - A 37-year-old man was transferred to our emergency center because of heat stroke with circulatory shock. Despite aggressive body cooling, massive intravenous transfusion, and supply of inotropic agents, shock was persistent. To evaluate adrenal function, an adrenocorticotropic hormone stimulation test was conducted and the results indicated that he had critical illness-related corticosteroid insufficiency (CIRCI) as a result of adrenal insufficiency. Continuous hydorocortisone administration was started and he recovered from shock within a few hours. He was discharged on the thirty-seventh hospital day. Serum cortisol and cytokine concentrations were initially high and the cytokines decreased subsequent to hydrocortisone administration. It is speculated that CIRCI is an exacerbating factor in heat stroke, and hydrocortisone may be a potential therapeutic approach in such patients. PMID- 19444569 TI - Anesthetic management for severe aortic regurgitation in an infant repaired by Ross procedure. AB - We report the anesthetic management of a 7-month-old male infant with severe aortic regurgitation (AR) scheduled for the Ross procedure. To the best of our knowledge, this is the first report from the viewpoint of anesthetic management for the Ross procedure performed in an infant. He had been suffering from severe AR that occurred suddenly when he was 5 months old. The cause of the AR was considered to be spontaneous rupture of a fenestrated aortic valve, owing to congenital tissue defect in part of the aortic valvular leaflet. The Ross procedure was scheduled to be performed under general anesthesia using deep hypothermic cardiopulmonary bypass (CPB). Continuous infusion of nitroglycerin was started during CPB and continued after CPB to dilate the newly implanted coronary arteries for the prevention of myocardial ischemia and to decrease afterload and pulmonary vascular resistance. Weaning from CPB was performed without difficulty, but after the prolonged CPB he had a bleeding tendency that needed transfusion and a hemostatic drug. Monitoring with transesophageal echocardiography was very useful for evaluating myocardial ischemia, and for assessing the procedure and the completion of surgical repair. His postoperative course was uneventful and he was discharged on the 25th postoperative day. PMID- 19444570 TI - Unanticipated complication of a malpositioned central venous catheter. AB - We report an unusual complication that occurred late in the postoperative period, due to a damaged and malpositioned peripherally inserted central catheter (PICC) used for central venous pressure monitoring during esophagocoloplasty and for postoperative parenteral nutrition. On the seventh postoperative day, the development of a leak from the neck wound coincided with the administration of intravenous fluids via the PICC. The leak had occurred as a result of slow erosion of the left internal jugular vein (IJV) by the damaged edges of the catheter. PMID- 19444571 TI - Difficult laryngoscopy caused by massive mandibular tori. AB - Mandibular tori, defined as bony protuberances located along the lingual aspect of the mandible, are a possible cause of difficult intubation. We describe a case of mandibular tori that resulted in difficult intubation. A 62-year-old woman who had speech problems was diagnosed with mandibular tori, and was scheduled for surgical resection. On physical assessment, the patient had a class II Mallampati view and bilateral mandibular tori. Preoperative computed tomography images demonstrated that the bilateral mandibular tori arose from the lingual aspects of the second incisor to the first molar regions of the mandibular corpus, and occupied the floor of the mouth. In the operating room, anesthesia was induced with remifentanil and propofol. After complete paralysis was achieved, laryngoscopy was attempted several times with Macintosh blades. The massive tori prevented insertion of the tip of the blade into the oropharynx, and neither the epiglottis nor the arytenoids could be visualized, i.e., Cormack and Lehane grade IV. Blind nasotracheal intubation was successful and the surgery proceeded uneventfully. The anesthesiologist should examine any space-occupying lesion of the oral floor and should be vigilant for speech problems in order to detect mandibular tori that might impede intubation. PMID- 19444572 TI - Management of difficult airway in pediatric patients with right ventricular outflow tract obstruction. AB - We present two cases of difficult airway management for patients with Pierre Robin syndrome and right ventricular outflow tract obstruction in infants. To prevent the exacerbation of right ventricular outflow tract obstruction, adequate oxygenation and ventilation are mandatory in this population. This rule needs to be followed even while dealing with a difficult airway. Depending on the prediction of mask ventilation capability, we took two different approaches to difficult airway. In the first case, we fiberoptically intubated the patient while allowing him to breathe spontaneously with the aid of a nasopharyngeal airway under deep sedation. In the second case, we fiberoptically intubated the patient through a laryngeal mask airway while controlling ventilation. Through both cases, we highlight options of difficult airway management in the pediatric population. Although we can approach a difficult airway with or without spontaneous breathing, the important point is how we will prepare the methods to oxygenate and ventilate patients throughout the procedure. Patients with difficult airway and right ventricular outflow tract obstruction are good examples to make us realize this point. PMID- 19444573 TI - Low-density lipoprotein apheresis in a pediatric patient with refractory nephrotic syndrome due to focal segmental glomerulosclerosis. AB - Focal segmental glomerulosclerosis (FSGS) often leads to refractory nephrotic syndrome (NS). A high level of low-density lipoprotein (LDL) is a risk factor for the progression of NS. An 8-year-old girl presented with severe proteinuria refractory to steroid therapy. She was diagnosed with non-IgA diffuse mesangial proliferative glomerulonephritis. Oral prednisolone, methylprednisolone (mPL) pulse therapy, and cyclosporine and cyclophosphamide therapy failed to achieve remission. Follow-up renal biopsy revealed FSGS. Her serum level of LDL was high, and LDL-apheresis (LDL-A) was performed five times, followed by mPL pulse therapy. Urinary protein decreased from 2-4 g x day(-) to 0.5-1.0 g x day(-). LDL A may be beneficial in the treatment of multidrug-resistant FSGS. PMID- 19444574 TI - Sivelestat treatment for acute respiratory distress syndrome in an infant. AB - Resuscitation and acute cerebral damage after cardiopulmonary arrest often induce a systemic inflammatory response and subsequently cause multiple organ failure, including acute lung injury (ALI). Sivelestat has been reported to be effective for ALI associated with systemic inflammatory response syndrome (SIRS), but the effectiveness and safety of the drug for infants has not been confirmed. We report a 33-day-old infant who developed acute respiratory distress syndrome (ARDS) following hypoxic encephalopathy immediately after successful resuscitation from cardiopulmonary arrest. Sivelestat was administered continuously for 7 days with no adverse reactions, and consolidations on a chest radiograph were diminished and impaired oxygenation was markedly alleviated. Our experience suggests that intravenous sivelestat offers a new therapeutic strategy for infantile ARDS/ALI, but further investigation of the indication, administration period, and dosage is required. PMID- 19444575 TI - Severe allergic contact dermatitis resulting from occupational exposure to tincture of benzoin aerosol spray in an anesthesiologist. AB - We describe the clinical presentation and management of an anesthesiologist who developed a severe allergic contact dermatitis resulting from occupational exposure to tincture of benzoin aerosol spray. A previously healthy male anesthesiologist with a small laceration between his right thumb and forefinger used a tincture of benzoin aerosol spray to improve adhesion of a small bandage immediately before performing a spinal anesthetic. He had previously used benzoin for skin reinforcement on several occasions during weight-lifting. The anesthesiologist experienced severe pruritus in the affected hand 48 h after benzoin exposure. A well-demarcated, bright red erythematous confluent vesicular dermatitis with and without painful hemorrhagic bullae erupted on the palmar and dorsal surfaces, respectively, of his hand, accompanied by pronounced edema. The palmar bullae were drained with several small incisions and the anesthesiologist was treated with intravenous methylprednisolone. He was unable to work for 10 days while the dermatitis gradually resolved. The case emphasizes that occupational exposure to benzoin represents a potential risk for operating room personnel who may be susceptible to cutaneous delayed hypersensitivity-mediated allergic reactions as a result of previous exposure to benzoin or chemically related cross-reacting substances. PMID- 19444576 TI - Complex of branched cyclodextrin and lidocaine prolonged the duration of peripheral nerve block. AB - Although laboratories have tried to synthesize new local anesthetics, currently available local anesthetics rarely provide prolonged regional blockade. New models of sustained-release preparations of local anesthetics with liposomes and microspheres have been studied to prolong the duration of the effects of the local anesthetics. In the present study, we examined whether a complex of a branched cyclodextrin (CD), 6-O-alpha-D-maltosyl-beta-cyclodextrin (G2-beta-CD) and lidocaine could prolong local nerve block when compared with plain lidocaine. The sciatic nerve in male Sprague-Dawley rats was blocked with plain lidocaine (n = 10), the complex of G2-beta-CD + lidocaine (n = 10), or plain G2-beta-CD (n = 4). Sensory block was assessed with a hotplate set at 56 degrees C. The median duration of the block was longer in the complex group than in the plain lidocaine group (110 min; range, 70-150 min vs 55 min; range, 40-80 min; P < 0.05), thus demonstrating that the complex with CyD significantly prolonged the nerve block effect of lidocaine. In conclusion, the present study showed that this encapsulating technique with CyD is useful to expand local anesthetic effect in peripheral nerve blockade. PMID- 19444577 TI - Serum concentration of lidocaine after transversus abdominis plane block. AB - We measured the serum concentration of lidocaine after transversus abdominis plane (TAP) block with 40 ml of 1% lidocaine in 12 patients under general anesthesia, using a fluorescence polarization immunoassay. The peak mean serum concentration of lidocaine occurred 30 min after the block (3.6 +/- 0.7 microg x ml(-1)). The highest concentration of lidocaine (5.microg x ml(-1)) was recorded 15 min after the block. These results indicate that a TAP block can potentially cause systemic toxicity of a local anesthetic. The analgesic effect of the TAP block may partially depend on the rise in serum concentration of the local anesthetic. PMID- 19444578 TI - Nociceptin receptor antagonist JTC-801 inhibits nitrous oxide-induced analgesia in mice. AB - The mechanism of the analgesic effect of nitrous oxide (N(2)O) has not been completely clarified. Although we have reported that the analgesic effect of N(2)O was significantly decreased in nociceptin-orphanin FQ (N/OFQ) receptor (NOP)-deficient mice, the effect of nociceptin receptor antagonists on N(2)O induced analgesia has not been reported. In this investigation, we examined the effect of the NOP antagonist JTC-801 on N(2)O-induced analgesia in 129Sv mice by the writhing test and tail flick test, and demonstrated that the analgesic effect of N(2)O was suppressed by the intraperitoneal administration of JTC-801. PMID- 19444579 TI - Radial artery cannulation using the Insyte-A device with ultrasound assistance. PMID- 19444580 TI - Kinked inner tube of coaxial Bain circuit--need for corrugated inner tube. PMID- 19444581 TI - Inadvertent intraarterial injection of propofol in a patient under general anesthesia. PMID- 19444582 TI - Discrepancy between soluble fibrin and D-dimer levels among sampling sites in elderly patients with femoral neck fracture. PMID- 19444583 TI - Late migration of subclavian venous catheter after initial correct placement. PMID- 19444584 TI - Ultrasound-guided neuroaxial anesthesia: accurate diagnosis of spina bifida occulta by ultrasonography. PMID- 19444586 TI - Localized cervical cancer (stage 0.05) in Cyclin D1 expression was found between As(2)O(3)-treated cells and the control. Cyclin A expression in As(2)O(3)-treated HL-60 cells was up-regulated at 6 microg/ml, suggesting that it is required for S phase and passage through G(2) phase in cell cycle progression. Taken together, these results indicate that As(2)O(3) has the potential to induce cell cycle arrest through activation of the 53-kDa tumor suppressor protein and repression of the c-fos transcription factor. Up-regulation of RARE by As(2)O(3) indicates that its cytotoxicity may be mediated through interaction/binding with the retinoic acid receptor, and subsequent inhibition of growth and differentiation. PMID- 19444596 TI - Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. AB - Chronic exposure to elevated free fatty acids, in particular long chain saturated fatty acids, provokes endoplasmic reticulum (ER) stress and cell death in a number of cell types. The perturbations to the ER that instigate ER stress and activation of the unfolded protein in response to fatty acids in hepatocytes have not been identified. The present study employed H4IIE liver cells and primary rat hepatocytes to examine the hypothesis that saturated fatty acids induce ER stress via effects on ER luminal calcium stores. Exposure of H4IIE liver cells and primary hepatocytes to palmitate and stearate reduced thapsigargin-sensitive calcium stores and increased biochemical markers of ER stress over similar time courses (6 h). These changes preceded cell death, which was only observed at later time points (16 h). Co-incubation with oleate prevented the reduction in calcium stores, induction of ER stress markers and cell death observed in response to palmitate. Inclusion of calcium chelators, BAPTA-AM or EGTA, reduced palmitate- and stearate-mediated enrichment of cytochrome c in post-mitochondrial supernatant fractions and cell death. These data suggest that redistribution of ER luminal calcium contributes to long chain saturated fatty acid-mediated ER stress and cell death. PMID- 19444597 TI - Functional capacity evaluation in subjects with early osteoarthritis of hip and/or knee; is two-day testing needed? AB - INTRODUCTION: The Work Well Functional Capacity Evaluation (WW FCE) is a two-day performance based test consisting of several work-related activities. Three lifting and carrying test items may be performed on both days. The objective of this study was to assess the need for repeated testing of these items in subjects with early osteoarthritis of the hip and/or the knee and to analyze sources of variation between the 2 days of measurement. METHODS: A standardized WW FCE protocol was applied, including repeated testing of lifting low, lifting overhead and carrying. Differences and associations between the 2 days were calculated using paired samples t-tests, intraclass correlation coefficients (ICC) and limits of agreement (LoA). Possible sources of individual variation between the 2 days were identified by Wilcoxon signed ranks tests. Pearson correlation coefficients were calculated for differences in performances between days and differences in possible sources of variation between days. RESULTS: Seventy-nine subjects participated in this study, their mean (SD) age was 56.6 (4.8) years, median (min-max) WOMAC (Western Ontario and McMaster Universities) index scores for pain, stiffness and physical function were 5 (0-17), 3 (0-7) and 14 (0-49), respectively. Median (min-max) SF36 physical function was 75 (5-95), and SF36 pain score was 67 (12-76). Mean performance differences ranged from -0.2 to -0.8 kg (P > 0.05). ICC's ranged from 0.75 (lifting overhead) to 0.88 (lifting low). LoA were: lifting low 8.0 kg; lifting overhead 6.5 kg; carrying 9.0 kg. Pearson's correlations were low and non-significant. CONCLUSIONS: All three tests show acceptable two-day consistency. WW FCE testing on two consecutive days is not necessary for groups of subjects with early osteoarthritis. Individual sources of variation could not be identified. PMID- 19444599 TI - Sequencing and computational analysis of complete genome sequences of Citrus yellow mosaic badna virus from acid lime and pummelo. AB - Citrus yellow mosaic badna virus (CMBV), a member of the Family Caulimoviridae, Genus Badnavirus, is the causative agent of Citrus mosaic disease in India. Although the virus has been detected in several citrus species, only two full length genomes, one each from Sweet orange and Rangpur lime, are available in publicly accessible databases. In order to obtain a better understanding of the genetic variability of the virus in other citrus mosaic-affected citrus species, we performed the cloning and sequence analysis of complete genomes of CMBV from two additional citrus species, Acid lime and Pummelo. We show that CMBV genomes from the two hosts share high homology with previously reported CMBV sequences and hence conclude that the new isolates represent variants of the virus present in these species. Based on in silico sequence analysis, we predict the possible function of the protein encoded by one of the five ORFs. PMID- 19444600 TI - Comparative analysis of the large fragment of the 5' untranslated region (LF-5' UTR) of serotype A foot-and-mouth disease virus field isolates from India. AB - India is endemic for foot-and-mouth disease (FMD) and in recent years a unique group within serotype A, carrying a codon deletion at an antigenically critical site in capsid protein VP3 has emerged (VP3(59)-deletion group). This tempted us to analyze the noncoding region, which is an under represented area, though critically associated with virus biology and pathogenesis. Analysis of the large fragment of 5' untranslated region (LF-5' UTR) of type A FMD virus revealed discrepancy in the overall tree topology between LF-5' UTR and 1D region possibly due to independent evolution of coding and noncoding regions. The VP3(59) deletion group maintained its phylogenetic distinctness even at the LF-5' UTR. Eighteen lineage specific signatures detected here support independent evolutionary paths for the lineages. Extensive deletions of 45 and 89 nucleotides corresponding to the pseudoknot region were noticed. Conservation pattern in the 'A(253)AACA' motif in the cre/bus stem-loop indicates the importance of first three 'A' residues in VPg uridylylation. Of the three polypyrimidine tract binding protein (PTB) binding sites mapped on the internal ribosome entry site (IRES), the pyrimidine tract (Py tract) in the loop of domain 2 was found to be maximally conserved and it might be the major PTB binding site. Strikingly, a deletion group lineage specific transversion was noticed in the Py tract at the 3' end of IRES without significantly affecting its in vitro infectious titer. Hence, we presume that for efficient cap-independent viral translation, either a minimum number of pyrimidine residues rather than a complete Py tract or a Py tract tolerating transversions only at specific locations and a core motif 'CUUU' within the Py tract is essential. PMID- 19444601 TI - Infection and replication of avian influenza H5N1 virus in an infected human. AB - The highly pathogenic avian influenza H5N1 viruses usually cause severe diseases and high mortality in infected humans. However, the tissue tropism and underlying pathogenesis of H5N1 virus infection in humans have not been clearly elucidated yet. In this study, an autopsy was conducted to better understand H5N1 virus distributions in tissues of infected humans, and whether H5N1 virus can replicate in extrapulmonary tissues. We found that the lungs had the higher viral load than the spleen, whereas no detectable viruses in tissues of heart, liver, kidney, large intestine, small intestine, or brain. Specifically, the viral load was higher in the left lung (7.1 log10 copies per ml) in relation to the right lung (5.7 log10 copies per ml), resulting in more severe pathological damage in the left lung, and lung tissues contained both positive- and negative-stranded viral RNA. However, there existed a low level of H5N1 viruses in the spleen (3.8 log10 copies per ml), with the absence of positive-stranded viral RNA. Our results indicate that replication of H5N1 viruses mainly occurs in the lungs, and the degree of lung damage is highly correlated with the viral load in the lungs. The low-load viruses in the spleen might be introduced through blood circulation or other ways. PMID- 19444602 TI - Reporting of race and ethnicity in breast cancer research: room for improvement. AB - Health disparities in breast cancer outcomes according to race/ethnicity are well documented. Randomized clinical trials (RCT) offer an opportunity to evaluate differences in disease biology and response to therapy that may contribute to disparities. We conducted a PubMed search to identify all English language original reports of breast cancer RCT from October 2001 to October 2006. The primary outcomes of interest were reporting of accrual and results by race or ethnicity of trial subjects. We evaluated the correlation between study characteristics and reporting of race/ethnicity. A total of 197 eligible trials were identified among 29 journals. Accrual was reported by race in 17% of studies and results analyzed by race in only 2%. Reporting of race was associated with National Cancer Institute funding (38 vs. 13%, P = 0.001), US cooperative group trials (52 vs. 13%, P < 0.0001), trials with US sites (43 vs. 5%, P < 0.0001), and trials enrolling > 500 subjects (24 vs. 12%, P = 0.055). Pharmaceutical industry funding, # of centers, stage of disease, nature of experimental intervention and study outcomes were not associated with reporting of race. Among US studies reporting trial accrual by race/ethnicity, the mean accrual distribution was 81% white, 7.6% black, 9.6% Asian, and 7.2% Hispanic subjects. The majority of breast cancer RCT fail to report the race/ethnicity of participants. Low accrual of black subjects and failure to report accrual and outcomes by race in RCT may contribute to difficulty in understanding and overcoming health disparities in breast cancer. PMID- 19444603 TI - High levels of E4-PHA-reactive oligosaccharides: potential as marker for cells with characteristics of hepatic progenitor cells. AB - Oligosaccharides serve as markers of the cell surface and have been used as certain kinds of tumor markers. In the present study, we established a simple method for isolating hepatic progenitor cells using a lectin, which recognizes a characteristic oligosaccharide structure. Rat liver epithelial (RLE) cells, which have been established as a hepatic stem-like cell, were used to identify characteristic oligosaccharide structures on hepatic stem cells. As a result from lectin micro array, several types of lectin including E4-PHA were identified to bind RLE cells specifically. Furthermore, lectin blot and lectin flow cytometry analyses showed that binding to E(4)-PHA lectin was significantly increased in RLE cells, compared to hepatocytes, and hepatoma cells. The induction of differentiation into a hepatocyte lineage of RLE cells by treatment with Oncostatin M and dexamethasone resulted in a decrease in E(4)-PHA binding. Using an E(4)-PHA column, we succeeded in isolating hepatic stem cells from LEC (Long Evans with cinnamon coat color) rat livers with fluminant hepatitis. The characteristics of the established cells were similar to RLE cells and had a potential of proliferating in rat liver. These results suggest that oligosaccharides can serve as a novel marker for the isolation of the hepatic progenitor cells. PMID- 19444604 TI - Changes in bacterial diversity and community structure following pesticides addition to soil estimated by cultivation technique. AB - An experiment was conducted under laboratory conditions to investigate the effect of increasing concentrations of fenitrothion (2, 10 and 200 mg a.i./kg soil), diuron (1.5, 7.5 and 150 mg a.i./kg soil) and thiram (3.5, 17.5 and 350 mg a.i./kg soil) on soil respiration, bacterial counts and changes in culturable fraction of soil bacteria. To ascertain these changes, the community structure, bacterial biodiversity and process of colony formation, based on the r/K strategy concept, EP- and CD-indices and the FOR model, respectively, were determined. The results showed that the measured parameters were generally unaffected by the lowest dosages of pesticides, corresponding to the recommended field rates. The highest dosages of fenitrothion and thiram suppressed the peak SIR by 15-70% and 20-80%, respectively, while diuron increased respiration rate by 17-25% during the 28-day experiment. Also, the total numbers of bacteria increased in pesticide treated soils. However, the reverse effect on day 1 and, in addition, in case of the highest dosages of insecticide on days 14 and 28, was observed. Analysis of the community structure revealed that in all soil treatments bacterial communities were generally dominated by K-strategists. Moreover, differences in the distribution of individual bacteria classes and the gradual domination of bacteria populations belonging to r-strategists during the experiment, as compared to control, was observed. However, on day 1, at the highest pesticide dosages, fast growing bacteria constituted only 1-10% of the total colonies number during 48 h of plate incubation, whereas in remaining samples they reached from 20 to 40% of total cfu. This effect, in case of fenitrothion, lasted till the end of the experiment. At the highest dosages of fenitrothion, diuron and at all dosages of thiram the decrease of biodiversity, as indicated by EP- and CD indices on day 1, was found. At the next sampling time, no significant retarding or stimulating effect was detected. However, in case of CD values the higher differences were observed. The significant impact of pesticides on the physiological state of soil bacteria was not found. They were generally in dormant state (lambda < 0.5), but immediately after pesticides application, the additional reduction of frequency of bacterial cell proliferation (max. decrease of lambda value to 0.15 for thiram on day 14) and prolonged retardation time of colony appearance (max. increase of t(r) value to 1.39 for fenitrothion on day 1) on agar plates were found. PMID- 19444605 TI - Regional and temporal changes in proteomic profile after middle cerebral artery occlusion with or without reperfusion in rats. AB - Although DNA microarray studies showed up-regulation of various genes, failures of translation of many genes are expected to occur under ischemic conditions even in the penumbra with mild reduction in cerebral blood flow. We applied surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) technology to study proteomic profile at 6, 12, and 24 h after photothrombotic middle cerebral artery (MCA) occlusion with or without YAG laser induced reperfusion in adult male spontaneously hypertensive rats. Of the 43 protein peaks that differed from the sham-operation group with a criterion (no overlap of peak intensities between the two groups), 36 peaks (84%) were down regulated, and seven were up-regulated. All increased peaks showed greater than twofold increases (up to 8.1 fold) compared with those in the sham-operation group. Effects of reperfusion were observed mainly at 24 h after 1 h of MCA occlusion only in the penumbra, where 23 of 32 peaks returned toward the control values, whereas none of 33 peaks showed such attenuation in the ischemic core. Major ischemia-induced changes in protein peaks detected with SELDI-TOF-MS were down-regulations. The present study showed that dynamic changes of protein profile were associated with progression and recovery of the ischemic core and penumbra. PMID- 19444606 TI - Neuroprotective effects of Withania somnifera dunal.: A possible mechanism. AB - Present study was carried out to understand the possible mechanism of neuroprotective action of the root extract of Withania somnifera Dunal (WS). The study is focused on WS mediated inhibition of nitric oxide production, which is known to mediate neurodegeneration during stress. Adult mice (28 +/- 5 g) were exposed to restraint stress for 30 days. Activity of NADPH diaphorase (NADPH-d) and factors (Acetylcholine, serotonin and corticosterone), which regulates NADPH d activity were studied. Treatment with WS extract for 30 days during stress, significantly reversed the stress induced NADPH-d activation. Observations suggest that inhibition of NADPH-d by WS is not a direct effect of extract on NADPH-d, instead it inhibits via suppressing corticosterone release and activating cholineacetyltransferase, which in turn increase serotonin level in hippocampus to inhibit NADPH-d. Together, the main mechanism underlying the neuroprotective effects of WS can be attributed to its role in the down regulation of nNOS and neurochemical alterations of specific neurotransmitter systems. These observations thus suggest that WS root extract could be developed as a potential preventive or therapeutic drug for stress induced neurological disorders. PMID- 19444607 TI - Modulation of alpha-synuclein aggregation by dopamine: a review. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by (1) the selective loss of dopaminergic neurons in the substantia nigra and (2) the deposition of misfolded alpha-synuclein (alpha-syn) as amyloid fibrils in the intracellular Lewy bodies in various region of the brain. Current thinking suggests that an interaction between alpha-syn and dopamine (DA) leads to the selective death of neuronal cells and the accumulation of misfolded alpha syn. However, the exact mechanism by which this occurs is not fully defined. DA oxidation could play a key role is the pathogenesis of PD by causing oxidative stress, mitochondria dysfunction and impairment of protein metabolism. Here, we review the literature on the role of DA and its oxidative intermediates in modulating the aggregation pathways of alpha-syn. PMID- 19444608 TI - Modulation of glutamate and glycine transporters by niflumic, flufenamic and mefenamic acids. AB - Three fenamates--niflumic, flufenamic and mefenamic acids--were tested for effects on substrate-induced currents of glutamate and glycine transporters (EAAT1, EAAT2, GLYT1b and GLYT2a) expressed in Xenopus laevis oocytes. All fenamates inhibited EAAT1 currents; 100 microM flufenamic acid produced the most inhibition, decreasing the I (max) by 53 +/- 4% (P < 0.001). EAAT2 currents were less sensitive, but 100 microM flufenamic acid inhibited the I (max) by 34 +/- 5% (P = 0.006). All fenamates inhibited GLYT1b currents; 100 microM flufenamic acid produced the most inhibition, decreasing the I (max) by 61 +/- 1% (P < 0.001). At 100 microM, effects on the GLYT2a I (max) were mixed: 13 +/- 2% inhibition by flufenamic acid (P = 0.002), 30 +/- 6% enhancement by niflumic acid (P = 0.002), and no effect by mefenamic acid. Minor effects on substrate affinity suggested non-competitive mechanisms. These data could contribute to the development of selective transport modulators. PMID- 19444609 TI - Acculturation factors and substance use among Asian American youth. AB - In this study of 329 Cambodian, Chinese, Laotian/Mien, and Vietnamese youth in Oakland, California, acculturation factors of individualism-collectivism and acculturative dissonance were examined as risk and protective factors for substance use. Results of structural equation modeling and bootstrapping revealed that peer substance use was a robust mediator between individualism and youth's self-reported substance use, particularly among Vietnamese and males. Peer substance use also significantly mediated the relation between collectivism and substance use for females. As such, there appears to be ethnic and gender group variations in the saliency of cultural/acculturation factors with respect to substance use. Implications for substance use prevention programs for ethnic and immigrant youth are discussed. PMID- 19444610 TI - Phenolics, sugars, antimicrobial and free-radical-scavenging activities of Melicoccus bijugatus Jacq. fruits from the Dominican Republic and Florida. AB - Edible fruits of the native South American tree Melicoccus bijugatus Jacq. are consumed fresh or in traditional food, drink and medicinal preparations. Some therapeutic effects of these fruits may be due to phenolics and sugars. Aqueous acetone, methanol or ethanol tissue extracts of different cultivars or collections of M. bijugatus fruits from the Dominican Republic and Florida were analyzed for total phenolics and free radical scavenging activity by UV-vis spectroscopy, sugars by gas chromatography, and antimicrobial activity by the disc diffusion assay. Total phenolics and free radical scavenging activities ranked: seed coat > embryo > pulp extracts. Montgomery cultivar fruits had the highest total phenolics. For sugars: pulp > embryo and highest in Punta Cana fruit pulp. In all extracts: sucrose > glucose and fructose. Glucose:fructose ratios were 1:1 (pulp) and 0.2:1 (embryo). Pulp extracts had dose-response antibacterial activity and pulp and embryo extracts had antifungal activity against one yeast species. Phenolics and sugars were confirmed with thin-layer chromatography and nuclear magnetic resonance. Sugar-free pulp fractions containing phenolics had slightly more antimicrobial activity than H2O-soluble pulp fractions with sugars. Results indicate M. bijugatus fruits contain phenolics, sugars and other H2O-soluble compounds consistent with therapeutic uses. PMID- 19444611 TI - Antioxidant properties of isolated isorhamnetin from the sea buckthorn marc. AB - In the present study, the process of separation and purification of isohamnetin from marc of sea buckthorn was obtained. The antioxidant properties of the pure isolated isorhamnetin were evaluated by the scavenging of the diphenylpicrylhydrazyl radical (DPPH), iron (III) to iron (II)-reducing, and iron chelating assays. High purity isorhamnetin (92.1%) was obtained and the results of antioxidant assays showed that isorhamnetin performed significantly compared with ascorbic acid and BHT, and the linear correlations were good in these assays. In conclusion, isorhamnetin may have potential as a natural antioxidant to alternate synthetic substances as food additive with its antioxidant activity. PMID- 19444612 TI - Antioxidant enzymes in barley green biomass. AB - Green biomass of young barley plants exhibited statistically significant higher activity of superoxide dismutase (SOD) and catalase (CAT) at sampling I (in the phase of plant development DC 29) compared to the later sampling II (DC 31). Significant effects of varieties, years and interactions of the studied factors on the activity of the studied antioxidants were determined. During the experiment period (2005-2007), the variety Sebastian provided statistically significant higher average SOD activity (486 U.g-1) versus the variety Malz (416 U.g-1 dry matter) and line KM1910 (418 U.g-1 dry matter). No statistically significant difference was recorded between the latter two varieties. Average catalase activity of the varieties did not show any significant difference. Significantly higher CAT activity in the sampling I was recorded on average of years and locations in the variety Sebastian and hull-less line KM1910 (935 and 907 U.g-1) compared to the variety Malz (675 U.g-1). We can state that green biomass of young spring barley plants taken during the growth phase DC 29 was a significant source of enzymes catalase and superoxide dismutase in the course of the experiment (2005-2007). PMID- 19444613 TI - Bioavailability of phenolic antioxidants associated with dietary fiber: plasma antioxidant capacity after acute and long-term intake in humans. AB - Most studies on bioavailability of phenolic antioxidants are focused in foods and beverages in which they may be easily released from the food matrix, reaching a peak in plasma antioxidant capacity 1-2 h after the intake. However, plant foods contain significant amounts of polyphenols associated with dietary fiber. The aim of the present work was to seek the bioavailability of total phenolic antioxidants associated with dietary fiber by measuring plasma antioxidant capacity in human volunteers. An acute intake of 15 g of a dietary fiber rich in associated phenolic antioxidants in healthy volunteers (n = 10) increased antioxidant capacity of plasma in relation to a control group (n = 4), becoming significant 8 h after the intake. This shows that phenolic antioxidants associated with dietary fiber are at least partially bioavailable in humans, although dietary fiber appears to delay their absorption. No significant changes were observed after long-term intake (16 weeks, 34 subjects). PMID- 19444614 TI - Cognitive remediation in schizophrenia. AB - Cognitive deficits are routinely evident in schizophrenia, and are of sufficient magnitude to influence functional outcomes in work, social functioning and illness management. Cognitive remediation is an evidenced-based non pharmacological treatment for the neurocognitive deficits seen in schizophrenia. Narrowly defined, cognitive remediation is a set of cognitive drills or compensatory interventions designed to enhance cognitive functioning, but from the vantage of the psychiatric rehabilitation field, cognitive remediation is a therapy which engages the patient in learning activities that enhance the neurocognitive skills relevant to their chosen recovery goals. Cognitive remediation programs vary in the extent to which they reflect these narrow or broader perspectives but six meta-analytic studies report moderate range effect sizes on cognitive test performance, and daily functioning. Reciprocal interactions between baseline ability level, the type of instructional techniques used, and motivation provide some explanatory power for the heterogeneity in patient response to cognitive remediation. PMID- 19444615 TI - Health of the homeless and climate change. AB - The homeless are amongst the most vulnerable groups in developed regions, suffering from high rates of poorly controlled chronic disease, smoking, respiratory conditions, and mental illness, all of which render them vulnerable to new and resurgent disease processes associated with climate change. To date, there have been no papers reviewing the impacts of climate change on the homeless population. This paper provides a framework for understanding the nature of such an impact. We review four pathways: increased heat waves, increased air pollution, increased severity of floods and storms, and the changing distribution of West Nile Virus. We emphasize the need for further debate and research in this field. PMID- 19444616 TI - Mixed method approaches to understanding cancer-related dietary risk reduction among public housing residents. AB - Improving diet is one important pathway for addressing cancer disparities. We conducted mixed-method analyses of 468 24-h dietary recalls from 156 African American women residents of Washington DC public housing to better understand dietary patterns. Recalls were rated for five cancer-related preventive characteristics (adequate fruits/vegetables, moderate fat, moderate calories, no alcohol, and adequate Healthy Eating Index score), combined as a scale. Bivariate and multivariate analyses identified psychosocial and dietary characteristics associated with scale scores. Qualitative analyses of dietary records identified contextual aspects of food patterns within and across score groups. Sixty-one percent of respondents met zero or one dietary goal; alcohol abstention was most common (64%). Only 12% achieve either three (6%), four (4%), or all five (<1%) goals; five fruit and vegetable servings were least common (15%). The underlying scalar structure of responses suggests that fruit and vegetable consumption is seldom achieved in this population without other scale components. Poorer scores were associated with younger age, depressive symptoms, stressful life events, smoking, and food-purchasing practices. Qualitative analyses identified eight themes related to differences between dietary patterns. Findings reinforce the value of nonreductionist approaches to cancer-related nutrition intervention. PMID- 19444617 TI - Methamphetamine-induced behavioral sensitization is enhanced in the HIV-1 transgenic rat. AB - Methamphetamine (METH) addiction is prevalent among individuals with HIV infection. We hypothesize that HIV-positive individuals are more prone to METH use and to the development of METH dependence. To test this hypothesis, we examined the effects of METH (daily intraperitoneal injection 2.5 mg/kg for 6 days) on rearing and head movement in 12-13-week-old male HIV-1 transgenic (HIV 1Tg) rats compared to F344 control rats as an indicator of behavioral sensitization, also representing neural adaptation underlying drug dependence and addiction. Body and brain weights were also recorded. The involvement of the dopaminergic system was investigated by examining dopamine receptors 1 (D1R) and 2 (D2R) and dopamine transporter (DAT) expression in the striatum and prefrontal cortex. METH increased rearing number and duration in both F344 and HIV-1Tg rats. Rearing number was attenuated over time, whereas rearing duration remained constant. METH also induced a progressive increase in stereotypical head movement in both F344 and HIV-1Tg rats, but it was greater in the HIV-1Tg rats than in the F344 animals. The brain to body weight ratio was significantly lower in METH treated HIV-1Tg rats compared to F344 controls. There was no significant difference in striatal D1R, D2R, or DAT messenger RNA in HIV-1Tg and F344 rats. However, D1R expression was greater in the prefrontal cortex of HIV-1Tg rats than F344 rats and was attenuated by METH. Our results indicate that METH-induced behavioral sensitization is greater in the presence of HIV infection and suggest that D1R expression in the prefrontal cortex may play a role in METH addiction in HIV-positive individuals. PMID- 19444618 TI - Fabrication of triple-layer matrix tablets of venlafaxine hydrochloride using xanthan gum. AB - The objective of present investigation was to develop venlafaxine hydrochloride layered tablets for obtaining sustained drug release. The tablets containing venlafaxine hydrochloride 150 mg were prepared by wet granulation technique using xanthan gum in the middle layer and barrier layers. The granules and tablets were characterized. The in vitro drug dissolution study was conducted in distilled water. The tablets containing two lower strengths were also developed using the same percentage composition of the middle layer. Kinetics of drug release was studied. The optimized batches were tested for water uptake study. Radar diagrams are provided to compare the performance of formulated tablets with the reference products, Effexor XR capsules. The granules ready for compression exhibited good flow and compressibility when xanthan gum was used in the intragranular and extragranular fractions. Monolayer tablets failed to give the release pattern similar to that of the reference product. The drug release was best explained by Weibull model. A unified Weibull equation was evolved to express drug release from the formulated tablets. Lactose facilitated drug release from barrier layers. Substantial water uptake and gelling of xanthan gum appears to be responsible for sustained drug release. The present study underlines the importance of formulation factors in achieving same drug release pattern from three strengths of venlafaxine hydrochloride tablets. PMID- 19444619 TI - Investigations on the physical structure and the mechanism of drug release from an enteric matrix microspheres with a near-zero-order release kinetics using SEM and quantitative FTIR. AB - The objectives of this study were to evaluate the physical structure and the release mechanisms of theophylline microspheres made of Eudragit S 100 polymer as an enteric polymer, combined with a nonerodible polymer, Eudragit RL 100. In the preparation process, polymer combinations (1:1) were dissolved in an organic solvent mixture composed of acetone and methanol at a specific ratio containing a theoretical drug loading of approximately 15%. Two microsphere formulations (LS1 and LS2) were prepared at two different total polymer concentrations (10% in LS1 and 12.7% in LS2). Dissolution studies were carried out using US Pharmacopeia Dissolution Apparatus II in an acidic medium for 8 h and in an acidic medium (2 h) followed by a slightly basic-buffered medium for 10 h. Both LS1 and LS2 microsphere formulations produced particles that were spherical in shape and had very narrow size distributions with one size fraction comprising 70-80% of the yield. Scanning electron microscopy and quantitative Fourier transform infrared were used for microsphere physical structure evaluation. Except for the absence of drug crystals, photomicrographs of both LS microspheres after dissolution in pH 1.2 and 7.2 buffer solutions were similar to those before dissolution. Dissolution results indicated the ability of LS microspheres to minimize drug release during the acid stage. However, in the slightly basic medium that followed the acidic stage, the drug release was sustained and controlled in its kinetics and data fitted to Peppas equation indicated a case II transport suggesting that the drug release is mainly through swelling/erosion mechanism. PMID- 19444620 TI - Preparation and characterization of co-grinded mixtures of aceclofenac and neusilin US2 for dissolution enhancement of aceclofenac. AB - The present study was carried out with a view to enhance the dissolution of poorly water-soluble BCS-class II drug aceclofenac by co-grinding with novel porous carrier Neusilin US(2.) (amorphous microporous granules of magnesium aluminosilicate, Fuji Chemical Industry, Toyama, Japan). Neusilin US(2) has been used as an important pharmaceutical excipient for solubility enhancement. Co grinding of aceclofenac with Neusilin US(2) in a ratio of 1:5 was carried out by ball milling for 20 h. Samples of co-ground mixtures were withdrawn at the end of every 5 h. and characterized for X-ray powder diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. The analysis revealed the conversion of crystalline aceclofenac to its amorphous form upon milling with Neusilin US(2). Further, in vitro dissolution rate of aceclofenac from co-ground mixture was significantly higher compared to pure aceclofenac. The accelerated stability study of co-ground mixture was carried out at 40 degrees C/75%RH for 4 weeks, and it showed that there was no reversion from amorphous to crystalline form. Thus, it is advantageous to use a porous carrier like Neusilin US(2) in improvement of dissolution of poorly soluble drugs. PMID- 19444621 TI - Response to Dr. Russell Kirby. PMID- 19444622 TI - How accurate are continuum solvation models for drug-like molecules? AB - We have estimated the hydration free energy for 20 neutral drug-like molecules, as well as for three series of 6-11 inhibitors to avidin, factor Xa, and galectin 3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finite-difference solution of the Poisson equation, and the generalised Born method), and several variants of each, giving in total 24 different methods. All four types of methods have been thoroughly calibrated for a number of experimentally known small organic molecules with a mean absolute deviation (MAD) of 1-6 kJ/mol for neutral molecules and 4-30 kJ/mol for ions. However, for the drug-like molecules, the accuracy seems to be appreciably worse. The reason for this is that drug-like molecules are more polar than small organic molecules and that the uncertainty of the methods is proportional to the size of the solvation energy. Therefore, the accuracy of continuum solvation methods should be discussed in relative, rather than absolute, terms. In fact, the mean unsigned relative deviations of the best solvation methods, 0.09 for neutral and 0.05 for ionic molecules, correspond to 2 20 kJ/mol absolute error for the drug-like molecules in this investigation, or 2 3,000 in terms of binding constants. Fortunately, the accuracy of all methods can be improved if only relative energies within a series of inhibitors are considered, especially if all of them have the same net charge. Then, all except two methods give MADs of 2-5 kJ/mol (corresponding to an uncertainty of a factor of 2-7 in the binding constant). Interestingly, the generalised Born methods typically give better results than the Poison-Boltzmann methods. PMID- 19444623 TI - Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis. AB - Increased platelet counts and systemic coagulation activation are associated with ovarian cancer progression. Platelet activation occurs in the tumor microenvironment and may influence local invasion and metastasis. We used a cellular model of tumor invasion to investigate the effect of activated platelets on the human ovarian cancer cell line, SKOV3. SKOV3 cells were exposed to washed, thrombin receptor activating peptide (TRAP)-activated or TRAP-naive platelets under various experimental conditions, and tumor cell invasion was assayed in Matrigel chambers. The effect of platelets on the content of urokinase plasminogen activator (uPA) and VEGF in SKOV3 cell conditioned medium was measured using an ELISA assay. TRAP-activated platelets stimulated a dose dependent increase in SKOV3 cell invasion. Exposure to activated platelet membranes and to soluble proteins contained in activated platelet releasate both contributed to the observed increase in invasion. The inhibition of platelet activation with prostaglandin E1 (PGE(1)) attenuated the invasive capacity of SKOV3 cells. Exposure to platelets resulted in significantly increased uPA and VEGF content of SKOV3 cell conditioned medium. Activated platelets enhance SKOV3 human ovarian cancer cell invasion through Matrigel and increase the amount of uPA and VEGF secreted into SKOV3 cell conditioned medium. If generalizable to additional cell lines and human disease, this observation may partially explain the adverse prognosis associated with thrombocytosis in ovarian cancer. Platelets, therefore, may represent a potential target for therapeutic intervention in human ovarian cancer. PMID- 19444624 TI - Morphological alterations induced by boric acid and fipronil in the midgut of worker honeybee (Apis mellifera L.) larvae : Morphological alterations in the midgut of A. mellifera. AB - Morphological alterations, by means of histological and ultrastructural analysis, have been used to determine the effects of boric acid and fipronil on midgut tissues of honeybee worker, Apis mellifera L. larvae. In order to observe possible morphological alterations in the midgut, two groups of bioassays were performed. In the first one, the larvae were chronically treated with different concentrations of boric acid added to the food (1.0, 2.5 and 7.5 mg/g). In the second group, the larvae were fed with diets containing different concentrations of fipronil (0.1 and 1 microg/g) and compared with control groups without these chemical compounds. In the first bioassay, the larvae were collected on day 3 and in the second bioassay on day 4, when the mortality rate obtained in the toxicological bioassay was not very high. The larval midguts were removed and processed for morphological analyses using a light and transmission electron microscopy. We observed cytoplasmic vacuolizations, with the absence of autophagic vacuoles, and chromatinic compacting in most of the cells in the groups treated with pesticides. The morphological alterations were far greater in the larvae treated with boric acid than in the larvae treated with fipronil. Our data suggest that the midgut cell death observed was in response to boric acid and fipronil action. This study significantly improves the understanding of the toxicological effect of these insecticides from the ecotoxicological perspective. PMID- 19444625 TI - Re: Vitamin and mineral use and risk of prostate cancer: the case-control surveillance: Zhang et al. Cancer Causes Control. 2008 Dec 18 [Epub ahead of print]. PMID- 19444627 TI - Ionizing radiation: a risk factor for mesothelioma. AB - In the majority of mesothelioma cases worldwide, asbestos is a likely causal factor, but several alternative factors, such as ionizing radiation, have been recognized. We reviewed ionizing-radiation evidence from epidemiology studies of (1) patients exposed to the diagnostic X-ray contrast medium "Thorotrast," (2) patients undergoing radiation therapy (i.e., to treat cancer), and (3) atomic energy workers chronically exposed to lower levels of radiation. The results from these populations are also supported by case reports of mesothelioma following therapeutic radiation. Statistically significant associations were found in many, but not all, epidemiology studies (particularly those of Thorotrast- and radiation-treated patients). Given the low mesothelioma rate in the general population, the consistently increased risk among these radiation-exposed individuals is noteworthy. Many studies were limited by the lack of a uniform manner in which mesothelioma was reported prior to introduction of a uniform classification system (ICD-10). Future studies that rely on ICD-10 should have greater power to detect an association. While the evidence falls short of a definitive causal link, considering studies in which statistical significance was achieved, the case reports, and the plausible mode of action, we conclude that the evidence is supportive of a causal link between ionizing radiation exposure and mesothelioma risk. PMID- 19444628 TI - Wnt2 acts as an angiogenic growth factor for non-sinusoidal endothelial cells and inhibits expression of stanniocalcin-1. AB - Recently, we have shown that Wnt2 is an autocrine growth and differentiation factor for hepatic sinusoidal endothelial cells. As Wnt signaling has become increasingly important in vascular development and cancer, we analyzed Wnt signaling in non-sinusoidal endothelial cells of different vascular origin (HUVEC, HUAEC, HMVEC-LLy). Upon screening the multiple components of the Wnt pathway, we demonstrated lack of Wnt2 expression, but presence of Frizzled-4, one of its receptors, in cultured non-sinusoidal endothelial cells. Treatment of these cells by exogenous Wnt2 induced endothelial proliferation and sprouting angiogenesis in vitro. Upon analysis of Wnt2 tissue expression as a basis for paracrine Wnt2 effects on non-sinusoidal endothelial cells in vivo, Wnt2 was found to be expressed in densely vascularized murine malignant tumors and in wound healing tissues in close proximity to CD31+ endothelial cells. By gene profiling, stanniocalcin-1 (STC1), a known regulator of angiogenesis, was identified as a target gene of Wnt2 signaling in HUVEC down-regulated by Wnt2 treatment. Tumor-conditioned media counter-acted Wnt2 and up-regulated STC1 expression in HUVEC. In conclusion, we provide evidence that Wnt2 acts as an angiogenic factor for non-sinusoidal endothelium in vitro and in vivo whose target genes undergo complex regulation by the tissue microenvironment. PMID- 19444629 TI - Assessment of anthropogenic sources of water pollution using multivariate statistical techniques: a case study of the Alqueva's reservoir, Portugal. AB - Multivariate statistical techniques were applied to evaluate spatial/temporal variations, and to interpret water quality data set obtained at Alqueva reservoir (south of Portugal). The water quality was monitored at nine different sites, along the water line, over a period of 18 months (from January 2006 to May 2007) using 26 water quality parameters. The cluster analysis allowed the formation of five different similarity groups between sampling sites, reflecting differences on the water quality at different locations of the Alqueva reservoir system. The PCA/FA identified six varifactors, which were responsible for 64% of total variance in water quality data set. The principal parameters, which explained the variability of quality water, were total phosphorus, oxidability, iron, parameters that at high concentrations indicate pollution from anthropogenic sources, and herbicides indicative of an intensive agricultural activity. The spatial analysis showed that the water quality was worse in the north of the reservoir. PMID- 19444630 TI - Indoor air pollution evaluation with emphasize on HDI and biological assessment of HDA in the polyurethane factories. AB - Today, many raw materials used in factories may have a dangerous effect on the physiological system of workers. One of them which is widely used in the polyurethane factories is diisocyanates. These compounds are widely used in surface coatings, polyurethane foams, adhesives, resins, elastomers, binders, and sealants. Exposure to diisocyanates causes irritation to the skin, mucous membranes, eyes, and respiratory tract. Hexamethylene diamine (HDA) is metabolite of hexamethylene diisocyanate (HDI). It is an excretory material by worker's urine who is exposed to HDI. Around 100 air samples were collected from five defined factories by midget impinger which contained dimethyl sulfoxide absorbent as a solvent and tryptamine as reagent. Samples were analyzed by high-performance liquid chromatography with EC?UV detector using NIOSH 5522 method of sampling. Also, 50 urine samples collected from workers were also analyzed using William's biological analysis method. The concentration of HDI into all air samples were more than 88 microg/m(3), and they have shown high concentration of pollutant in the workplaces in comparison with NIOSH standard, and all of the workers' urine were contaminated by HDA. The correlation and regression test were used to obtain statistical model for HDI and HDA, which is useful for the prediction of diisocyanates pollution situation in the polyurethane factories. PMID- 19444631 TI - Acetylcholinesterase activity in Corbicula fluminea Mull., as a biomarker of organophosphate pesticide pollution in Pinacanauan River, Philippines. AB - Organophosphates are known to inhibit the enzyme acetylcholinesterase. In this study, the AChE activity from the total soft tissues of Corbicula fluminea Mull. was used as a biomarker of organophosphate pollution in Pinacanauan River. Clams were collected from two different sites and at different seasons of the year. A colorimetric assay on the total soft tissues of the clams showed a directly proportional relationship between enzyme activity and condition of the riverine system. In vitro experiments on the total soft tissue, adductor muscles, digestive glands, and gills were conducted to assess the degree of localization of AChE as well as the sensitivity and tolerance of the enzymes in these tissues to varying concentrations of malathion. The degree of enzyme localization from highest to lowest is as follows: adductor muscle > gills > digestive gland whereas sensitivity to OP from greatest to least is: gills > adductor muscles > digestive gland. PMID- 19444632 TI - Heavy metal bioaccumulation and metallothionein content in tissues of the sea bream Sparus aurata from three different fish farming systems. AB - The distribution and potential bioaccumulation of dietary and waterborne cadmium and lead in tissues of sea bream (Sparus aurata), a major aquaculture species, was studied in relation to three different fish farming systems. Metallothionein levels in fish tissues were also evaluated. Results demonstrate that metal concentrations in various tissues significantly vary among fish culture systems. Different tissues show different capacity for accumulating heavy metals. The content of both cadmium and lead is not strictly correlated with that of metallothionein. Indeed, the marked accumulation of both metals in liver, as well as the high lead content found in gills and kidney, are not accompanied by a concomitant accumulation of metallothioneins in these tissues. No correlation is present between heavy metals and metallothionein content in muscle tissue. The results also demonstrate that cadmium accumulates mainly via dietary food, whereas lead accumulation is not of food origin. Noteworthy is that the concentration of the two metals found in muscle in all instances is lower than the limits established by European Union legislation for fish destined for human consumption. PMID- 19444633 TI - Water and sediment quality of Ashtamudi estuary, a Ramsar site, southwest coast of India--a statistical appraisal. AB - Ashtamudi estuary, situated on the southwest coast of India, is enormously affected by anthropogenic interventions. Physicochemical quality of water and sedimentological features of the estuary are evaluated during monsoon and nonmonsoon seasons to elucidate its quality variations and to link the same with existing environmental scenario. The whole data has been factorized using principal component analysis for extracting the total variability and linear relationships existing among a set of different physicochemical parameters of the backwater system. In PCA, high loadings were obtained for conductivity, salinity, fluoride, calcium, magnesium, sulfate, boron, and pH. The results were revealed that all the physicochemical processes depend upon seasonal fluctuation of freshwater input and seawater intrusion. Wide spatial concentration fluctuations of organic carbon and iron in bottom sediment have been noticed and both constituents reveal good correlation with sediment texture. The results showed high deterioration of the physicochemical quality of water during nonmonsoon season with respect to monsoon season. PMID- 19444634 TI - Variations of measured and simulated soil-loss amounts in a semiarid area in Turkey. AB - The main goal of this research was soil-loss determination and comparison of the plot measurement results with simulation model (universal soil loss equation (USLE)) results in different land use and slope classes. The research took place in three different land-use types (Scotch pine forest, pasture land, and agricultural land) and in two different slope classes (15-20%, 35-40%). Within six measurement stations (for each land-use type and slope class-one station), totally 18 measurement plots have been constituted, and soil-loss amount measurements have been investigated during the research period (3 years along). USLE simulation model is used in these measurement plots for calculation the soil loss amounts. The results pointed out that measured (in plots) and simulated (with USLE) soil-loss amounts differ significantly in each land-use type and slope class. PMID- 19444635 TI - Roadmap for assessing regional trends in groundwater quality. AB - Assessing regional trends in groundwater quality can be a difficult task. Data are often scattered in space and time, and the inertia of groundwater systems can create natural, seemingly persistent changes in concentration that are difficult to separate from anthropogenic trends. Here, we show how statistical methods and software for joint analysis of multiple time series can be integrated into a roadmap for trend analysis and critical examination of data quality. Ordinary and partial Mann-Kendall (MK) tests for monotonic trends and semiparametric smoothers for multiple time series constitute the cornerstones of our procedure. The MK tests include a simple and easily implemented method to correct for serial dependence, and the associated software is designed to enable convenient handling of numerous data series and to accommodate covariates and nondetects. The semiparametric smoothers are intended to facilitate detection of synchronous changes in a network of stations. A study of Swedish groundwater quality data revealed true upward trends in acid-neutralizing capacity and downward trends in sulfate but also a misleading shift in alkalinity level that would have been difficult to detect if the time series had been analyzed separately. PMID- 19444636 TI - Microbial activities and trace element contents in an urban soil. AB - Soil biological properties are influenced by trace metals. The main sources of these pollutants in the urban areas are industrial plants, power stations, domestic heating systems and motor vehicles. The aim of this work was to evaluate, in relation to distance from urban roads, soil trace metal concentrations (Pb, Cu, Cr, Cd and V) and their influence on C-microbial biomass as well as on soil respiration and enzyme activities (phosphatase glucosidase, galactosidase, xylanase, cellulase, trealase, protease and invertase). The samplings were carried out at four sites, along a route that goes from Giannone Street to Passionisti Street, two heavily travelled roads at two different times of the year (spring and autumn). Heavy metal contents and microbial activities were highest at the sites near the roads. The highest values of microbial activities were found in the inner site; here, on the contrary, the lowest concentrations of heavy metals were measured. Significant and negative correlations were found between microbial activity and heavy metal contents. PMID- 19444637 TI - Water quality time series for Big Melen stream (Turkey): its decomposition analysis and comparison to upstream. AB - Big Melen stream is one of the major water resources providing 0.268 [corrected] km(3) year(-1) of drinking and municipal water for Istanbul. Monthly time series data between 1991 and 2004 for 25 chemical, biological, and physical water properties of Big Melen stream were separated into linear trend, seasonality, and error components using additive decomposition models. Water quality index (WQI) derived from 17 water quality variables were used to compare Aksu upstream and Big Melen downstream water quality. Twenty-six additive decomposition models of water quality time series data including WQI had R (2) values ranging from 88% for log(water temperature) (P < or = 0.001) to 3% for log(total dissolved solids) (P < or = 0.026). Linear trend models revealed that total hardness, calcium concentration, and log(nitrite concentration) had the highest rate of increase over time. Tukey's multiple comparison pointed to significant decreases in 17 water quality variables including WQI of Big Melen downstream relative to those of Aksu upstream (P < or = 0.001). Monitoring changes in water quality on the basis of watersheds through WQI and decomposition analysis of time series data paves the way for an adaptive management process of water resources that can be tailored in response to effectiveness and dynamics of management practices. PMID- 19444638 TI - Detecting micronuclei frequency in some aquatic organisms for monitoring pollution of Izmir Bay (Western Turkey). AB - Micronuclei tests is a system of mutagenicity testing used for determining the pollution and chemicals causing changes in DNA fragments such as micronuclei in the cytoplasm of interphase cells. Damage caused on the DNA by genotoxic pollutants is the first consequence occurring in the aquatic organisms. Thus, it was attempted to determine whether pollution affected the erythrocytes and gills of fish Gobius niger and haemolymph and gills of mussels Mytilus galloprovincialis living in Izmir Bay at the level of DNA by the means of micronuclei (MN) test. Organisms used in the MN test were collected from seven locations (Alsancak, Alaybey Shipyard, Karsiyaka, Bostanli, Goztepe, Konak and Pasaport) which are known as the most polluted part of inner Bay of Izmir (Western Coast of Turkey). According to the results of the present study, frequency of MN was found at high level in Alaybey Shipyard and Pasaport where wastes from existing dockyard contributed to high level of pollution. In conclusion, this study indicates that the micronuclei test gives sensitive results in monitoring the pollution, especially the pollution of harbor, and thus it might be used as standard method in regular monitoring of pollution of coastal ecosystem. PMID- 19444639 TI - Investigations on boron levels in drinking water sources in China. AB - To evaluate boron contamination of public drinking water in China, both dissolved and total boron contents in 98 public drinking water sources from 49 cities, 42 brands of bottled water samples from supermarkets in several cities, and 58 water samples from boron industrial area were measured by inductively coupled plasma mass spectrometry (ICP-MS). Our experimental results showed that boron existed in public drinking water sources mainly in dissolved status with total concentrations ranging from 0.003 to 0.337 mg/L (mean = 0.046 mg/L). The mean boron concentrations in mineral and pure bottled water were 0.052 and 0.028 mg/L, respectively. The results obtained in this work showed that there was no health risk on view of boron in public drinking water sources and bottled water. In boron industrial area, boron concentrations in surface water and ground water were 1.28 mg/L (range = 0.007-3.8 mg/L) and 18.3 mg/L (range = 0.015-140 mg/L), respectively, which indicated that boron industry caused boron pollution in local water system. PMID- 19444640 TI - Modulation of aging profiles in isogenic populations of Caenorhabditis elegans by bacteria causing different extrinsic mortality rates. AB - It has been postulated that the presence of parasites causing high extrinsic mortality may trigger an inducible acceleration of the host aging. We tested this hypothesis using isogenic populations of Caenorhabditis elegans nematodes and different Escherichia coli strains. When exposed to pathogenic bacteria, nematodes showed up to fourfold higher mortality rates, reproduced earlier, produced more H(2)O(2), and accumulated more autofluorescence, than when exposed to an innocuous strain. We also observed that mortality increased at a slower rate in old animals, a phenomenon known as mortality deceleration. Mortality deceleration started earlier in populations dying faster, likely as a consequence of lifelong heterogeneity between individual tendencies to die. Taken together, our results strongly suggest that the high extrinsic mortality imposed by the pathogens results in the modulation of nematodes' life-history traits, including aging and reproduction. This could be an adaptive response aiming at the maximization of Darwinian fitness. PMID- 19444641 TI - Low-dose CT angiography: sufficient contrast for vessel imaging? PMID- 19444642 TI - Curcumin decreases the expression of Pokemon by suppressing the binding activity of the Sp1 protein in human lung cancer cells. AB - Pokemon, which stands for POK erythroid myeloid ontogenic factor, can regulate expression of many genes and plays an important role in tumorigenesis. Curcumin, a natural and non-toxic yellow compound, has capacity for antioxidant, free radical scavenger, anti-inflammatory properties. Recent studies shows it is a potential inhibitor of cell proliferation in a variety of tumour cells. To investigate whether curcumin can regulate the expression of Pokemon, a series of experiments were carried out. Transient transfection experiments demonstrated that curcumin could decrease the activity of the Pokemon promoter. Western blot analysis suggested that curcumin could significantly decrease the expression of the Pokemon. Overexpression of Sp1 could enhance the activity of the Pokemon promoter, whereas knockdown of Sp1 could decrease its activity. More important, we also found that curcumin could decrease the expression of the Pokemon by suppressing the stimulation of the Sp1 protein. Therefore, curcumin is a potential reagent for tumour therapy which may target Pokemon. PMID- 19444643 TI - Proteome analysis of haptoglobin in cerebrospinal fluid of neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease with generally poor prognosis that selectively targets optic nerves and spinal cord. Although diagnostic criteria for NMO are available, there is still a need for biomarkers, predicting disease development and progression to improve individually tailored treatment. CSF proteins were separated by two-dimensional electrophoresis and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The interaction between these proteins was further analyzed by Pathway Studio software. Seven protein spots in CSF were significantly altered in NMO patients compared with controls. Identification made by mass spectrometry revealed that the most significant protein was haptoglobin, which was increased in the NMO gels. The subsequent ELISA test were performed to validate it, which confirmed the results of proteomic analysis. Protein network was built, which showed some biological interactions among the seven proteins. These results support a correlation between the level of haptoglobin and NMO. Haptoglobin may be a potential useful biomarker for diagnosis or a medicine target for treatment of NMO. PMID- 19444644 TI - pcDNA3.1(-)-mediated ribozyme targeting of HER-2 suppresses breast cancer tumor growth. AB - The HER-2 proto-oncogene (also called c-erbB-2/neu) encodes the protein, p185, which is closely related to the growth and metastasis of adenocarcinoma, and is overexpressed in 25-30% of human breast cancers. In this study, we attempt to reverse the malignant phenotype of the breast cancer cell line, MCF-7, using a HER-2-specific hammerhead ribozyme. Two anti-HER-2 hammerhead ribozymes, RZ1 and RZ2, were synthesized, inserted separately into the nonviral eukaryotic expression vector, pcDNA3.1(-), and transfected into MCF-7 cells. Analyses showed that the HER-2 mRNA and p185, as well as oncogene k-ras were down-regulated remarkably in the ribozyme-transfected cells, while the onco-suppressor gene, p53, was up-regulated. Furthermore, the tumorigenicity of the RZ1-stably transfected MCF-7 cells was decreased dramatically in nude mice. These results demonstrate that the use of anti-HER-2 ribozymes may be a beneficial strategy for gene therapy of breast cancer. PMID- 19444645 TI - The Xmn1 polymorphic site 5' to the (G)gamma gene and its correlation to the (G)gamma:(A)gamma ratio, age at first blood transfusion and clinical features in beta-thalassemia patients from Western Iran. AB - beta-Thalassemia is the most common single gene disorder in Iran and more than 25,000 affected individuals have been reported. It has been reported that in patients with beta-thalassemia in the presence of Xmn1 polymorphic site the level of Hb F and (G)gamma: (A)gamma ratio is increased. The prevalence of Xmn1 polymorphic site, (G)gamma: (A)gamma ratio and Hb F in 197 beta-thalassemia major patients from the Kermanshah Province of Iran were studied. The Xmn1 polymorphic site was determined by PCR-RFLP procedure. The levels of (G)gamma and (A)gamma chains were detected by HPLC. The percent of Hb F was determined using electrophoresis method. In beta-thalassemia major patients the frequency of presence Xmn1 was 0.39. The mean of (G)gamma: (A)gamma ratio was found to be 2.5. In the present study it was found that in the presence of Xmn1 polymorphic site (G)gamma percent and (G)gamma: (A)gamma ratio were significantly increased (P = 0.01) and the clinical features such as splenomegaly and bone marrow expansion were significantly improved (P = 0.01). We found that in the presence of Xmn1 polymorphic site on both chromosomes (+/+) the level of Hb F tended to be increased compared to the absence of Xmn1 (-/-). The present investigation has studied the frequency of Xmn1 polymorphic site in beta-thalassemia major patients from Western Iran and has revealed that the presence of this polymorphic site caused a positive influence on Hb F production and the (G)gamma percent which could improve the clinical symptoms of beta-thalassemia patients. PMID- 19444646 TI - The polymorphisms of UCP1 genes associated with fat metabolism, obesity and diabetes. AB - Uncoupling protein 1 (UCP1), a 32-kDa protein located in the inner mitochondrial membrane, is abundant in brown adipose tissue, as a proton transporter in mitochondria inner membrane which uncouples oxidative metabolism from ATP synthesis and dissipates energy through the heat. UCP1 has been reported to play important roles for energy homeostasis in rodents and neonate of larger mammals including human. Recently, numerous candidate genes were searched to determine the genetic factors implicated in the pathogenesis of obesity, related metabolic disorders and diabetes. UCP-1, which plays a major role in thermogenesis, was suggested to be one of the candidates. This review summarizes data supporting the existence of brown adipocytes and the role of UCP1 in energy dissipation in adult humans, and the genetic variety association with the fat metabolism, obesity and diabetes. PMID- 19444648 TI - Disease proteomics. PMID- 19444647 TI - Identification and characterization of interferon regulatory factor-1 from orange spotted grouper (Epinephelus coioides). AB - Interferon-regulatory factor 1 (IRF-1) is the first member of IRF family, which is involved in many biological processes such as immune response, antiviral defense, cell growth regulation, and apoptosis. In this study, an IRF-1 gene, EcIRF-1, was isolated and characterized from orange-spotted grouper (Epinephelus coioides). The full-length cDNA of EcIRF-1 is 1,730 bp, including an open reading frame of 906 bp, a 5'-terminal untranslated region (5'-UTR) of 153 bp, and a 3' UTR of 671 bp. The EcIRF-1 gene consists of 10 exons and 9 introns, spanning over approximate 4.3 kb of genomic sequence. The 5'-UTR sequence contains an exon and an intron, and the 3'-UTR sequence is included in the last exon. Expression analysis by real-time PCR reveals that the EcIRF-1 gene is ubiquitously expressed in various healthy fish tissues, whereas its expression is upregulated in vivo in response to polyinosinic-polycytidylic acid or lipopolysaccharide stimulation. Subcellular localization analysis shows the EcIRF-1 is an intranuclearly localized and immobile protein in the cultured fish cells. Data presented in this paper provide an important base to further understand EcIRF-1 gene function and its regulation associated with interferon immune system in orange-spotted grouper. PMID- 19444649 TI - HGM2008 complex disease genomics II symposium abstracts (neuropsychiatric and ocular disorders). PMID- 19444650 TI - Chemical genomics and molecular medicine. PMID- 19444651 TI - HGM2008 cancer and epigenomics symposium abstracts. PMID- 19444653 TI - Inflammatory pseudotumor of the thyroid gland showing prominent fibrohistiocytic proliferation. A case report. AB - Inflammatory pseudotumor of the thyroid gland (IPT) appears to be exceedingly rare. Histologically, 14 previously reported cases demonstrated plasma cell granuloma variant. We report here an IPT showing a predominantly fibrohistiocytic proliferation that occurred in a 75-year-old Japanese woman. Histologically, the lesion was characterized by haphazardly arranged spindle cells, histiocytes having foamy cytoplasm containing intracytoplasmic brown pigments, and small lymphocytes. Immunohistochemical study demonstrated that the spindle cells were vimentin+, desmin-, muscle-specific actin+, cytokeratin-, endomysial antibody-, anaplastic lymphoma kinase-, CD34-- CD68+/-, CD99-, cyclin D1-, bcl-2-, and antifollicular dendritic cell antibody-. IPT showing a predominant fibrohistiocytic proliferation should be differentiated from various nonneoplastic or neoplastic disorders showing spindle cell proliferation and/or exuberant fibrosis. They include Riedel's thyroiditis, fibrous variant of chronic thyroiditis, papillary carcinoma with exuberant nodular fasciitis-like stroma, paucicellular variant of anaplastic thyroid carcinoma, and solitary fibrous tumor. PMID- 19444652 TI - Pitfalls in the diagnosis of brain death. AB - Since the establishment of the concept of declaring death by brain criteria, a large extent of variability in the determination of brain death has been reported. There are no standardized practical guidelines, and major differences exist in the requirements for the declaration of brain death throughout the USA and internationally. The American Academy of Neurology published evidence-based practice parameters for the determination of brain death in adults in 1995, requiring the irreversible absence of clinical brain function with the cardinal features of coma, absent brainstem reflexes, and apnea, as well as the exclusion of reversible confounders. Ancillary tests are recommended in cases of uncertainty of the clinical diagnosis. Every step in the determination of brain death bears potential pitfalls which can lead to errors in the diagnosis of brain death. These pitfalls are presented here, and possible solutions identified. Suggestions are made for improvement in the standardization of the declaration of brain death. PMID- 19444655 TI - Olecranon bursitis in patients treated with sunitinib for renal cell carcinoma. AB - Sunitinib is a recently approved tyrosine-kinase inhibitor that targets the vascular endothelial growth factor receptors (VEGFR). We report two cases of patients with metastatic renal cell cancer who developed olecranon bursitis while receiving sunitinib. In both cases other causes of bursitis were excluded and the symptoms resolved after treatment with sunitinib was discontinued. Recurrence of symptoms during subsequent treatment cycles was also observed. This adverse event has not been previously reported for sunitinib and we believe it is directly attributable to the drug. This is an unexpected adverse event, given the mechanism of action of the drug. The pathophysiology of this event remains unexplained, although we describe some hypotheses. PMID- 19444654 TI - Revisiting the stimulus-secretion coupling in the adrenal medulla: role of gap junction-mediated intercellular communication. AB - The current view of stimulation-secretion coupling in adrenal neuroendocrine chromaffin cells holds that catecholamines are released upon transsynaptic sympathetic stimulation mediated by acetylcholine released from the splanchnic nerve terminals. However, this traditional vertical scheme would merit to be revisited in the light of recent data. Although electrical discharges invading the splanchnic nerve endings are the major physiological stimulus to trigger catecholamine release in vivo, growing evidence indicates that intercellular chromaffin cell communication mediated by gap junctions represents an additional route by which biological signals (electrical activity, changes in intracellular Ca(2+) concentration,...) propagate between adjacent cells and trigger subsequent catecholamine exocytosis. Accordingly, it has been proposed that gap junctional communication efficiently helps synapses to lead chromaffin cell function and, in particular, hormone secretion. The experimental clues supporting this hypothesis are presented and discussed with regards to both interaction with the excitatory cholinergic synaptic transmission and physiopathology of the adrenal medulla. PMID- 19444656 TI - Current therapy and drug pipeline for the treatment of patients with acromegaly. AB - INTRODUCTION: Acromegaly is a multisystem disease resulting from chronic exposure to supraphysiological levels of growth hormone (GH), and is associated with significant morbidity and excess mortality. The etiology is almost exclusively an underlying pituitary adenoma. Current therapeutic interventions include surgery, radiotherapy, and medical therapy. RESULTS: Despite surgery, around 50% of patients fail to achieve the biochemical targets shown to correlate with normalization of mortality rates. Radiotherapy is efficacious in controlling tumor growth and GH secretion; still, achievement of biochemical targets may take up to a decade and a number of safety issues have been raised with this treatment modality. Medical therapy, therefore, has an important role as adjuvant therapy in patients who fail to achieve control with surgery, or while awaiting the effects of radiotherapy to be realized. Furthermore, medical therapy is increasingly being used as primary therapy. Current medical therapies include dopaminergic agonists, somatostatin analogs, and GH receptor (GHR) antagonists. Dopaminergic agonists achieve biochemical targets in up to 30% of patients, and somatostatin analogs in around 60%. The currently available GHR antagonist pegvisomant effectively controls insulin-like growth factor-I levels in over 90% of patients; however, it has no effect on the tumor itself and has considerable financial implications. Research into optimizing the somatostatin and dopaminergic systems has led to promising advances in agonist development. Moieties with selectivity for various combinations of somatostatin receptor subtype receptors have been examined, along with molecules that additionally show high affinity for the dopaminergic D2 receptor. Of the molecules studied in vitro, only pasireotide (SOM230) and BIM-23A760 are currently undergoing further development. Other innovations to improve convenience of currently available drugs are also being investigated. CONCLUSION: Significant advances in under standing of the somatostatin and dopaminergic system have aided drug development. This may lead to new clinically available therapies enabling control of acromegaly in a larger proportion of patients, and at an earlier stage in their disease management. PMID- 19444657 TI - Psychotropic drugs and renal failure: translating the evidence for clinical practice. AB - INTRODUCTION: The kidney is a primary route of drug elimination; abnormal kidney function is predicted to alter the pharmacokinetics of agents metabolized and/or excreted predominantly through this route. The high prevalence of mental disorders associated with psychotropic drug use in individuals with deteriorating renal function suggests there is a need to investigate the effects of renal failure on psychotropic pharmacokinetics. The aim of this review is to provide a clinically accessible overview of the effect of chronic renal failure on the pharmacokinetics for each of the major classes of prescribed psychotropic agents. METHODS: All English language articles published between 1977 and 2008 were searched through PubMed, using the following keywords: "renal," "kidney," "pharmacokinetics," "renal impairment," "renal insufficiency," and "renal failure." Each of these search words was cross-referenced with the non proprietary name of each psychotropic agent. The manufacturer's product insert was also reviewed for some agents for updated dosing. Owing to the lack of adequately powered studies, an inclusive manner was used. RESULTS: Chronic renal failure variably affects the pharmacokinetic parameters of psychotropic drugs. A review of each psychotropic drug is provided, with an emphasis on the individual pharmacokinetic parameters and recommended dosing. CONCLUSIONS: The adjudication of safe and effective doses for any psychotropic agent needs to be individualized. Tactics including dosage adjustment, slow titration, and careful monitoring for serious adverse events should be incorporated into practice. PMID- 19444658 TI - A randomized clinical comparison of OPTI-FREE EXPRESS and ReNu MultiPLUS multipurpose lens care solutions. AB - OBJECTIVE: To evaluate subjective symptoms and clinical signs of tolerability and comfort in silicone and non-silicone hydrogel contact lens (CL) wearers using two different multipurpose solution (MPS) CL care regimens. METHODS: This was a randomized, double-masked, contralateral, crossover, multicenter (n=9) study. One hundred and eleven subjects were enrolled in the study, and were randomly assigned either silicone hydrogel CLs or non-silicone hydrogel CLs. Before wear, the CLs were randomly conditioned for at least 10 hours in a multipurpose disinfection solution (MPDS) preserved with either: Regimen 1-polyquaternium-1 0.001% and myristamidopropyl dimethylamine 0.0005% (POLYQUAD and ALDOX, respectively; OPTIFREE EXPRESS MPDS, Alcon Laboratories, Inc., Fort Worth, TX, USA); or Regimen 2-multipurpose solution preserved with polyhexamethylene biguanide 0.0001% (PHMB, ReNu MultiPLUS MPS, Bausch & Lomb, Rochester, NY, USA). The study had two in-office visits, 1 week apart. Subjects wore assigned CLs for approximately 4 hours at each visit. At each visit, subjects' eyes were examined before CL insertion and at 2 hours and 4 hours after insertion. Corneal staining type and area, conjunctival staining, conjunctival injection, subjective symptoms (tolerability), and comfort were evaluated. RESULTS: One hundred and five subjects (210 eyes) completed the study. The total corneal staining score of area and type were statistically significantly less in Regimen 1 than in Regimen 2 (P<0.000001). The area of conjunctival staining was statistically significantly less in Regimen 1 than in Regimen 2 (P=0.03). No clinically significant hyperemia was observed for either regimen. Both tolerability (P=0.02) and patient preference (P=0.05) were in favor of Regimen 1. CONCLUSIONS: Statistically significant clinical differences were evident between the two CL care regimens when used with silicone and non-silicone hydrogel CLs. OPTI-FREE EXPRESS MPDS users showed less corneal and conjunctival staining and reported greater comfort and tolerability to the CL/solution combination than ReNu MultiPLUS MPS users. PMID- 19444659 TI - Surgical results of external canal cholesteatoma. AB - CONCLUSION: The treatment plan should be adapted in accordance with the individual cause for each patient with external canal cholesteatoma (EACC). Outpatient surgery with eradication of the cholesteatoma and canal reconstruction at an early stage to enable epithelial recovery and migration was proved to be the choice that was effective, low cost, and produced less suffering for the patient to achieve optimal results for most primary EACCs. OBJECTIVES: To assess the indications, operation methods, and results of surgery for EACC. PATIENTS AND METHODS: This retrospective case review was conducted in a tertiary referral center, Chi Mei Medical Center, from 1989 to 2007. Outpatient surgery to eradicate diseased canal epithelium and reconstruct a funnel-shaped canal was performed in the cases with primary EACC at an early stage, while inpatient surgery was conducted in the advanced cases. Assessments of cause and outcome were based on the combination of clinical history, physical examination, and radiographic appearance. RESULTS: Clinical records of 45 patients (7 with bilateral lesions) were reviewed; 34 patients were noted with primary EACC and 11 patients with secondary EACC. Surgery was conducted in 42 ears to restore normal epithelial migration. Successful results on an outpatient basis were obtained in most patients. PMID- 19444660 TI - Lexical tone identification and consonant recognition in acoustic simulations of cochlear implants. AB - CONCLUSION: Cochlear implant (CI) recipients' performance of lexical tone identification and consonant recognition can be enhanced by providing greater spectral details. OBJECTIVE: To evaluate the effects of increasing the number of total spectral channels on the lexical tone identification and consonant recognition by normally hearing listeners who are native speakers of Mandarin Chinese. SUBJECTS AND METHODS: Lexical tone identification and consonant recognition were measured in 15 Mandarin-speaking, normal-hearing (NH) listeners with varied numbers of total spectral channels (i.e. 4, 6, 8, 10, 12, 16, 20, and 24), using acoustic simulations of CIs. RESULTS: The group of NH listeners' performance of lexical tone identification ranged from 44.53% to 66.60% with 4-24 spectral channels. The performance of tone identification between channels 4 and 16 remained similar; between channels 16 and 20 performance improved significantly. As regards consonant recognition, the NH listeners' overall accuracy ranged from 73.17% to 95.33% with 4-24 channels. Steady improvement in consonant recognition accuracy was observed as a function of increasing the spectral channels. With about 12-16 spectral channels, the NH listeners' overall accuracy in consonant recognition began to be comparable to their accuracy with the unprocessed stimuli. PMID- 19444661 TI - Adherence to antiretroviral medication in older adults living with HIV/AIDS: a comparison of alternative models. AB - The CDC estimates that by 2015, half of all persons living with HIV/AIDS in the USA will be over the age of 50. Despite increasing HIV seroprevalence rates in older adults, most research examining adherence to antiretroviral therapy (ART) has focused on young HIV-infected persons and, in general, has been atheoretical in nature. This study examined two ART adherence conceptual frameworks to determine whether these models generalize to HIV-seropositive older adults. Two hundred and forty-four HIV-positive adults 50-plus years of age were recruited through AIDS service organizations in Ohio and New York. Participants completed a neuropsychological battery and an audio computer-assisted self-interview. FIML SEM analyses revealed that neuropsychological functioning was not associated with adherence. Fit indices supported a stress and coping model, with negative affect mediating the effects of social support and maladaptive coping on ART adherence. Results were consistent with stress and coping models and suggest that interventions intending to increase adherence to ART in HIV-infected older adults may be more effective if they address negative affect and enhance adaptive coping and social support. PMID- 19444662 TI - MOMS: formative evaluation and subsequent intervention for mothers living with HIV. AB - The Making Our Mothers Stronger (MOMS) Project is a randomized controlled behavioral trial, comparing a stress-reduction and social support intervention (Healthy MOMS) to a parenting skills intervention (Parenting Skills for MOMS) for mothers living with HIV. Outcomes include maternal mental and physical health, parenting behaviors, and children's behavior. To ensure that these interventions were tailored to the needs of HIV+ mothers, extensive formative work was conducted with members of the intended audience and relevant service providers. Findings from focus groups and semi-structured interviews highlighted the need for Healthy MOMS to: (1) include appropriate approaches to group discussion and problem solving; (2) address the stressors of being both a parent and a woman living with HIV; and (3) enhance social support. Six weekly group sessions focused on topics including coping with stress and anxiety; enhancing nutrition, exercise, and sexual health; improving medical adherence; improving communication with health care providers; and communicating health needs to family, friends, and co-workers. Initial anecdotal responses from participants suggest that the Healthy MOMS intervention addresses several salient issues for the growing population of HIV+ mothers who can benefit from long-term support in adapting to this chronic disease. PMID- 19444663 TI - Young women and limits to the normalisation of condom use: a qualitative study. AB - Encouraging condom use among young women is a major focus of HIV/STI prevention efforts but the degree to which they see themselves as being at risk limits their use of the method. In this paper, we examine the extent to which condom use has become normalised among young women. In-depth interviews were conducted with 20 year old women from eastern Scotland (N=20). Purposive sampling was used to select a heterogeneous group with different levels of sexual experience and from different social backgrounds. All of the interviewees had used (male) condoms but only three reported consistent use. The rest had changed to other methods, most often the pill, though they typically went back to using condoms occasionally. Condoms were talked about as the most readily available contraceptive method, and were most often the first contraceptive method used. The young women had ingrained expectations of use, but for most, these norms centred only on their new or casual partners, with whom not using condoms was thought to be irresponsible. Many reported negative experiences with condoms, and condom dislike and failure were common, lessening trust in the method. Although the sexually transmitted infection (STI) prevention provided by condoms was important, this was seen as additional, and secondary, to pregnancy prevention. As the perceived risks of STIs lessened in relationships with boyfriends, so did condom use. The promotion of condoms for STI prevention alone fails to consider the wider influences of partners and young women's negative experiences of the method. Focusing on the development of condom negotiation skills alone will not address these issues. Interventions to counter dislike, method failure, and the limits of the normalisation of condom use should be included in STI prevention efforts. PMID- 19444664 TI - Potential pathways to HIV/AIDS transmission in the Niger Delta of Nigeria: poverty, migration and commercial sex. AB - HIV prevalence in the Niger Delta of Nigeria is generally attributed to concurrent sexual partnerships and weak public sector health care and education systems. This paper examines the likelihood of additional factors, such as the intersection of widespread poverty, migration, and sex work, as contributory channels of HIV transmission in the region. To explore this issue, we conducted a Delphi survey with 27 experts to formulate consensus about the impact of poverty, migration, and commercial sex on AIDS in the Niger Delta. Results suggest that these factors and others have exacerbated the epidemic in the region. To stop the further spread of HIV in the region, efforts to address poverty, sex work, and multiple sexual partnerships require building a public-private partnership which involves participatory action strategies among key stakeholders. PMID- 19444665 TI - Methamphetamine use, sexual activity, patient-provider communication, and medication adherence among HIV-infected patients in care, San Francisco 2004 2006. AB - While numerous studies examine methamphetamine use and associated risky sexual behaviors in HIV-uninfected individuals, few studies have surveyed HIV-infected individuals in the health care setting. To assess the frequency and trends of methamphetamine use, sexual activity, injection drug use, patient-provider communication, and medication adherence among HIV-infected persons in care, we administered a one-page anonymous survey in 2004 and 2006. The survey was conducted at the two University of California, San Francisco outpatient HIV clinics: at Moffitt Hospital (Moffitt), serving primarily privately insured patients, and at San Francisco General Hospital (SFGH), a county hospital serving primarily patients who are uninsured or publicly insured. In 2006, 39% of men who have sex with men (MSM), 33% of heterosexual men, and 11% of women reported methamphetamine use in the prior 12 months. Methamphetamine use was significantly associated with an increased number of sex partners among MSM and heterosexual men, and poor anti-retroviral medication adherence. Among MSM, methamphetamine use was more common at the SFGH clinic. Between 2004 and 2006, reported methamphetamine use in the last 12 months decreased among MSM at Moffitt (38 to 20%, p<0.01), but increased at SFGH (40 to 50%, p<0.05). Among methamphetamine users we found a high frequency of injection of methamphetamine, which increased at SFGH from 38 to 55%, p<0.05. Patient-provider communication regarding methamphetamine use has increased from 2004 to 2006 but no significant change has been found for providers asking patients about sexual activity. Overall, we found methamphetamine use to be common among HIV-infected patients in care, and associated with an increased number of sex partners, a high frequency of injection drug use, and poor adherence to anti-retroviral medications. These findings support the need for improved screening and clinic-based interventions to reduce and treat methamphetamine abuse and associated high risk sexual behaviors. PMID- 19444666 TI - Reducing vertical HIV transmission in Kinshasa, Democratic Republic of Congo: trends in HIV prevalence and service delivery. AB - Scale-up of vertical HIV transmission prevention has been too slow in sub-Saharan Africa. We describe approaches, challenges, and results obtained in Kinshasa. Staff members of 21 clinics managed by public servants or non-governmental organizations were trained in improved basic antenatal care (ANC) including nevirapine (NVP)-based HIV transmission prevention. Program initiation was supported on-site logistically and technically. Aggregate implementation data were collected and used for program monitoring. Contextual information was obtained through a survey. Among 45,262 women seeking ANC from June 2003 through July 2005, 90% accepted testing; 792 (1.9%) had HIV of whom 599 (76%) returned for their result. Among 414 HIV+ women who delivered in participating maternities, NVP coverage was 79%; 92% of newborns received NVP. Differences were noted by clinic management in program implementation and HIV prevalence (1.2 to 3.0%). Initiating vertical HIV transmission prevention embedded in improved antenatal services in a fragile, fragmented, severely resource-deprived health care system was possible and improved over time. Scope and quality of service coverage should further increase; strategies to decrease loss to follow-up of HIV+ women should be identified to improve program effectiveness. The observed differences in HIV prevalence highlight the importance of selecting representative sentinel surveillance centers. PMID- 19444667 TI - Secrecy and risk among MSM in Tbilisi, Georgia. AB - There is concern that the tremendous economic, social, and political upheavals that the Republic of Georgia has undergone in the years since the fall of the Soviet Union may have created an environment fertile for HIV transmission. Notably absent from official statistics and HIV-related research in Georgia is discussion of men who have sex with men (MSM) and, therefore, little is known about the MSM population or its potential to acquire or transmit HIV. Data were collected from 30 MSM recruited through a testing and counseling center in Tbilisi, the capital of Georgia. Two focus groups with six men each and 18 individual in-depth interviews were conducted between October 2006 and February 2007. The study participants described a Georgian culture that is largely intolerant of sexual contact between men. In describing the various forms of discrimination and violence that they would face should their sexual identities be discovered, the MSM in this sample described a variety of behaviors that they and other Georgian MSM undertake to conceal their sexual behavior. Many of these could put these men and their partners at risk for HIV. Although official HIV rates in Georgia are still low, results from this qualitative study indicate that efforts to educate and to provide unobtrusive and anonymous testing and counseling services to MSM may be critical to the deterrence of an HIV epidemic in the Republic of Georgia. PMID- 19444668 TI - Reliability and validity of two HIV/AIDS-specific quality of life instruments adapted for use in HIV-positive Zimbabweans. AB - We sought to assess the reliability and construct validity of the HIV/AIDS Targeted Quality of Life instrument (HAT-QoL) and the Medical Outcomes Study HIV Health Survey (MOS-HIV) adapted for use in Shona-speaking rural Zimbabwe. HAT-QoL and MOS-HIV were translated and culturally adapted into Shona, and administered to a convenience-sample of 400 patients with HIV-related opportunistic infections. HIV disease severity and bereavement history were assessed. Factor analysis of the HAT-QoL items produced seven factors that were nearly identical to the factor structure reported for an American sample that was the basis for the current HAT-QoL scales. Factor analysis of the MOS-HIV scales resulted in a single factor, not the expected two-factor structure (physical and mental). Convergent and discriminant validity assessments confirmed, in general, that similar Shona HAT-QoL and MOS-HIV dimensions were correlated and dissimilar ones not correlated. Construct validity assessments indicated that, on the whole, most Shona HAT-QoL and MOS-HIV dimensions were capturing anticipated subgroup differences. The exceptions were the Shona MOS-HIV dimensions of general health perceptions, cognitive function, and the quality of life (QoL) item. The reliability and validity of most Shona-adapted HAT-QoL and MOS-HIV dimensions suggest that both instruments are likely useful in measuring the QoL of rural, Shona-speaking populations in Zimbabwe, Mozambique, Zambia, and Botswana. PMID- 19444669 TI - Integrating HIV clinical services into primary health care in Rwanda: a measure of quantitative effects. AB - BACKGROUND: With the intensive scale-up of care and treatment for HIV/AIDS in developing countries, some fear that intensified attention to HIV programs may overwhelm health care systems and lead to declines in delivery of other primary health care. Few data exist that confirm negative or positive synergies on health care provision generally resulting from HIV-dedicated programs. METHODS: Using a retrospective observational design we compare aggregate service data in Rwandan health facilities before and after the introduction of HIV care on selected measures of primary health care. The study tests the hypothesis that non-HIV care does not decrease after the introduction of basic HIV care. FINDINGS: Overall, no declines were observed in reproductive health services, services for children, laboratory tests, and curative care. Statistically significant increases were found in utilization and provision of some preventive services. Multivariate regression, including introduction of HIV care and two important health care financing initiatives in Rwanda, revealed positive associations of all with observed increases. Introduction of HIV services was especially associated with increases in reproductive health. While hospitalization rates increased for the whole sample, declines were observed at health facilities that offered basic HIV care plus highly active antiretroviral therapy. INTERPRETATION: Our results partially counter fears that HIV programs are producing adverse effects in non HIV service delivery. Rather than leading to declines in other primary health care delivery, our findings suggest that the integration of HIV clinical services may contribute to increases. PMID- 19444670 TI - Factors influencing consent to HIV testing among wives of heavy drinkers in an urban slum in India. AB - The study examined the influence of socio cultural factors, perception of risk and exposure to violence on consent to HIV testing among at risk women in an urban slum. Married women chosen via a multistage probability sampling in a section of Bangalore, India, between 18 and 44 years, sexually active and considered to be at risk because of their husband's hazardous drinking were recruited for the study. Written informed consent was obtained and measures of risk behavior and violence were administered. Pretest HIV counseling was then conducted and consent for HIV testing was sought. Factors influencing refusal of and consent to HIV testing were documented. Data collected on 100 participants indicated that over half the sample (58%) refused consent for HIV testing. There were no significant differences between the groups who consented and those who refused on perception of risk and exposure to violence. Reasons women refused testing include the following: spouse/family would not allow it (40%), believed that they were not at risk or would test negative (29%) and underwent HIV testing during an earlier pregnancy (21%). Among those who consented for HIV testing, 79% did so because the testing site was easily accessible, 67% consented because testing was free and because the importance of HIV testing was understood. The findings highlight the role of social, logistic and awareness related factors in utilizing voluntary counseling and testing services by women in the slum community. They have important implications for HIV testing, particularly among at risk monogamous women. PMID- 19444671 TI - +CLICK: harnessing web-based training to reduce secondary transmission among HIV positive youth. AB - Adolescents and young adults account for over 10 million HIV infections worldwide. Prevention of secondary transmission is a major concern as many HIV positive youth continue to engage in risky sexual behavior. This study pilot tested " + CLICK", an innovative, web-based, sexual risk reduction intervention for HIV-positive youth as an adjunct to traditional clinic-based, self-management education. The theory-based application, developed for perinatally and behaviorally infected youth 13-24 years of age, provides tailored activities addressing attitudes, knowledge, skills, and self-efficacy related to sexual risk reduction. HIV-positive youth (N=32) pilot-tested " + CLICK" to assess usability (ease of use, credibility, understandability, acceptability, motivation) and short-term psychosocial outcomes (importance and self-efficacy related to abstinence and condom use) using a single group, pre-/post-test study design in a hospital-based pediatric clinic and community locations. A subsample of participants (n=20) assessed feasibility for clinic use. Participants were 62.5% female, 68.8% Black, and 28.1% Hispanic. Mean age was 17.8 years (SD = 2.55), 43.8% were infected behaviorally, 56.2% perinatally, and 68.8% were sexually experienced. Usability ratings were high: 84.4% rated the application very easy to use; 93.8% perceived content as trustworthy; 87.5% agreed most words were understandable; 87.5% would use the application again. Short-term psychosocial outcomes indicate a significant increase in condom use self-efficacy (p=0.008) and positive trends toward importance (p=0.067) and self-efficacy (p=0.071) for waiting before having sex. Regarding feasibility, participants accessed " + CLICK" during waiting periods (average time, 15 minutes) in their routine clinic visit. Clinic staff rated " + CLICK" highly in providing consistent, confidential, and motivational sexual health education without significant disruption to clinic flow. Results suggest that the application is a feasible tool for use in the clinic and has the potential to affect psychological antecedents to sexual behavior change. Further research on long-term and behavioral effects is indicated prior to broader dissemination into clinical practice. PMID- 19444672 TI - Doubts, denial and divine intervention: understanding delayed attendance and poor retention rates at a HIV treatment programme in rural Tanzania. AB - Irregular or delayed attendance at HIV treatment clinics among HIV-positive individuals can have negative implications for clinical outcomes and may ultimately undermine the effectiveness of national treatment programmes. This study explores factors influencing attendance at HIV clinic appointments among patients in a rural ward in north-west Tanzania. Forty-two in-depth interviews (IDI) and four focus group discussions were conducted with HIV-infected persons who had been referred to a nearby antiretroviral therapy (ART) clinic, and IDI were undertaken with 11 healthcare workers involved in diagnosis, referral and care of HIV-positive patients. The Health Belief Model was applied to explore the role of health-related beliefs and the perceived barriers and benefits associated with regular clinic attendance. Perceived susceptibility to HIV-related illnesses emerged as an important factor influencing clinic attendance, and was often manifest through expressions of acceptance or denial of HIV status and knowledge of HIV disease progression. Denial of HIV status was often associated with using alternative healers, and could occur prior to, during, or after starting ART. Perceptions of illness severity also influenced HIV clinic attendance, and often evolved in relation to changes in physical symptoms. Barriers to clinic attendance frequently included health systems factors, while physical and social benefits encouraged regular clinic attendance. Self-confidence in being able to sustain clinic attendance was often determined by patients' expectations or experiences of family support. These findings suggest that multi-faceted interventions are required to promote regular HIV clinic attendance, including on going education, counselling and support in both clinic and community settings. These interventions also need to recognise the evolving needs of patients that accompany changes in physical health, and should address local beliefs around HIV aetiology. Decentralisation of HIV services to rural communities should be considered as a priority to redress the balance between perceived barriers to, and benefits of accessing HIV treatment programmes. PMID- 19444673 TI - An integrated supervised injecting program within a care facility for HIV positive individuals: a qualitative evaluation. AB - While there has been growing interest in comprehensive models of treatment and care for individuals living with HIV/AIDS, little attention has been given to the potential role that supervised injecting programs could play in increasing access to prevention and care services for HIV-positive injection drug users (IDU). We conducted 22 semi-structured interviews with HIV-positive IDU regarding a supervised injection program integrated in an HIV focused care facility known as the Dr. Peter Centre (DPC). We also interviewed seven staff members who supervise injections within the facility. All interviews were audio recorded, transcribed verbatim, and a thematic analysis was conducted. Participant and staff reports indicated that the integrated supervised injection program influenced IDUs' access to care by building more open and trusting relationships with staff, facilitating engagement in safer injection education and improving the management of injection-related infections. Participants and staff viewed the program as facilitating the delivery of care through mediating overdose risks, reducing the need to punitively manage drug use on-site and reducing the risks of encountering used syringes on the premises. For some participants, however, feelings of shame and fear of judgment in relation to their drug use limited initial uptake of the program. Our findings identify mechanisms through which integrated supervised injection programs may serve to better facilitate access and delivery of comprehensive care for HIV-positive IDU and highlight the benefits of addressing HIV-positive IDUs' drug use in the context of comprehensive models of healthcare. PMID- 19444674 TI - Risk and protective factors in association with mental health problems among people living with HIV who were former plasma/blood donors in rural China. AB - A random sample of 271 people living with HIV (PLWH) who were former plasma/blood donors and a convenience sample of 67 HIV negative villagers were anonymously interviewed. Compared with the non-PLWH, PLWH reported higher prevalence of symptoms of depression (adjusted OR = 2.53, p=0.001), anxiety (adjusted OR = 1.85, p=0.04), and stress (adjusted OR = 1.77, p=0.06). Of the PLWH respondents, 81.7% received Highly Active Antiretroviral Therapy (HAART); 32.1% of whom reported some side effects. Respectively 13.7%, 37.4%, and 38.4% PLWH perceived discrimination from their family members, relatives/friends, and neighbors. Absence of HAART, poor physical function, perceived discrimination from relatives and friends, and low level of resilience were associated with depression (stepwise regression; beta = - 0.28-0.17, R-square = 0.22), anxiety and stress (R square = 0.32 and 0.16, respectively). The majority of respondents (70.1%) desired group intervention as a means for providing psychological support services. Relevant programs should both remove risk factors (e.g., absence of medical treatment, HIV-related discrimination) and promote protective factors (e.g., resilience). Support group is one of the potentially useful approaches to provide psychological support services. PMID- 19444676 TI - Cost consequences of HIV-associated lipoatrophy. AB - HIV-associated lipoatrophy may affect up to 35% of patients who have received antiretroviral (ARV) regimens for more than one year, and may result in depression, social isolation, and career barriers. Interventions including the injection of dermal fillers for restoration of facial fat loss are being used for treating HIV-associated lipoatrophy. Since reimbursement is often lacking, patients must consider the pros and cons of such interventions, weighed against the other costs of daily life. The primary goal of the study is to provide reliable estimates of the costs of treating HIV-associated lipoatrophy, specifically facial lipoatrophy. Costs are provided for a single site and are estimated from published studies reporting administration patterns of dermal fillers, publicly available list prices, and physician service fees for similar subcutaneous injections of the face. Fourteen studies were identified that reported experience with five dermal fillers used to treat HIV-associated facial lipoatrophy: poly-L-lactic acid, calcium hydroxylapatite, polyalkylimide gel, hyaluronic acid, and silicone oil. Typical courses involve four physician visits, but could vary from 1 to 13. The cost of a course of dermal filler treatment at a single site ranges across four products (all other than hyaluronic acid) from $3690 to $16,544, and is typically not covered by the payers. Physician fees for an entire course of similar outpatient procedures reimbursed by insurers are approximately $500, and may vary according to location, specialty, and market conditions. These procedures need to be repeated per site injected with intervals of 1-3 years. Treatment of HIV-associated lipoatrophy may represent a considerable out-of-pocket expense for many patients with HIV. This could have implications for deciding whether to undergo a restorative procedure, which procedure to undergo, and whether to pursue other options that may include switching ARV regimens. PMID- 19444675 TI - HAART receipt and viral suppression among HIV-infected patients with co-occurring mental illness and illicit drug use. AB - Mental illness (MI) and illicit drug use (DU) frequently co-occur. We sought to determine the individual and combined effects of MI and DU on highly active antiretroviral therapy (HAART) receipt and HIV-RNA suppression among individuals engaged in HIV care. Using 2004 data from the HIV Research Network (HIVRN), we performed a cross-sectional study of HIV-infected patients followed at seven primary care sites. Outcomes of interest were HAART receipt and virological suppression, defined as an HIV-RNA <400 copies/ml. Independent variables of interest were: (1) MI/DU; (2) DU only; (3) MI only; and (4) Neither. We used chi squared analysis for comparison of categorical variables, and logistic regression to adjust for age, race, sex, frequency of outpatient visits, years in clinical care, CD4 nadir, and study site. During 2004, 10,284 individuals in the HIVRN were either on HAART or HAART eligible defined as a CD4 cell count < or =350. Nearly half had neither MI nor DU (41%), 22% MI only, 15% DU only, and 22% both MI and DU. In multivariate analysis, co-occurring MI/DU was associated with the lowest odds of HAART receipt (Adjusted Odds Ratio: 0.63 (95% CI: (0.55-0.72]), followed by those with DU only (0.75(0.63-0.87)), compared to those with neither. Among those on HAART, concurrent MI/DU (0.66 (0.58-0.75)), DU only (0.77 (0.67 0.88)), were also associated with a decreased odds of HIV-RNA suppression compared to those with neither. MI only was not associated with a statistically significant decrease in HAART receipt (0.93(0.81-1.07)) or viral suppression (0.93 (0.82-1.05)) compared to those with neither. Post-estimation testing revealed a significant difference between those with MI/DU and DU only, and MI/DU and MI only. Co-occurring MI and DU is associated with lower HAART receipt and viral suppression compared to individuals with either MI or DU or neither. Integrating HIV, substance abuse, and mental healthcare may improve outcomes in this population. PMID- 19444679 TI - Participant evaluations of rate and communication efficacy of an AAC application using natural language processing. AB - This research explores the efficacy of an AAC application, Converser, that uses natural language processing to assist in communication. Converser uses speech recognition of the speaking partner to predict contextually appropriate utterances. This article reports on the subjective data gathered from an experimental evaluation of Converser's efficacy (see Wisenburn and Higginbotham, 2008 for a full description of Converser and the objective results). Converser was evaluated in two communication tasks (a Conversation and an Interview task) under two conditions: a simple alphabet board without Converser (alpha-only condition), and an identical board with Converser (alpha-Converser condition). Subjective data was gathered through rating questionnaires and written comments. Program users rated the speed of communication faster in the alpha-Converser condition. Program user ratings of quality, and speaking partner ratings of speed and quality, showed no difference between the two conditions; however, the participant comments about Converser were positive. PMID- 19444680 TI - Telephone talk: effects of timing and use of a floorholder message on telephone conversations using synthesized speech. AB - Telephone interaction remains a challenging form of communication for many who use speech-generating devices (SGDs). The purpose of this study was to investigate the effect of delayed starts and floorholder information at the beginning of synthesized-speech telephone calls to local businesses. Calls were placed to 100 randomly selected businesses asking for business hours. Each call was randomly assigned to one of four experimental conditions: a floorholder present with no delay, a floorholder present with a delay, floorholder absent and no delay, and floorholder absent with a delay. Overall, 76% of the calls were unsuccessful because the participant hung up or otherwise did not provide the information requested. The majority of successful calls occurred in the floorholder present and no delay condition. PMID- 19444681 TI - A comparison of picture exchange and speech-generating devices: acquisition, preference, and effects on social interaction. AB - Augmentative and alternative communication (AAC) includes picture exchange (PE) and speech-generating devices (SGD), but these two systems have rarely been compared. We therefore conducted three studies comparing PE and SGD for an adolescent boy with a developmental disability. Study 1 compared acquisition of a PE- and SGD-based requesting response and monitored the effects on social interaction. For Study 2, both communication modes were made simultaneously available and the child could choose to use either PE or the SGD. For Study 3, only PE intervention continued, with the distance between the child and trainer systematically increased to prompt social interaction. The results showed equally rapid acquisition of the PE- and SGD-based requesting response, but only the distancing manipulation had any positive effect on social interaction. We conclude that PE and SGD are equally viable modes of communication, but acquisition of an initial PE- or SGD-based requesting response may not be sufficient to promote social interaction. PMID- 19444682 TI - "All children can and should have the opportunity to learn": general education teachers' perspectives on including children with autism spectrum disorder who require AAC. AB - A qualitative online focus group methodology was used to investigate the experiences of five elementary school teachers (grades K-5) who had included in their general education classrooms children with autism spectrum disorders (ASD) who required augmentative and alternative communication (AAC). Information was obtained from the participants in the following areas: (a) the benefits of educational inclusion, (b) the negative impacts of educational inclusion, (c) the challenges of educational inclusion, (d) the supports for educational inclusion, and (e) recommendations for other teachers and individuals involved in the inclusion process. Participants primarily chose to focus on inclusion as a beneficial practice for all involved, but did describe a few barriers and challenges of inclusion. The results are discussed as they relate to these themes and with reference to published literature. Recommendations for future directions are also presented. PMID- 19444683 TI - Teaching sound letter correspondence and consonant-vowel-consonant combinations to young children who use augmentative and alternative communication. AB - The purpose of this study was to provide a preliminary examination of an intervention strategy designed to teach sound-letter correspondence and spelling of consonant-vowel-consonant (CVC) combinations to young children who use Augmentative and Alternative Communication (AAC). A multiple baseline probe design across behaviors was used to assess the effects of the intervention on the percentage of correct responses provided by two participants on the target skills during free-choice play activities in the literacy center of inclusive classrooms. The results of this study provide preliminary support for the use of the intervention strategy within inclusive classrooms. PMID- 19444684 TI - Comparison of fixed and gradual array when teaching sound-letter correspondence to two children with autism who use AAC. AB - The purpose of this study was to compare two conditions for teaching two children with autism (ages 4;10 and 5;4) who used Augmentative and Alternative Communication (AAC) to point to the printed letter that corresponded to the spoken letter sounds of /t/ and /m/. In one condition (gradual array), the printed letter was first presented in isolation and then distracter letters were gradually introduced. In the other condition (fixed array), the printed letter was immediately presented in combination with seven distracter letters. Using an alternating treatment design, results revealed that the fixed array condition resulted in a faster rate of acquisition of target skills for both participants. Implications and directions for future research are discussed. PMID- 19444685 TI - The discourse of gay men's group sex: The importance of masculinity. AB - Group sex has consistently been identified as one of a group of risk behaviours among gay men associated with HIV seroconversion. This paper presents a detailed description of how gender, and specifically masculinity, operates as an aspect of the discourse of gay men's group sex. The findings presented in this paper are one part of a multi-aspected discourse analysis through which we are aiming to develop an account of the discourse of gay men's group sex as it was produced in a series of qualitative interviews conducted with gay men who participate in group sex. The interviews were conducted as part of the Three or More Study (TOMS), a larger project that involved a substantial quantitative component. The overarching intent of the discourse analysis is to provide as comprehensive a mapping as possible of this discursive terrain to facilitate the targeted development of HIV and sexual health educational initiatives. The discourse of gay men's group sex reproduces some key formations of masculinity within discourses of gender, which present specific challenges for HIV prevention education. These challenges are outlined at the conclusion of this paper. PMID- 19444686 TI - The lived experience of Malawian women with obstetric fistula. AB - Data on women who experience obstetric fistula paints an often tragic picture. The majority of previous research has focused on facility-based data from women receiving surgical treatment. The goal of this qualitative study was to gain an understanding of the lived experience of obstetric fistula in Malawi. Forty-five women living with fistula were interviewed in their homes to learn how the condition affected them and their families on a daily basis. Findings indicate that the experiences of Malawian women with fistula were more varied than anticipated. Concerning relationships with husbands and family, we found high rates of divorce and stigma, yet these outcomes were far from universal or inevitable. Many women, in addition to their families, discussed high levels of support from those individuals closest to them. Nonetheless, many women experienced the fistula as a direct assault on their ability to fulfil social expectations of them as women, wives and mothers. Women identified fertility and continued childbearing as central concerns. The data suggest that we cannot discount the experiences of women living with fistula from continued participation in marriage, community and childbearing. Programmes for outreach and services should consider a broadened range of outcomes of women living with fistula. PMID- 19444687 TI - Engaging men who have sex with men in operations research in Kenya. AB - Research on men who have sex with men (MSM) in Africa is severely constrained. This paper examines the process of engaging MSM in research in a context where same-sex relationships are criminalised and socially stigmatised. Despite difficulties in researching MSM in Kenya, a convenient sample of 500 men was enrolled into a study aimed at understanding HIV/STI risks and prevention needs. Lessons drawn from this study highlight innovative methodological approaches and processes to working with and researching MSM in homophobic communities. Researchers willing to venture into MSM research in such contexts should be prepared to deal with among others, issues such as, seeking ethical approval for a study whose subjects are considered to engage in illegal activities, assuring study participants of their privacy and confidentiality and questioning of their own integrity. This study shows that despite difficulties, research of this kind can be carried out in Kenya. PMID- 19444688 TI - 'I am like a woman': constructions of sexuality among gay men in a low-income South African community. AB - South African research on same-sex sexuality is sparse. Black men living in rural areas, and particularly coloured men, have often been neglected in same-sex sexuality research. This paper describes the findings from a study that explored the sexuality constructions of a group of young, coloured, self-identified gay men who live in a semi-rural, low-income, South African community. Social constructionist grounded theory was used to analyse interviews conducted with 12 men between the ages of 20 and 31. It was found that these men construct their sexuality as being 'like a woman'. In our exploration of this core category, we show how men use notions of femininity to construct their sexuality. We conclude by considering how this group of gay men's performance of femininity could be viewed as reproducing mainstream ideas of gender within their community, while at the same time functioning as acts of subversion. PMID- 19444689 TI - Sexual risk behaviour for women working in recreational venues in Mwanza, Tanzania: considerations for the acceptability and use of vaginal microbicide gels. AB - Qualitative research was conducted to explore the social context of sexual-risk behaviour among women working in recreational occupations, during a feasibility study in preparation for the Phase III clinical trial of vaginal microbicides in Mwanza, Tanzania. Participant observation was conducted in 68 recreational venues. Six focus group discussions were conducted with women working in recreational occupations and two with male customers at these venues. Findings revealed that these women are at risk of HIV due their dependence on sexual transactions to improve their economic circumstances, which take place in environments and relationships where condom use is difficult. However, the findings revealed that, in spite of constraints, women did take actions to prevent HIV by negotiating for condom use or avoiding perceived risky practices or partnerships, in particular moving to more casual partnerships where condom negotiation is more acceptable. This indicates that, given their perception of their own risk, women working in recreational occupations will welcome an effective microbicide. However, sustained use will depend on how formulations overcome the difficulties women currently experience with condom negotiation and the specific environments and relationships in which they engage in sex. PMID- 19444691 TI - Occlusive therapy in atopic dermatitis: overview. AB - INTRODUCTION: Occlusive therapy, including both dry and wet ('wet-wrap therapy') offers a treatment option in atopic dermatitis (AD) which may be underutilized in clinical practice due to concerns about burdensome regimens and potential complications. This review examines current evidence for the use of occlusion in AD. METHODS: Keyword and title searches in PubMed and EMBASE were used to examine data on the use of occlusive therapy in AD from January 1966 to February 2009. RESULTS: Eighteen studies were found examining the use of occlusive therapy in AD. Of the 14 studies examining wet-wrap therapy, five were randomized controlled trials. All wet-wrap therapy studies demonstrated efficacy in severe or acute, moderate and chronic AD. Of the four studies examining dry occlusive therapy, a single controlled study of dry occlusion does not support a benefit over conventional open therapy. Increased cutaneous bacterial counts or clinical infection were reported in all studies using dry occlusion and in four of 14 studies utilizing wet-wrapping techniques. CONCLUSIONS: Available data are encouraging, though limited by the lack of adequate study controls and standardized designs. More controlled trials are indicated. PMID- 19444690 TI - Local and systemic oxidant/antioxidant status before and during lung cancer radiotherapy. AB - To examine local and systemic oxidative status of lung cancer (LC) and oxidant effects of radiotherapy (RT), this study evaluated antioxidants and markers of oxidative and nitrosative stress in bronchoalveolar lavage (BAL) fluid and in the blood of 36 LC patients and 36 non-cancer controls at baseline and during and after RT for LC. LC patients had higher baseline serum urate, plasma nitrite and lower serum oxidized proteins than controls (p=0.016, p<0.001 and p=0.027, respectively), but BAL fluid oxidative stress markers were similar. RT tended to raise some antioxidants, however, significant increases were seen in serum urate, conjugated dienes and TBARS (p=0.044, p=0.034 and p=0.004, respectively) 3 months after RT. High urate at baseline may compensate against the oxidative stress caused by LC. RT shifts the oxidant/antioxidant balance towards lipid peroxidation, although the antioxidant defense mechanisms of the body appear to counteract the increased oxidative stress rather effectively. PMID- 19444692 TI - Calcitriol ointment: a review of a topical vitamin D analog for psoriasis. AB - Topical vitamin D analogs are a safe and effective treatment for psoriasis vulgaris. This is a brief review of calcitriol 3 microg/g ointment in the treatment of psoriasis. Calcitriol has been safely used outside the USA in Europe under the trade name Silkis Ointment for almost a decade in the treatment of psoriasis, and it is currently FDA-approved as Vectical Ointment. Calcitriol 3 microg/g ointment is a synthetic topical vitamin D analog considered to be as effective as other vitamin D analogs but with a better tolerability in sensitive areas. PMID- 19444693 TI - Varicella-zoster virus vasculopathy and central nervous system immune reconstitution inflammatory syndrome with human immunodeficiency virus infection treated with steroids. AB - Immune reconstitution inflammatory syndrome (IRIS) is widely recognized and rarely involves the central nervous system (CNS). Patients with acquired immunodeficiency syndrome (AIDS) are at an increased risk for developing CNS-IRIS upon initiation of highly active antiretroviral therapy (HAART). This syndrome can be fatal and requires extreme vigilance in determining if a treatable underlying opportunistic infection exists. We report here a case of varicella zoster virus (VZV) vasculopathy and CNS-IRIS in a human immunodeficiency virus (HIV)-infected patient who required prolonged steroid treatment for clinical stabilization. There are no established treatment regimens for IRIS and the use of corticosteroids in this syndrome remains controversial. Similar to our patient, severe cases of CNS-IRIS may benefit from high-dose intravenous corticosteroid treatment followed by an oral prednisone taper. PMID- 19444694 TI - Nocodazole delays viral entry into the brain following footpad inoculation with West Nile virus in mice. AB - West Nile virus (WNV) infection in humans can cause neurological deficits, including flaccid paralysis, encephalitis, meningitis, and mental status change. To better understand the neuropathogenesis of WNV in the peripheral and the central nervous systems (PNS and CNS), we used a mouse footpad inoculation model to simulate a natural peripheral infection. Localization of WNV in the nervous system using this model has suggested two routes of viral invasion of the CNS: axonal retrograde transport (ART) from the PNS and hematogenous diffusion via a breakdown in the blood-choroid-plexus barrier. C57BL/6J mice were treated with nocodazole, a microtubule inhibitor that blocks ART, prior to infection with WNV. Nocodazole-treated WNV-infected mice developed a viremia 1.5 log(10) greater than untreated WNV-infected control mice at days 3 to 4 post infection (PI). Although viremia was greater in nocodazole-treated mice, detection of virus in brain tissue (spinal cord, cortex, brainstem, and cerebellum), as measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), did not occur until day 7. At these later time points (7 and 9 days PI), nocodazole-treated WNV-infected animals attained viral titers in these tissues similar to titers in the untreated WNV-infected control animals. These results demonstrate that a single dose of nocodazole delays, but does not block, WNV infection of the brain. PMID- 19444695 TI - Coxsackie B meningoencephalitis in a patient with acquired immunodeficiency syndrome and a multiple sclerosis-like illness. AB - Both Coxsackie infection and multiple sclerosis (MS) are rare in human immunodeficiency virus (HIV) infection. We report a 35-year-old woman with known HIV infection of 12 years' duration and a clinical illness of 4 years' duration consistent with MS. The latter was characterized by optic neuritis, bilateral abducens palsies, recurrent Bell's palsy, hemiparesis, and ataxia coupled with white matter abnormalities on magnetic resonance imaging (MRI). Autopsy revealed Coxsackie B meningoencephalitis; no other infectious disease were detected and no histopathological features of MS were evident. We suggest that the relapsing remitting neurological disease in this patient was the consequence of Coxsackie B meningoencephalitis. This is the first case report, to the best of our knowledge, of an enteroviral meningoencephalitis complicating human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). PMID- 19444696 TI - Serum matrix metalloproteinase levels correlate with brain injury in human immunodeficiency virus infection. AB - Circulating levels of specific matrix metalloproteinases (MMPs; 1 and 7) were evaluated as correlates of brain injury in eight individuals in advanced human immunodeficiency virus (HIV) infection. Neurological status was quantified in vivo with automated segmentation algorithms and with diffusion tensor imaging. Both metalloproteinases correlated with microstructural brain alterations and the degree of atrophy. MMPs may influence neurological outcome through involvement in neuroimmune response, blood-brain barrier permeability, leukocyte migration, and MMP-mediated neurotoxicity. PMID- 19444697 TI - The proteoglycan bamacan is a host cellular ligand of vaccinia virus neurovirulence factor N1L. AB - Neurovirulence is one of the pathological complications associated with vaccinia virus (VV) infection/vaccination. Although the viral N1L protein has been identified as the neurovirulence factor, none of the host N1L-interacting factors have been identified so far. In the present study, we identified N1L-interacting proteins by screening a human brain cDNA expression library with N1L as a bait protein in a yeast two-hybrid analysis. The analysis revealed that N1L interacts with human brain-originated cellular basement membrane-associated chondroitin sulfate proteoglycan (bamacan). The N1L-binding domain of bamacan was mapped to its C-terminal 227 amino acids. The N1L-bamacan interaction was further confirmed in both VV-infected and N1L-transfected mammalian cells. Following the confirmation of the protein interactions by coimmunoprecipitation experiments, confocal microscopic analysis revealed that N1L colocalizes with bamacan both in VV-infected B-SC-1 cells as well as in mice neuronal tissue. Furthermore, a human neural cell line, which expresses bamacan to moderately elevated levels relative to a non-neural cell line, supported enhanced viral growth. Overall, these studies clearly suggest that bamacan interacts with the VV-N1L and such interactions seem to play a positive role in promoting the viral growth and perhaps contribute to the virulence of VV in neural cells. PMID- 19444698 TI - Invasive mould infections: a multi-disciplinary update. AB - Systemic fungal infections remain a significant cause of mortality in neutropenic and immunocompromised patients, despite advances in their diagnosis and treatment. The incidence of such infections is rising due to the use of intensive chemotherapy regimens in patients with solid tumours or haematological cancers, the increasing numbers of allogeneic haematopoietic stem cell and solid organ transplants, and the use of potent immunosuppressive therapy in patients with autoimmune disorders. In addition, the epidemiology of systemic fungal infections is changing, with atypical species such as Aspergillus terreus and zygomycetes becoming more common. Treatment has traditionally focused on empirical therapy, but targeted pre-emptive therapy in high-risk patients and prophylactic antifungal treatment are increasingly being adopted. New treatments, including lipid formulations of amphotericin B, second-generation broad-spectrum azoles, and echinocandins, offer effective antifungal activity with improved tolerability compared with older agents; the potential impact of these treatments is reflected in their inclusion in current treatment and prophylaxis guidelines. New treatment strategies, such as aerosolized lipid formulations of amphotericin B, may also reduce the burden of mortality associated with systemic fungal infections. The challenge is to identify ways of coupling potentially effective treatments with early and reliable identification of patients at highest risk of infection. PMID- 19444699 TI - Evolutionary genetics of Zaprionus. II. Mitochondrial DNA and chromosomal variation of the invasive drosophilid Zaprionus indianus in Egypt. AB - Zaprionus indianus is an Afrotropical drosophilid species that has expanded its geographical range in the Palearctic region and the Americas during the second half of the last century. It has invaded Egypt within the past two decades from East Africa or Asia and became a dominant species in the drosophilid fauna therein, but the exact date of introduction and source of the propagule remain unknown. Here, we investigate the genetic structure of eight geographical populations within and around the Nile Delta using mitochondrial DNA sequences of the cox2 gene and chromosomal inversion polymorphism. A very low level of genetic variability was detected for both markers, mainly attributed to the introduction bottleneck. Nonetheless, both indicate a significant population structure, with a southeastern-northwestern cline. Demographic history analysis suggested northwestern populations to be younger (expanding in ca. 1992) than southeastern ones (expanding in ca. 1985). The In(II)A polymorphism was only observed in the northwestern population, but one-year interval analysis of the Alexandria population revealed the lack of seasonal fluctuation and a trend toward the loss of the polymorphism. Based on these data and faunistic records, we propose a multiple introduction scenario for Z. indianus in Egypt-according to which a first wave in the early 1980s from Sudan through normal northward range expansion or fruit trade, and a second wave in the early 1990s from Asia via fruit trade. We also suggest, from ecological observations, fruit trade data and known adaptive versatility of Z. indianus, date palm, the dominant fruit in Egypt and in the oases where Z. indianus predominates, to play a major role in the spread of the species in the Middle East. PMID- 19444700 TI - Complete mitogenome sequence of the jewel beetle, Chrysochroa fulgidissima (Coleoptera: Buprestidae). AB - In this study, we determined the complete mitochondrial genome of the jewel beetle, Chrysochroa fulgidissima (Coleoptera: Buprestidae), from four overlapping fragments. The 15,592 bp C. fulgidissima mitogenome exhibits a gene arrangement and content identical to the most common type in insects. The start codon of the C. fulgidissima COI gene is unusual, in that no typical ATN codon is available. The 875 bp A+T-rich region is the shortest among the coleopteran mitogenomes that have thus far been sequenced in their entirety. The most unusual feature of the genome is the presence of three tRNA-like sequences within the A+T-rich region: two tRNA(Leu)(UUR)-like sequences and one tRNA(Asn)-like sequence. These sequence stretches have the proper anticodon sequence and the potential to form secondary structures, but also harbor many mismatches in the stems. Phylogenetic analysis using a concatenation of 13 amino acid sequences of protein-coding genes among the available sequenced species of coleopteran superfamilies (Buprestoidea and Elateroidea belonging to the infraorder Elateriformia, and Chrysomeloidea and Tenebrioroidea belonging to the infraorder Cucujiformia) by Bayesian inference, maximum-likelihood analysis, and maximum-parsimony analysis revealed a lack of strong support for monophyletic Elateriformia. PMID- 19444703 TI - The effects of dietary cholesterol-lowering on psychological symptoms: a randomised controlled study. AB - The relationship of plasma cholesterol-reducing interventions to emotional states, such as depression and hostility, remains a topic of debate. The present study employed a randomised, controlled design, and was conducted at a clinical research center to test the effect of dietary cholesterol-lowering on psychological symptoms. Ten women and eight men were randomly assigned to one of two counterbalanced diet cycles (low-fat versus high-fat diet; isocaloric; 6 weeks each; separated by a washout period). Analyses for repeated measures revealed that the low-fat diet significantly reduced total, LDL and HDL cholesterol, when compared with baseline and the high-fat diet. As expected, weight remained unchanged. Ratings of depression, hostility and global severity of psychological symptoms as measured by the SCL-90-R also improved significantly on the low-fat, high-complex carbohydrate diet when compared with baseline. These results suggest that plasma cholesterol-lowering in the context of a low-fat, high-complex carbohydrate diet may have a beneficial effect on psychological symptoms. PMID- 19444704 TI - Explaining the effect of event valence on unrealistic optimism. AB - People typically exhibit 'unrealistic optimism' (UO): they believe they have a lower chance of experiencing negative events and a higher chance of experiencing positive events than does the average person. UO has been found to be greater for negative than positive events. This 'valence effect' has been explained in terms of motivational processes. An alternative explanation is provided by the 'numerosity model', which views the valence effect simply as a by-product of a tendency for likelihood estimates pertaining to the average member of a group to increase with the size of the group. Predictions made by the numerosity model were tested in two studies. In each, UO for a single event was assessed. In Study 1 (n = 115 students), valence was manipulated by framing the event either negatively or positively, and participants estimated their own likelihood and that of the average student at their university. In Study 2 (n = 139 students), valence was again manipulated and participants again estimated their own likelihood; additionally, group size was manipulated by having participants estimate the likelihood of the average student in a small, medium-sized, or large group. In each study, the valence effect was found, but was due to an effect on estimates of own likelihood, not the average person's likelihood. In Study 2, valence did not interact with group size. The findings contradict the numerosity model, but are in accord with the motivational explanation. Implications for health education are discussed. PMID- 19444705 TI - Clinical and behavioural aspects of aging with HIV infection. AB - Scant attention has been paid to the effects of ageing and HIV. This study examined age distribution and explored the impact of age on the experience of illness. One thousand and seven consecutive attenders at five UK HIV clinics were approached, 904 met inclusion criteria and 778 agreed to participate (86% response rate). They provided detailed information on demographics, experience of illness, physical and psychological symptoms, quality of life, treatment experience and doctor-patient communications. Twelve percent were aged over 50. There were significantly more males in the over 50s (86% vs. 75%), more gay males x(2) = 7, p = 0.04 and fewer females (14% vs. 25%) x(2) = 5; p = 0.03. No significant differences were found on measures of education, employment or migration status or physical symptom experience. The older group had significantly lower psychological and global burden scores and were more likely to take antiretrovirals (88% vs. 79%; p = 0.04). Triggers for treatment switching showed older participants significantly less burdened by food restrictions, pill burden, taste, nausea, diarrhoea, sleep disturbance, concentration problems, anxiety depression, skin rashes, liver complaints or a need for a simpler regimen. The older group were similar in employment, education and disclosure, but complained less and reported much higher tolerance. PMID- 19444706 TI - Social support network structure in older people: underlying dimensions and association with psychological and physical health. AB - Social networks have been associated with a wide variety of health outcomes in older people. We examined the dimensions underlying the Wenger social support network type assessment to identify dimensions associated with mental and physical health. We interviewed 1334 community-dwelling participants aged 65+. The Geriatric Mental State automated geriatric examination for computer-assisted taxonomy interview was used to rate psychiatric symptoms and quality of life. Cognitive impairment was defined as a score of <24 on the mini mental state examination. Clustering around latent variables identified two uncorrelated social support network domains: family (distance from and contact with relatives) and social engagement. Social engagement was associated with a lower age- and sex adjusted prevalence of depression (odds ratio for a one-tertile increase 0.48), generalised anxiety disorder (OR 0.60), cognitive impairment (OR 0.68) and physical disability (OR 0.62) all p < 0.001. Adjusted for age, sex, depression, cognitive impairment and disability, the social engagement domain was also associated with better quality of life (OR 1.5) self-rated happiness (OR 1.3) and rating life as worth living (OR 1.4). The family domain, on the other hand, was not significantly associated with any health outcome. The results suggest that elective relationships and social engagement are the 'active ingredients' of social networks which promote health in later life. PMID- 19444707 TI - Psychological distress as a correlate of a biologically confirmed STI, risky sexual practices, self-efficacy and communication with male sex partners in African-American female adolescents. AB - Previous research has established the association between psychosocial factors and risky sexual behaviour. However, few studies have examined the relationship between psychological distress and sexually transmitted infection (STI)/HIV associated behaviours in African-American youth. The present study examined the association of psychological distress with STI/HIV-risk behaviour and psycho social mediators of HIV-preventive behaviours. A sample of 715 African-American female adolescents, 15-21 years old, completed an audio computer assisted self interviewing (ACASI) assessing sociodemographics, psychological distress, self efficacy, communication and STI/HIV-associated sexual behaviours. Participants also provided self-collected vaginal swab specimens, which were assayed for STIs. High levels of psychological distress were defined as having a score of > or =7 on the eight-item Centre for Epidemiological Studies-Depression Scale. The overall prevalence of high levels of psychological distress was 44.5%. Logistic regression analyses revealed that adolescents with high psychological distress, relative to those with low psychological distress, were more likely to have a biologically confirmed STI (adjusted odd ratio (AOR) = 1.40), use condoms inconsistently (AOR = 1.50), not use condoms during their last casual sexual encounter (AOR = 1.89), have sex while high on alcohol or drugs (AOR = 1.47), have male sexual partners with concurrent female sexual partners (AOR = 1.98), have low condom use self-efficacy (AOR = 1.54), partner sexual communication self efficacy (AOR = 1.77), refusal self-efficacy (AOR = 2.05) and be more fearful of communicating with their partners (AOR = 1.98). These findings, although preliminary, could be used to inform HIV intervention programs and physicians/clinicians providing regular health care maintenance to African American female adolescents engaging in risky sexual behaviour. PMID- 19444708 TI - Health professionals as stigmatisers of tuberculosis: insights from community members and patients with TB in an urban district in Ghana. AB - Health professionals are in a power category within any social setting so when they identify and label diseases with negative attributes, it can be recognised by society with discriminatory consequences for individuals affected in the community. This article reports how activities of health professionals, as perceived and construed by community members can be a basis of stigmatisation of patients with tuberculosis (TB) in society. One hundred individual interviews and 22 focus groups were held with community members and patients with TB, and the generated data analysed using the grounded theory techniques and procedures. Through examination of the words and statements of the participants, five inter related ways by which activities of health professionals may expose patients with TB to stigmatisation in the community were identified: isolation and exclusionary practices; behaviours of health professionals towards patients with TB; public health discourse; food safety and hygiene practices and prohibition of full burial rites to those who died from TB. These activities are mirrored in the attitudes and behaviours of community members, and often become the basis of stigmatisation of individuals affected by TB in society. This may considerably contribute to diagnostic delay and low case finding in Ghana. Because, for fear of stigmatisation, community members who may be experiencing symptoms suggestive of TB may fail to go to the hospital. The stigma attached to TB in society may also contribute to the poor adherence to treatment seen among patients with TB in Ghana. To help to improve case finding and defaulter rate, the TB control programme should organise regular refresher courses in TB control and management for health professionals, and address the fear of infection by developing a national guidelines on how to prevent transmission of TB to health professionals within the hospital setting. PMID- 19444709 TI - Assessing lay beliefs about generic medicines: Development of the generic medicines scale. AB - The aims of this study were to develop a scale to assess lay beliefs about generic medicines, and to investigate whether these beliefs differ according to demographic factors in an opportunistic general public sample. In the pilot study, the participants were 92 men and 136 women, and in the main study there were 314 men and 505 women. At both stages, the participants completed a questionnaire measuring beliefs about generic medicines, preference for medicines and demographic information. The scale has good face validity, showing a satisfactory level of internal consistency. An exploratory principal component analysis revealed a two-factor structure concerning beliefs about generic medicines, comprising two core themes (efficacy and similarity to brand medicines), in two different samples. Older participants showed a stronger belief in similarity with brand names than the younger group. Higher educated participants showed a stronger belief in the efficacy of generics. The opportunity to assess beliefs about generic medicines may have implications for adherence, for the implementation of health policies and for decision making about medicines. PMID- 19444710 TI - Individuals and illnesses as sources of perceived preventability. AB - Perceived preventability of illness is an important predictor of health behaviour and response to illness. Yet, health experts remain largely unaware of the extent to which preventability attributions reflect characteristics of persons, illnesses and their interaction. Quantifying the sources of variance that compose illness preventability attributions may be especially useful for designing effective preventative health interventions. In the present study, we used generalisability theory to examine the sources of variance in illness preventability attributions. Undergraduate college students (N = 44) rated the personal preventability of 12 well-known physical illnesses. Preventability attributions were shown to most substantially reflect characteristics of illnesses (57.5% target effect). However, preventability attributions also strongly reflected interactions of individuals and illnesses (26.0% relationship effect). Characteristics of individuals were also significant, although they explained a relatively smaller amount of variance (7.1% perceiver effect). In general, these results suggest new directions for conceptualising theory and research on perceived preventability of illness. PMID- 19444711 TI - General and health-related life satisfaction of patients with community-acquired pneumonia. AB - When assessing the quality of care, patients' characteristics such as general and health-related life satisfaction, are of major significance. Our study examined the general and health-related life satisfaction of patients with community acquired pneumonia (CAP). To quantify the general and health-related life satisfaction, we used the validated instrument Questions on Life Satisfaction(Modules) by Henrich and Herschbach. CAP cases included in the German competence network on CAP (CAPNETZ) were asked to answer questions on their personal satisfaction with aspects of their life and health and on the individual importance of each addressed aspect. Data were compared with a normal population sample. In addition, several subgroup analyses were conducted. One thousand eight hundred ninety-nine (50.5%) CAP patients returned the questionnaire within a median time of 3 days. The mean age of the study sample was 55.1 +/- 17.1 years, 47.0% were female. The CAP patients reported not only a lower satisfaction with health (52.1 +/- 42.6 vs. 74.4 +/- 41.5, p < 0.001), but also a lower general life satisfaction (55.0 +/- 35.2 vs. 60.5 +/- 37.3, p < 0.001) than the normative German sample. Subgroup analyses revealed a significantly impaired general life satisfaction in patients with comorbidities (52.2 +/- 34.7) compared with patients without any underlying disease (58.1 +/- 35.4, p = 0.001). A non significant lower general life satisfaction (53.3 +/- 35.1 vs. 57.0 5 +/- 35.2, p = 0.052) as well as a lower health-related life satisfaction (49.25 +/- 42.0 vs. 55.3 +/- 43.0, p = 0.602) could be observed in men compared with those in women. Patients aged 65 years and older and patients with a severe CAP reported a lower health-related life satisfaction, but a higher general life satisfaction than younger patients or patients with mild CAP. The lower general life satisfaction observed in patients with CAP was found to reflect comorbidity rather than the effects of the pneumonia itself. PMID- 19444712 TI - Predictors of a health promoting lifestyle in women with fibromyalgia syndrome. AB - The purpose of this study was to describe the health practices of women with fibromyalgia syndrome (FMS) and the predictors of an overall health promoting lifestyle in these individuals. The predictors of a health promoting lifestyle examined in this study were barriers, social support, self-efficacy, demographic characteristics and illness factors. The sample consisted of 198 women who participated in a randomised clinical trial to test the effectiveness of a health promotion intervention for women with FMS. The women in this sample engaged most frequently in health practices in the domains of interpersonal relations and spiritual growth and least frequently in the domain of physical activity. Self efficacy and social support were significant predictors of an overall health promoting lifestyle. PMID- 19444713 TI - The Oxford Worries about Labour Scale: women's experience and measurement characteristics of a measure of maternal concern about labour and birth. AB - This study describes the measurement characteristics of a short (9-item) multi dimensional measure of worry about labour and birth, the Oxford Worries about Labour Scale (OWLS-9), and its use in a large-scale study of women's experience of care. The data utilised were from 2960 women who participated in a national survey of a random sample of women who had recently given birth in England. Exploratory factor analysis revealed three sub-scales within the instrument assessing specific concerns about labour pain and distress, pre-labour uncertainty and interventions. The characteristics of each sub-scale revealed good divergent and discriminant validity. Further, the labour and distress subscale score was found to be significantly associated with both self-reported 'baby blues' and self-reported postnatal depression. The study findings suggest that the three sub-scales embedded can be utilised or the OWLS-9 employed as a full-scale instrument. Used antenatally, the OWLS-9 and OWLS sub-scales may offer a relevant and clinically useful measure of worry about labour and birth. Limitations of the study are discussed and the direction of future research indicated. PMID- 19444714 TI - Development and initial validation of a measure of perceived stigma in irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a poorly understood digestive disorder prone to stigmatization. We developed a measure of condition-specific perceived stigma to better understand the role of stigma in this common disorder. Questionnaire items were established through structured patient interviews. A 10-item measure assessing relevant stigma variables across social domains was then administered to 148 patients with IBS. Test-retest reliability was assessed by having a subset of 26 patients re-complete the measure after 2 weeks. Twenty-eight out of 49 (57%) interview subjects with some degree of perceived stigma related to their IBS. A 10-item measure was developed with the following areas of perceived stigmatization: limited disclosure of IBS; belief that public knowledge about IBS was low; feeling that IBS was not taken seriously; people implying that IBS symptoms are self-inflicted; role limitations because of IBS; and others having the belief that IBS is 'all in their head'. Respondents rated the 10 items on the new measure with respect to perceived stigma in the social domains of healthcare providers; spouses/significant others; family members; friends; boss/supervisor; and coworkers/classmates. Stigma scores were significantly correlated with scores from the modified HIV stigma instrument (r = 0.56; p < 0.0001). Cronbach's alpha was estimated at 0.91. Mean inter-item correlation was 0.50 and ranged from 0.29 to 0.71. Guttman's split-half reliability coefficient was estimated at 0.89. Test retest reliability was high (r = 0.91; p < 0.0001). Patients with IBS reported the greatest degrees of perceived stigma related to coworkers, employers, and friends. Stigma dimensions which received the highest scores focused upon limited knowledge of IBS by others along with a lack of interest or understanding of others towards the condition. The IBS perceived stigma scale is a reliable, valid measure of perceived stigma related to IBS. PMID- 19444715 TI - Gender differences in cardiac patients: a longitudinal investigation of exercise, autonomic anxiety, negative affect and depression. AB - Female cardiac patients frequently experience greater anxiety and depression and engage in less exercise when compared with their male counterparts. This study considered whether exercise had similar effects on male and female cardiac patients' autonomic anxiety, negative affect and depression, and whether exercise behavior explained the gender difference in their affective functioning (e.g. autonomic anxiety, negative affect and depression). Eight hundred one participants completed the Hospital and Anxiety Depression Scale (HADS) and the leisure score index (LSI) of the Godin Leisure-Time Exercise Questionnaire at baseline, 6 months, 12 months, and 24 months. Female cardiac patients had greater autonomic anxiety, negative affect and depression and reduced exercise when compared with male cardiac patients at all time points. Although exercise was significantly related to affective outcomes at various time points for both men and women, gender did not moderate any of the exercise/affective relationships, and exercise did not mediate any of the gender/affective relationships. Further research is needed to clarify the complex relationships between gender, exercise, and the affective functioning of cardiac patients. PMID- 19444716 TI - Changes in blood polyamine levels in human acute pancreatitis. AB - OBJECTIVE: Experimental studies have shown that pancreatic activation of polyamine catabolism occurs during the early stage of acute pancreatitis. Changes in pancreatic polyamines are reflected in the red blood cell (RBC) polyamine contents, correlating with the extent of pancreatic necrosis. The aim of this human study was to examine the changes in polyamine levels in the RBCs of patients with acute pancreatitis. MATERIAL AND METHODS: Twenty-four patients with acute pancreatitis (7 alcoholic, 10 gallstone and 7 of unknown etiology) were recruited in the study. Eighteen patients with non-pancreatic acute abdominal diseases were included as controls, and 6 volunteers were studied as references. Blood samples were collected on admission and during hospitalization to assess polyamine levels. After clinical recovery, the patients revisited the clinic, and RBC polyamine levels were measured again. For comparison, plasma interleukin-6 (IL-6), IL-10 and C-reactive protein (CRP) were measured. RESULTS: In acute pancreatitis patients, there was no difference in RBC polyamine levels on admission compared with those in controls or in volunteers. Putrescine levels on admission were higher in patients with pancreatic necrosis than in patients without necrosis, but there was no difference in spermidine and spermine levels. Patients with pancreatitis of unknown etiology had significantly higher levels of polyamines on admission and throughout hospitalization, but they also had more necrosis, which explained the difference in multivariate analysis. Spermidine and spermine levels increased after clinical recovery. RBC putrescine correlated with IL-6 and IL-10, and spermine correlated with CRP. CONCLUSIONS: The results of this study suggest that RBC polyamines change in human acute pancreatitis in several respects, as has been previously observed in experimental pancreatitis. PMID- 19444717 TI - Disseminated Histoplasma capsulatum infection presenting with panniculitis and focal myositis in rheumatoid arthritis treated with etanercept. AB - We report the case of a patient with rheumatoid arthritis (RA) on etanercept who presented with panniculitis and focal myositis as manifestations of disseminated histoplasmosis. Systematic search of the literature showed 11 additional case reports of disseminated histoplasmosis with tumour necrosis factor-alpha (TNFalpha) blockade therapy (infliximab, n = 8; etanercept, n = 3). Although disseminated histoplasmosis may manifest with classical symptoms of fever and respiratory complaints, it may also present atypically, such as with panniculitis and focal myositis. This review illustrates and emphasizes the importance of being highly suspicious for infection, including by opportunistic organisms, and to exclude such process in patients treated with a TNFalpha inhibitor when faced with unusual complications, even when an alternative aetiology appears plausible. PMID- 19444718 TI - Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. AB - OBJECTIVES: T-cell DNA hypomethylation is thought to contribute to the development of systemic erythematosus lupus (SLE). However, it is unknown whether impaired T-cell DNA methylation occurs in other connective tissue diseases, such as systemic sclerosis (SSc) and dermatomyositis (DM). METHODS: We quantified global methylation in CD4+ T cells from 12 healthy donors and patients with SLE, SSc, and DM (10 patients in each group). mRNA levels of DNA methyltransferases (DNMTs) and methyl-CpG-binding domain proteins (MBDs) were measured by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: CD4+ T-cell DNA from patients with SLE (both active and inactive) and SSc, but not DM, was significantly hypomethylated relative to controls. The average expression levels of DNMT1 and MBD4 mRNA were significantly lower whereas MBD2 and MeCP2 mRNA levels were significantly higher in the SLE group. DNMT1, MBD3, and MBD4 mRNA was significantly decreased in the SSc group, whereas MBD2 and MeCP2 mRNA was significantly higher in the DM group. The degree of global DNA hypomethylation correlated positively with the relative level of DNMT1 across SLE samples and MBD4 across the SSc samples. CONCLUSION: Reduced DNA methylation and abnormal expression of methylation-related genes in CD4+ T cells are associated with SLE and SSc. PMID- 19444720 TI - Adult awareness of a youth-focused anti-tobacco campaign: does having children matter? AB - Data from a survey of tobacco use conducted in 2001 was used to examine if Florida's youth-focused anti-tobacco media campaign, which focused on cigarette smoking, reached adults. The majority of the sample was white (87%), high school or college educated (85%), and over half with children (56%). Differences in awareness and intentions to quit among adult smokers with and without children were examined. About 50% of adults were aware of the campaign and the awareness of the tobacco industry manipulation theme was associated with intentions to quit, independent of having children. These findings provide evidence that youth targeted anti-tobacco media campaigns can reach adults; however, to change the behavior of adults who smoke, it may not be appropriate to have a "one-size-fits all" program. The study's limitations are noted. PMID- 19444719 TI - Association of distinct clinical subsets with myositis-specific autoantibodies towards anti-155/140-kDa polypeptides, anti-140-kDa polypeptides, and anti aminoacyl tRNA synthetases in Japanese patients with dermatomyositis: a single centre, cross-sectional study. AB - OBJECTIVE: To determine the association of distinct clinical subsets with myositis-specific autoantibodies (MSAs) towards anti-155/140-kDa polypeptides [anti-155/140 antibodies (Abs)], anti-140-kDa polypeptides (anti-140 Abs), and anti-aminoacyl tRNA synthetases (ARS Abs) in Japanese patients with dermatomyositis (DM). METHODS: We compared the clinical features and short-term prognoses of 30 DM patients whose serological status included these MSAs. The MSAs were determined by immunoprecipitation. RESULTS: Anti-155/140 Abs (n = 5), anti-140 Abs (n = 8), and anti-ARS Abs (n = 7) did not overlap each other. All of the anti-155/140 Ab-positive patients (n = 5) were complicated by malignancies, as were all of the anti-140 Ab-positive patients (n = 8), who showed rapidly progressive interstitial lung disease (ILD). The survival rate at 6 months from the diagnosis of DM was significantly lower in the anti-140 Ab-positive patients than in the other patients. CONCLUSION: This is the first study to report, in a single cohort of DM patients, that distinct clinical subsets are distributed in an anti-155/140 Ab-positive group, an anti-140 Ab-positive group, or an anti-ARS Ab-positive group. Our data also confirm previous evidence that anti-155/140 Abs are involved in malignancies and that anti-140 Abs are involved in rapidly progressive ILD. PMID- 19444721 TI - Client/general medical practitioner interaction during brief intervention for hazardous drinkers: a pilot study. AB - Brief Intervention (BI) for hazardous drinkers at a Primary Health Care (PHC) level can be implemented during the interaction between a GP and his/her client in a range of contexts and opportunities, the GP's office being a primary context. Communication skills are needed for professionals in order to deliver the BI and they should be familiar with motivational interviewing. This pilot study, carried out during 2006-2007, observed how GPs are able to effectively communicate with their hazardous drinking clients when implementing BI. Four GPs have voluntarily participated in the study, altogether interviewing 13 clients in their office in the province of Florence (Italy). Two types of questionnaires were used: a questionnaire on the quality of BI and a questionnaire on the reformulation and summarizing skills. At the end of each interview both questionnaires were independently completed by both the GP and an attending research psychologist. Also, 12 interviews were videotaped and subsequently evaluated by two clinicians. On the whole, GPs scored high regarding their effective communication skills as well as in terms of the quality of BI implemented during the interviews at their offices. The study's limitations are noted and research needed in the future is suggested. PMID- 19444722 TI - Supervised methadone consumption: client issues and stigma. AB - Supervised methadone consumption is an important part of methadone maintenance treatment (MMT) but may contribute to stigma for clients. Data from qualitative interviews with MMT clients (n = 64) conducted in 2002-2003 in Canada were analyzed using thematic analytic methods. Three themes dominated clients' accounts of supervised consumption (convenient access to services, relationships with pharmacists and dispensing staff, and attributes of the dispensing space) and were interwoven with experiences of stigmatization. While some dispensing contexts may help clients manage a stigmatized identity, others confer or make visible this identity. Reducing stigmatizing experiences within dispensing environments may improve MMT outcomes and decrease barriers to treatment. The study's limitations are noted. PMID- 19444724 TI - Screening for substance abuse among adolescents validity of the CAGE-AID in youth mental health care. AB - OBJECTIVE: To examine the diagnostic accuracy of the four-item self-report and parent-report versions of the CAGE-AID as a screen for substance-use disorders (SUD) among adolescents in mental health care. METHOD: Patients were 190 Dutch treatment-seeking adolescents (12-18 years old, mean age 15.5 years, 53% boys) and their parents who completed the CAGE-AID questionnaire during intake. DSM-IV clinical diagnoses were used as gold standard in receiver operating characteristic analyses to determine psychometric properties. RESULTS: Psychometric properties for both the self-report and the parent-report versions showed the CAGE-AID's excellent diagnostic accuracy in predicting SUD. CONCLUSIONS: The CAGE-AID seems to be a brief and valid instrument for detecting SUD among adolescents in mental health care. However, denial may play a role in both the CAGE-AID and the clinical interviews. More research is needed to further establish the CAGE-AID's usefulness in other settings. The study's limitations have been noted. PMID- 19444723 TI - Predictors of DSM and Fagerstrom-defined nicotine dependence in African American and Puerto Rican young adults. AB - This study examined the psychosocial predictors of nicotine dependence, as defined by a variant of the criteria employed in the DSM-IV-specifically that of the University of Michigan Composite International Diagnostic Interview (UM-CIDI) and the Fagerstrom Test for Nicotine Dependence (FTND). The study was conducted with a community sample of African American and Puerto Rican young adults (N = 475; mean age = 26). Predictor variables included physiologically based psychosocial (i.e., depressive symptoms and family problems with smoking) as well as social-behavioral psychosocial (i.e., rebelliousness and partner's problems with smoking) predictors of nicotine dependence. Using multiple regression analyses, UM-CIDI-defined dependence was predicted by each of the four psychosocial variables, while FTND-defined dependence was predicted only by the social-behavioral variables. These findings bear out the disparate dimensions of nicotine dependence each measure taps. Research and clinical implications of the findings are discussed, and the study's limitations are noted. PMID- 19444725 TI - Creating a developmentally sensitive measure of adolescent alcohol misuse: an application of item response theory. AB - This study, funded by the US National Institute of Drug Abuse, evaluates the usefulness of item response theory (IRT) to create a developmental alcohol misuse scale. Data were collected during 1997-2006 from 5,828 Midwestern US students who completed annual surveys at grades 7 through 11 and 2 and 4 years after high school. Seventeen alcohol misuse items were calibrated with IRT and examined for differential item functioning (DIF) across 5 study waves. Eight items displayed DIF; in most cases, properties for items assessed 2 years after high school were different from those assessed in grades 8-11. Implications and suggestions for future research are discussed. PMID- 19444726 TI - Polydrug use among club-going young adults recruited through time-space sampling. AB - The Club Drugs and Health Project was supported by a grant from the National Institute on Drug Abuse (R01-DA014925-02, Jeffrey T. Parsons, Principal Investigator). Christian Grov was supported as a postdoctoral fellow in the Behavioral Sciences training in drug abuse research program sponsored by Public Health Solutions and the National Development and Research Institutes, Inc. (NDRI) with funding from the National Institute on Drug Abuse (T32 DA07233). The authors recognize the contributions of the Club Drug and Health Project team Michael Adams, Virginia Andersen, Anthony Bamonte, Jessica Colon, Armando Fuentes, Sarit A. Golub, Chris Hietikko, Eda Inan, Juline Koken, Jose E. Nanin, Anthony Surace, Julia Tomassilli, Jon Weiser, Brooke E. Wells, and the recruitment team. An earlier version of this paper was presented at the 2008 meeting of the College on Problems of Drug Dependence (CPDD). Though some researchers have indicated club drug users are more likely to be polydrug users, there remains little known about the prevalence and specific combinations of the substances they use. Between 2004 and 2006, and using time-space sampling, a stratified sample of 400, 18-29-year-old New York City club-going, drug-using young adults were recruited into the Club Drugs and Health Project. Most participants (91.7%) had engaged in polydrug usage and 1,670 combinations of drugs were reported. Ecstasy (86.6% of users) and cocaine (85.7% of users) were the two most-frequently reported club drugs used in combination with other substances. In terms of poly-club drug combinations, ecstasy appeared to be the "universal compliment" as this drug was most often cited in combinations with other club drugs (specifically ecstasy + ketamine, ecstasy + cocaine, ecstasy + gamma hydroxybutyrate or GHB). Other frequently cited drug combinations included cocaine and marijuana, ecstasy and marijuana, LSD and marijuana, and cocaine and alcohol. These data highlight the need to develop drug health-education and prevention messages targeted at polydrug usage. PMID- 19444727 TI - The making of the chronic addict. AB - Inspired by social problems theory, this article analyzes the "formula story" of harm reduction in a Danish addiction-treatment context. In Denmark, very few opiate addicts are in drug-free therapeutic treatment. Instead, they are offered methadone (often on a permanent basis) accompanied by practical help in tackling the negative social, economic, and health-related consequences of their drug use. The aim of this article is to show how the formula story of harm reduction-and first and foremost the idea that opiate addiction is an incurable condition-tends to work as a self-fulfilling prophesy. Opiate addicts entering the treatment system risk being "made up" as chronic addicts regardless of how they themselves look upon their own addiction problem and notwithstanding that many of them have not given up their hope of becoming drug-free. The article is based on two types of data: (1) file records (gathered in 2007) describing the addiction problems and treatment careers of clients enrolled at outpatient treatment centers in Copenhagen, and (2) qualitative interviews (conducted in 2006) with 30 methadone program participants at the centers. The analysis is qualitative and the empirical results cannot necessarily be generalized to other methadone maintenance programs. Yet the theoretical message of the article is applicable to all treatment institutions and social problems work in general. Definitions and categorizations of clients are not innocent, and naming people and their problems is the same as changing them. PMID- 19444728 TI - HIV-risk behavior among injecting or non-injecting drug users in Cape Town, Pretoria, and Durban, South Africa. AB - The rapid assessment aimed to describe drug use and sexual practices that place injection and noninjection drug users (IDUs/NIDUs) at risk for HIV in South Africa. The sample comprised 85 key-informant (KI) and focus-group (FG) interviewees in or serving locations with high levels of drug use in Cape Town, Durban, and Pretoria. HIV testing of drug-using KIs was conducted using the SmartCheck Rapid HIV-1 Antibody Test. The findings indicated that commonly used drugs had differing effects on sexual and drug-use practices. Risky injecting behaviors among IDUs were common, and most interviewees engaged in sex when on drugs, some without condoms. These behaviors were also influenced by trust in intimate relationships. Injection drug users seemed more knowledgeable about HIV transmission than NIDUs, and 20% of IDUs who agreed to HIV screening tested positive. Views about drug- and HIV-intervention services, accessibility, and their efficacy were mixed. The findings suggest greater synergy is needed between drug- and HIV-intervention sectors and that consideration should be given to making various risk-reduction strategies more accessible. The study's limitations have been noted. PMID- 19444730 TI - The kappa-opiate receptor impacts the pathophysiology and behavior of substance use. AB - There is increasing evidence that the kappa-opiate receptor, in addition to the mu-opiate receptor, plays an important role in substance use pathophysiology and behavior. As dopamine activity is upregulated through chronic substance use, kappa receptor activity, mediated through the peptide dynorphin, is upregulated in parallel. Dynorphin causes dysphoria and decreased locomotion, and the upregulation of its activity on the kappa receptor likely dampens the excitation caused by increased dopaminergic activity. This feedback mechanism may have significant clinical implications for treating drug dependent patients in various stages of their pathology. PMID- 19444729 TI - Plasticity of addiction: a mesolimbic dopamine short-circuit? AB - The development of drug addiction progresses along a continuum from acute drug use to compulsive use and drug seeking behavior. Many researchers have focused on identifying the physiological mechanisms involved in drug addiction in order to develop effective pharmacotherapies. Neuroplasticity, the putative mechanism underlying learning and memory, is modified by drugs of abuse and may contribute to the development of the eventual addicted state. Innovative treatments directly targeting these drug-induced changes in brain reward components and circuits may be efficacious in reducing drug use and relapse. PMID- 19444731 TI - Engagement and retention in outpatient alcoholism treatment for women. AB - Reviews of the dropout literature note significant attrition from addiction treatment. However, consistent predictors have not been identified and few studies have examined factors related to retention and engagement for women in gender-specific treatment. The current study consisted of 102 women and their partners randomized to individual or couples outpatient alcoholism treatment. Women attended more treatment sessions if they were assigned to individual treatment, older, had fewer symptoms of alcohol dependence, had more satisfying marital relationships, had spouses who drank, and had matched preference for treatment condition. Women were more engaged in treatment (ie, completed more assigned homework) if they had fewer children at home, fewer alcohol dependence symptoms, later age of onset of alcohol diagnosis, more satisfying marital relationships, and spouses who accepted or encouraged their drinking. Results highlight important associations of treatment and relationship variables with treatment retention and engagement. PMID- 19444732 TI - HIV risk behavior in opioid dependent adults seeking detoxification treatment: an exploratory comparison of heroin and oxycodone users. AB - Heroin users are at high risk for HIV infection, but little is known about HIV risk in oxycodone users. This study examined HIV risk behaviors in heroin (n = 27) and oxycodone (n = 23) users seeking inpatient detoxification at a private psychiatric hospital. Drug use histories were similar, except oxycodone users used marijuana more frequently. Injection drug risk occurred exclusively among heroin users. The rates of sexual activity (66%), unprotected intercourse (69%), sex while intoxicated (74%), and sex with strangers (24%) were similar, but more oxycodone users had multiple partners (39% vs. 6%, p < .05). HIV prevention efforts should target both heroin and oxycodone users. PMID- 19444733 TI - Theories of addiction: methamphetamine users' explanations for continuing drug use and relapse. AB - A variety of preclinical models have been constructed to emphasize unique aspects of addiction-like behavior. These include Negative Reinforcement ("Pain Avoidance"), Positive Reinforcement ("Pleasure Seeking"), Incentive Salience ("Craving"), Stimulus Response Learning ("Habits"), and Inhibitory Control Dysfunction ("Impulsivity"). We used a survey to better understand why methamphetamine-dependent research volunteers (N = 73) continue to use methamphetamine, or relapse to methamphetamine use after a period of cessation of use. All participants met DSM-IV criteria for methamphetamine abuse or dependence, and did not meet criteria for other current Axis I psychiatric disorders or dependence on other drugs of abuse, other than nicotine. The questionnaire consisted of a series of face-valid questions regarding drug use, which in this case referred to methamphetamine use. Examples of questions include: "Do you use drugs mostly to make bad feelings like boredom, loneliness, or apathy go away?", "Do you use drugs mostly because you want to get high?", "Do you use drugs mostly because of cravings?", "Do you find yourself getting ready to take drugs without thinking about it?", and "Do you impulsively take drugs?". The scale was anchored at 1 (not at all) and 7 (very much). For each question, the numbers of participants rating each question negatively (1 or 2), neither negatively or affirmatively (3-5), and affirmatively (6 or 7) were tabulated. The greatest number of respondents (56%) affirmed that they used drugs due to "pleasure seeking." The next highest categories selected were "impulsivity" (27%) and "habits"(25%). Surprisingly, many participants reported that "pain avoidance" (30%) and "craving" (30%) were not important for their drug use. Results from this study support the contention that methamphetamine users (and probably other drug users as well) are more heterogeneous than is often appreciated, and imply that treatment development might be more successful if treatments targeted subtypes of patients, though a range of limitations to the approach used are acknowledged. PMID- 19444734 TI - Intermittent marijuana use is associated with improved retention in naltrexone treatment for opiate-dependence. AB - Naltrexone is a theoretically promising alternative to agonist substitution treatment for opioid dependence, but its effectiveness has been severely limited by poor adherence. This study examined, in an independent sample, a previously observed association between moderate cannabis use and improved retention in naltrexone treatment. Opioid dependent patients (N = 63), admitted for inpatient detoxification and induction onto oral naltrexone, and randomized into a six month trial of intensive behavioral therapy (Behavioral Naltrexone Therapy) versus a control behavioral therapy (Compliance Enhancement), were classified into three levels of cannabis use during treatment based on biweekly urine toxicology: abstinent (0% cannabis positive urine samples); intermittent use (1% to 79% cannabis positive samples); and consistent use (80% or greater cannabis positive samples). Intermittent cannabis users showed superior retention in naltrexone treatment (median days retained = 133; mean = 112.8, SE = 17.5), compared to abstinent (median = 35; mean = 47.3, SE = 9.2) or consistent users (median = 35; mean = 68.3, SE = 14.1) (log rank = 12.2, df = 2, p = .002). The effect remained significant in a Cox model after adjustment for baseline level of heroin use and during treatment level of cocaine use. Intermittent cannabis use was also associated with greater adherence to naltrexone pill-taking. Treatment interacted with cannabis use level, such that intensive behavioral therapy appeared to moderate the adverse prognosis in the consistent cannabis use group. The association between moderate cannabis use and improved retention on naltrexone treatment was replicated. Experimental studies are needed to directly test the hypothesis that cannabinoid agonists exert a beneficial pharmacological effect on naltrexone maintenance and to understand the mechanism. PMID- 19444735 TI - Reasons for quitting smoking prior to a self-quit attempt among smokers with and without posttraumatic stress disorder or other anxiety/mood psychopathology. AB - The present investigation examined intrinsic and extrinsic reasons for quitting among daily cigarette smokers with posttraumatic stress disorder (PTSD) as compared to clinical daily smokers with other anxiety and mood disorders (AM) and daily smokers with no current Axis I psychopathology (C) prior to a self-guided quit attempt. It was hypothesized that (1) the PTSD group would report greater intrinsic (ie, self-control and health concerns) reasons for quitting smoking, and (2) among those with PTSD, anxiety sensitivity (fear of anxiety; AS) would predict greater intrinsic reasons for quitting smoking. Participants were 143 (58.7% female; M(age) = 29.66 years, SD = 11.88) daily cigarette smokers. Partially consistent with prediction, the PTSD group reported significantly greater self-control intrinsic reasons for quitting, but not health concern intrinsic reasons, than the C group (p < .01). The PTSD group also reported greater immediate reinforcement extrinsic reasons for quitting than the C group (p < .05). The PTSD and AM groups did not significantly differ on any reasons for quitting. Also partially consistent with hypotheses, higher levels of anxiety sensitivity in daily smokers with Axis I psychopathology (both PTSD and AM groups) significantly predicted greater self-control intrinsic reasons for quitting. AS did not significantly predict immediate reinforcement extrinsic reasons for quitting. The current findings suggest that individuals with PTSD and other psychopathology may have unique motivations for quitting smoking that could be usefully explored within smoking cessation treatment programs. PMID- 19444736 TI - Cigarette smoking among opioid-dependent clients in a therapeutic community. AB - This study examines smoking behavior in a sample of 231 opioid-dependent clients entering therapeutic community treatment, and investigates the relationship between smoking behavior and drug treatment outcomes. We applied regression analyses for selected Addiction Severity Index composites (alcohol, drug, medical, psychiatric), including factors for smoking (number of cigarettes per day, expired-air carbon monoxide level, nicotine dependence), time (baseline, 6 and 12-month), and smoking-by-time interaction. This study confirmed a high smoking prevalence (95%) among opioid users. Among participants interviewed at all time points (n = 206), 13% shifted from smoking to non-smoking status at some time after admission. Participants who reported a greater number of cigarettes were more likely to report higher drug severity at any time point. PMID- 19444738 TI - Psychopathology of injecting abuser. PMID- 19444739 TI - Delusional parasitosis following heroin withdrawal: a case report. PMID- 19444740 TI - Comment on "Outcomes of DATA certification trainings for the provision of buprenorphine treatment in the Veterans Health Administration". PMID- 19444743 TI - High-level production of recombinant Arenicola marina globin chains in Escherichia coli: a new generation of blood substitute. AB - This work reports for the first time the expression of a soluble B2 globin chain that is part of the extracellular hexagonal-bilayer haemoglobin from Arenicola marina. Two recombinant B2 globins were produced, one fused with gluthatione S tranferase (B2-GST) and the other without a fusion tag (RecB2) and requiring a different purification procedure. We also describe a new method for the expression of globin that uses Studier's auto-induction medium together with the heme precursor delta-aminolevulinic acid. Media supplementation with the heme precursor delta-aminolevulinic acid in the culture increased heme synthesis by E. coli leading to the expression of the recombinant B2 globins in their active form. RecB2 and B2-GST were expressed with a yield of up to 105 mg/l of E. coli culture. Our approach is rapid and requires only one chromatographic purification step for B2-GST and three purification steps for RecB2. The overall results on RecB2 and B2-GST show that the recombinant globins exhibit similar properties to those of Arenicola marina native HBL-Hb with a great stability and a strong oxygen binding. The results and methodologies described in this paper are the beginning of a work aiming at reconstituting a recombinant HBL-Hb by genetic engineering in order to produce an innovative oxygen carrier for therapeutic applications. PMID- 19444744 TI - Temporal gradient in the clock gene and cell-cycle checkpoint kinase Wee1 expression along the gut. AB - Circadian clocks were recently discovered in the rat and mouse colon as well as mouse stomach and jejunum. The aim of this study was to determine whether clocks in the upper part of the gut are synchronized with those in the lower part, or whether there is a difference in their circadian phases. Moreover, the profiles of core clock-gene expression were compared with the profiles of the clock-driven Wee1 gene expression in the upper and lower parts of the gut. Adult rats were transferred to constant darkness on the day of sampling. 24 h expression profiles of the clock genes Per1, Per2, Rev-erbalpha, and Bmal1 and the cell-cycle regulator Wee1 were examined by a reverse transcriptase-polymerase chain reaction within the epithelium of the rat duodenum, ileum, jejunum, and colon. In contrast to the duodenum, the rhythms in expression of all genes but Rev-erbalpha and Bmal1 in the colon exhibited non-sinusoidal profiles. Therefore, a detailed analysis of the gene expression every 1 h within the 12 h interval corresponding to the previous lights-on was performed. The data demonstrate that rhythmic profiles of the clock gene Per1, Per2, Bmal1, Rev-erbalpha, and clock-driven Wee1 expression within the epithelium from different parts of the rat gut exhibited a difference in phasing, such that the upper part of the gut, as represented by the duodenum, was phase-advanced to the lower part, as represented by the distal colon. Our data demonstrate that the circadian clocks within each part of the gut are mutually synchronized with a phase delay in the cranio-caudal axis. Moreover, they support the view that the individual circadian clocks may control the timing of cell cycle within different regions of the gut. PMID- 19444745 TI - Clock genes display rhythmic expression in human hearts. AB - Thus far, clock genes in the heart have been described only in rodents, and alterations of these genes have been associated with various myocardial malfunctions. In this study, we analyzed the expression of clock genes in human hearts. Left papillary muscles of 16 patients with coronary heart disease, 39 subjects with cardiomyopathy, and 9 healthy donors (52 males and 12 females, mean age 55.7+/-11.2; 16-70 yrs) were obtained during orthotopic heart transplantation. We assessed the mRNA levels of PER1, PER2, BMAL1, and CRY1 by real time PCR and analyzed their rhythmic expression by sliding means and Cosinor functions. Furthermore, we sought for differences between the three groups (by ANOVAs) for both the total 24 h period and separate time bins. All four clock genes were expressed in human hearts. The acrophases (circadian rhythm peak time) of the PER mRNAs occurred in the morning (PER1: 07:44 h [peak level 187% higher than trough, p = .008]; PER2: 09:42 h [peak 254% higher than trough, p < .0001], and BMAL1 mRNA in the evening at 21:44 h [peak 438% higher than trough; p < .0001]. No differences were found in the rhythmic patterns between the three groups. No circadian rhythm was detected in CRY1 mRNA in any group. PER1, PER2, and BMAL1 mRNAs revealed clear circadian rhythms in the human heart, with their staging being in antiphase to those in rodents. The circadian amplitudes of the mRNA clock gene levels in heart tissue are more distinct than in any other human tissue so far investigated. The acrophase of the myocardial PER mRNAs and the trough of the myocardial BMAL1 coincide to the time of day of most frequent myocardial incidents. PMID- 19444746 TI - Myocardial infarction occurs with a similar 24 h pattern in the 4G/5G versions of plasminogen activator inhibitor-1. AB - PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with greater circadian variation of PAI-1 levels. We hypothesized that the 24 h variation of cardiac risk is more pronounced among persons with the 4G4G genotype than among ones with 4G5G and 5G5G genotypes. We assessed the time of onset of symptoms in 623 consecutive patients with acute myocardial infarction (AMI) enrolled in the MISSION! Study between February 1, 2004, and October 29, 2006. All of the patients were genotyped for the PAI-1 4G/5G polymorphism. We quantified the amplitude of the 24 h variation of AMI with a generalized linear model with Poisson distribution. A morning peak, between 06:00-11:59 h (n = 197; 32% of all cases), in the onset of symptoms of AMI was observed. The group composed of patients with the 4G4G genotype did not have a more pronounced morning peak than the groups composed of other genotypes; the 24 h variation was 38% (95% confidence interval 12-70%) in the group of 4G4G patients and 34% (14 58%) and 56% (20-100%) in the 4G5G and 5G5G groups of patients, respectively. Our findings show that 24 h variation of cardiac risk is not more pronounced among the 4G4G genotype of PAI-1. PMID- 19444747 TI - Synchronization of Indian weaver bird circadian rhythms to food and light zeitgebers: role of pineal. AB - This study investigates the relative strengths of food and light zeitgebers in synchronization of circadian rhythms of Indian weaver birds and the role of the pineal gland in food-induced synchronization of the circadian activity rhythms. Two experiments were performed. In the first experiment, six birds were concurrently exposed for 10 days to PA 12/12 (12 h food present: 12 h food absent) and LD 12/12 (12 h light: 12 h dark). Then, the PA 12/12 cycle was reversed: food was present during the dark period of the LD 12/12 cycle. After 15 days, birds were released into constant dim light (LL(dim)). During exposure to overlapping light and food availability periods, birds were active only during the daytime. When light and food availability periods were presented in antiphase, two of six birds became night active. However, with the removal of the light zeitgeber (i.e., under LL(dim)), all birds were synchronized with reversed PA 12/12; hence, they were active during the subjective night (i.e., the period corresponding to darkness [ZT12-0] of the preceding LD 12/12). The second experiment examined whether the pineal contributed to the food-induced synchronization. After two weeks of concurrent PA 12/12 and LD 12/12 exposure, six birds were released into LL(dim) for 2.5 weeks. Under LL(dim), five of six birds were synchronized to PA 12/12 with the circadian period (tau, tau) = 24 h. The LD 12/12 was restored, and after seven days, birds were pinealectomized (pinx). After 2.5 weeks, pinx birds were again released into LL(dim) for 2.5 weeks. Under LL(dim), pinx birds did not become arrhythmic; instead, they appeared synchronized to PA 12/12 with tau = 24 h (n = 4) or approximately 24 h (n = 2). We conclude that both food and light act as zeitgebers, although light appears to be the relatively stronger cue when the two are present together, as in the natural environment. We also found that the pineal is not necessary for food-induced synchronization. The findings suggest that food cycles could act as the synchronizer of circadian rhythmicity in biological functions in individuals held in an aperiodic environment. PMID- 19444748 TI - Circadian rhythms of locomotor activity in the Nile tilapia Oreochromis niloticus. AB - Behavioral rhythms of the Nile tilapia were investigated to better characterize its circadian system. To do so, the locomotor activity patterns of both male and female tilapia reared under a 12:12 h light-dark (LD) cycle were studied, as well as in males the existence of endogenous rhythmicity under free-running conditions (DD and 45 min LD pulses). When exposed to an LD cycle, the daily pattern of activity differed between individuals: some fish were diurnal, some nocturnal, and a few displayed an arrhythmic pattern. This variability would be typical of the plastic circadian system of fish. Moreover, reproductive events clearly affected the behavioral rhythms of female tilapia, a mouth-brooder teleost species. Under DD, 50% (6 of 12) of male fish showed circadian rhythms with an average period (tau) of 24.1+/-0.2 h, whereas under the 45 min LD pulses, 58% (7 of 12) of the fish exhibited free-running activity rhythms with an average tau of 23.9+/-0.5 h. However, interestingly in this case, activity was always confined to the dark phase. Furthermore, when the LD cycle was reversed, a third of the fish showed gradual resynchronization to the new phase, taking 7-10 days to be completely re-entrained. Taken together, these results suggest the existence of an endogenous circadian oscillator that controls the expression of locomotor activity rhythms in the Nile tilapia, although its anatomical localization remains unknown. PMID- 19444749 TI - Sleep deprivation in the dark period does not impair memory in OF1 mice. AB - There is increasing evidence that sleep facilitates memory acquisition and consolidation. Moreover, the sleep-wake history preceding memory acquisition and retention as well as circadian timing may be important. We showed previously that sleep deprivation (SD) following learning in OF1 mice impaired their performance on an object recognition task. The learning task was scheduled at the end of the 12 h dark period and the test 24 h later. To investigate the influence of the prominent circadian sleep-wake distribution typical for rodents, we now scheduled the learning task at the beginning of the dark period. Wakefulness following immediately after the learning task was attained either by gentle interference (SD; n = 20) or by spontaneous wheel running (RW; n = 20). Two control groups were used: one had no RW throughout the experiment (n = 23), while the other group's wheel was blocked immediately after acquisition (n = 16), thereby preventing its use until testing. Recognition memory, defined as the difference in exploration of a novel and of familiar objects, was assessed 24 h later during the test phase. Motor activity and RW use were continuously recorded. Remarkably, performance on the object recognition task was not influenced by the protocols; the waking period following acquisition did not impair memory, independent of the method inducing wakefulness (i.e., sleep deprivation or spontaneous running). Thus, all groups explored the novel object significantly longer than the familiar ones during the test phase. Interestingly, neither the amount of rest lost during the SD interventions nor the amount of rest preceding acquisition influenced performance. However, the total amount of rest obtained by the control and SD mice subjected to acquisition at "dark offset" correlated positively (r = 0.66) with memory at test, while no such relationship occurred in the corresponding groups tested at dark onset. Neither the amount of running nor intermediate rest correlated with performance at test in the RW group. We conclude that interfering with sleep during the dark period does not affect object recognition memory consolidation. PMID- 19444750 TI - Plasma corticosterone in rats is specifically increased at recovery from propofol anesthesia without concomitant rise of plasma ACTH. AB - General anesthesia combined with surgery is commonly associated with post operative stress-response in humans. Effects on the hypothalamic-pituitary adrenal axis (HPA) during and after anesthesia are correlated with the magnitude of surgery and choice of anesthetics. The aim of our study in rats was to characterize the effects of general anesthesia without any surgery on HPA regulation of corticosterone and adrenocorticotropic hormone (ACTH) secretions. First, to assess whether the acute effects of general anesthesia on corticosterone concentration depend on time of day, rats were anesthetized with propofol at three different Zeitgeber times (ZT6, ZT10, and ZT16; with lights-on and -off at ZT0 and ZT12, respectively). Second, to determine the prolonged effects of general propofol anesthesia on daily corticosterone and ACTH concentrations, rats were anesthetized at ZT16 (4 h after lights-off) and euthanized either 1, 4, 12, 16, 20, or 24 h later. Third, the effects of propofol anesthesia on corticosterone and ACTH secretion were studied in rats instrumented with intracarotid cannulation. This permitted us to examine the individual patterns of corticosterone responses to propofol anesthesia as compared to their respective baseline corticosterone secretion. All of the results obtained showed that general propofol anesthesia, independent of the time-of-day of its administration, induces a significant increase of corticosterone secretion during the early recovery period without effect on ACTH secretion (i.e., no pituitary mediated stress-response). PMID- 19444751 TI - Phase delaying the human circadian clock with blue-enriched polychromatic light. AB - The human circadian system is maximally sensitive to short-wavelength (blue) light. In a previous study we found no difference between the magnitude of phase advances produced by bright white versus bright blue-enriched light using light boxes in a practical protocol that could be used in the real world. Since the spectral sensitivity of the circadian system may vary with a circadian rhythm, we tested whether the results of our recent phase-advancing study hold true for phase delays. In a within-subjects counterbalanced design, this study tested whether bright blue-enriched polychromatic light (17000 K, 4000 lux) could produce larger phase delays than bright white light (4100 K, 5000 lux) of equal photon density (4.2x10(15) photons/cm(2)/sec). Healthy young subjects (n = 13) received a 2 h phase delaying light pulse before bedtime combined with a gradually delaying sleep/dark schedule on each of 4 consecutive treatment days. On the first treatment day the light pulse began 3 h after the dim light melatonin onset (DLMO). An 8 h sleep episode began at the end of the light pulse. Light treatment and the sleep schedule were delayed 2 h on each subsequent treatment day. A circadian phase assessment was conducted before and after the series of light treatment days to determine the time of the DLMO and DLMOff. Phase delays in the blue-enriched and white conditions were not significantly different (DLMO: -4.45+/-2.02 versus -4.48+/-1.97 h; DLMOff: -3.90+/-1.97 versus 4.35+/-2.39 h, respectively). These results indicate that at light levels commonly used for circadian phase shifting, blue-enriched polychromatic light is no more effective than the white polychromatic lamps of a lower correlated color temperature (CCT) for phase delaying the circadian clock. PMID- 19444752 TI - A personal light-treatment device for improving sleep quality in the elderly: dynamics of nocturnal melatonin suppression at two exposure levels. AB - Light treatment has been used as a non-pharmacological tool to help mitigate poor sleep quality frequently found in older people. In order to increase compliance to non-pharmacological light treatments, new, more efficacious light-delivery systems need to be developed. A prototype personal light-treatment device equipped with low brightness blue light-emitting diodes (LEDs) (peak wavelength near 470 nm) was tested for its effectiveness in suppressing nocturnal melatonin, a measure of circadian stimulation. Two levels of corneal irradiance were set to deliver two prescribed doses of circadian light exposure. Eleven older subjects, between 51 and 80 yrs of age who met the selection criteria, were exposed to a high and a low level of light for 90 min on separate nights from the personal light-treatment device. Blood and saliva samples were collected at prescribed times for subsequent melatonin assay. After 1 h of light exposure, the light induced nocturnal melatonin suppression level was about 35% for the low-light level and about 60% for the high-light level. The higher level of blue light suppressed melatonin more quickly, to a greater extent over the course of the 90 min exposure period, and maintained suppression after 60 min. The constant exposure of the low-light level resulted in a decrease in nocturnal melatonin suppression for the last sampling time, whereas for the high-light level, suppression continued throughout the entire exposure period. The present study performed with healthy adults suggests that the tested personal light-treatment device might be a practical, comfortable, and effective way to deliver light treatment to those suffering from circadian sleep disorders; however, the acceptance and effectiveness of personal light-treatment devices by older people and by other segments of the population suffering from sleep disorders in a real life situation need to be directly tested. PMID- 19444753 TI - Persistent rotating shift-work exposure accelerates development of metabolic syndrome among middle-aged female employees: a five-year follow-up. AB - Limited follow-up studies are available as to whether special job-types, such as day-night rotating shift work, contribute to the progression of metabolic syndrome among female industrial employees. A retrospective cohort study on the development of metabolic syndrome was conducted by utilizing health examination records for a five-year interval. The records of 387 female employees without metabolic syndrome at baseline were used for the analysis. Data analyzed included age, metabolic syndrome components, insulin resistance status, lifestyle factors, and job-types. The initial mean age of subjects was 32.8 yrs. Abnormal rates at baseline, including metabolic syndrome components and insulin resistance, were all significantly higher among the 34 female workers with metabolic syndrome outcome. Also, the persistent rotating shift-work exposure rates and five-year change of metabolic syndrome component measurements were significantly unfavorable for subjects with metabolic syndrome outcome. After controlling for the potential confounders, significant raised risks were found in the female worker with persistent rotating shift-work exposure (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.3-9.0 vs. day workers) and in smokers (OR, 5.4; 95% CI, 1.1-25.8 vs. non-smokers). At the same time, the female workers initially with one or two metabolic syndrome components had a 4.6-fold (95% CI, 1.3-17.0) and 12.7-fold (95% CI, 3.2-50.1), respectively, increased risk of progressing to metabolic syndrome within five years. In conclusion, persistent day-night rotating shift work, smoking, and baseline metabolic syndrome components associate with the progression toward metabolic syndrome for middle-aged female workers. PMID- 19444754 TI - Effects of one night of partial sleep deprivation upon diurnal rhythms of accuracy and consistency in throwing darts. AB - Sixty subjects were tested five times per waking day on two occasions for accuracy and reliability in throwing 20 darts at a target. Two experimental conditions were investigated: following a normal nocturnal sleep (7-8 h sleep, normal) and after having retired to bed 4 h later than normal the previous night but rising at the normal time (3-4 h sleep, sleep deprivation). Sublingual (core) temperature and subjective estimates of alertness and fatigue were measured in all sessions. Performance at throwing darts was assessed by three methods: mean distance of the dart from the bulls-eye; number of times the target was missed; and variability of the scores from the darts thrown. There was no evidence that performance was affected by physical fatigue arising during the course of throwing the 20 darts. All variables showed significant diurnal rhythms, those of alertness and performance being phased over 1 h earlier than core temperature, and that of fatigue over 1 h earlier than the inverse of temperature. Core temperature was not affected by sleep deprivation, but all other variables showed significant changes, indicative of mood and performance decrement. Increasing time awake was associated with decreased alertness and increased fatigue, as well as slight negative effects upon performance. We conclude that the simple task of throwing darts at a target provides information about chronobiological changes in circumstances where time awake and sleep loss might affect psychomotor performance. PMID- 19444755 TI - Blue-light phase shifts PER3 gene expression in human leukocytes. AB - The timing of clock gene expression in human leukocytes was investigated following a phase-advancing light stimulus to determine whether the response is wavelength- and/or age-dependent. PERIOD3 (PER3) clock gene expression in leukocytes and plasma melatonin were analyzed before and after monochromatic blue and green light exposure. Significant phase advances were observed in the peak timing of both PER3 expression and melatonin following blue but not green light. The amplitude of the PER3 rhythm at baseline was significantly reduced with age. However, age did not affect the response of the PER3 rhythm to light. PMID- 19444756 TI - Chronotype and body composition in bipolar disorder. AB - We explored whether obesity in patients with bipolar disorder is associated with their chronotype. A group of 29 patients with bipolar I disorder, not currently experiencing an affective episode, were assessed for total body fat, mood symptoms, and self-reported circadian chronotype and sleep quality. Chronotype explained 19% of the variance in body fat, after age, sex, mood state, and sleep quality were accounted for. This association suggested that evening chronotype patients have a higher percentage of total body fat. Evening chronotype could be a proxy for as yet unknown specific causes of the high rate of obesity and obesity-related diseases in bipolar disorder. PMID- 19444758 TI - Association between the -1562 C/T polymorphism of matrix metalloproteinase-9 gene and lumbar disc disease in the young adult population in North China. AB - Many studies have demonstrated that matrix metalloproteinase-9(MMP-9) is involved in the development of lumbar disc disease (LDD). The expression and activity of MMP-9 are significantly enhanced in degenerative discs. The polymorphism -1562C/T in the promoter region of MMP-9 gene alters the transcriptional activity of this gene. In this study we assessed the relationship between the -1562C/T polymorphism of matrix metalloproteinase-9 gene and the extent of degenerative disc disease in the young adult population in North China. Genotypes were defined by polymerase chain reaction and direct DNA sequencing in 408 young patients with LDD and 451 control subjects. The resulting genotypes were correlated with the presence of lumbar disc degeneration on MRI. The frequency of the MMP-9 -1562T genotype in patients with LDD was significantly higher than in healthy controls. Compared with CC genotype, subjects with the CT/TT genotype had a higher risk to develop LDD (odds ratio 2.14; 95% confidence interval 1.55-2.96). Moreover, an association was found between this genotype and more severe grades of disc degeneration observed on magnetic resonance imaging scan. These results indicated that the -1562C/T polymorphism of the MMP-9 gene is associated with a high risk of degenerative disc disease in the young adult population in North China. PMID- 19444759 TI - IL-1beta stimulates the expression of prostaglandin receptor EP4 in human chondrocytes by increasing production of prostaglandin E2. AB - Prostaglandin (PG) E(2), which exerts its actions via the PG receptors EP1-4, is produced from arachidonic acid by cyclooxygenase (COX)-1 and COX-2. The aim of this study was to investigate the mechanisms by which interleukin (IL)-1beta induces the expression of PG receptors in cultured human chondrocytes and to explore the role of PGE(2) in this process. The cells were cultured with 0, 10, or 100 U/mL IL-1beta with or without 1 muM celecoxib, a specific inhibitor of COX 2, for up to 28 days. Expression of the genes encoding COX-1, COX-2, and EP1-4 was quantified using real-time PCR, and expression of the corresponding proteins was examined using immunohistochemical staining. PGE(2) production was determined using ELISA. IL-1beta treatment caused a marked dose- and time-dependent increase in the levels of PGE(2), COX-2, and EP4 as compared with the untreated control. It did not affect the expression of COX-1, and it decreased the expression of EP1 and EP2. EP3 expression was not detected in either the absence or the presence of IL-1beta. When celecoxib was also present, IL-1beta failed to stimulate PGE(2) production and EP4 expression, but its stimulatory effect on COX-2 expression and its inhibitory effect on EP1 and EP2 expression were unchanged. IL-1beta increases the production of PGE(2), COX-2, and the PG receptor EP4 in cultured human chondrocytes. The increase in EP4 expression appears to be a result of the increased PGE(2) production. PMID- 19444760 TI - Stimulation of small proteoglycan synthesis by the hyaluronan synthesis inhibitor 4-methylumbelliferone in human skin fibroblasts. AB - Human skin fibroblasts cultured with 4-methylumbelliferone (MU), a hyaluronan synthesis inhibitor, produce a hyaluronan-deficient extracellular matrix (See [9]). Our present study investigated the effects of MU on proteoglycan, which is the other main component of the extracellular matrix, and interacts with hyaluronan. Proteoglycans isolated from culture medium in the presence or absence of MU were characterized by gel-filtration chromatography, ion-exchange HPLC, electrophoresis, and immunoblotting. We found that MU had only a negligible effect on the synthesis of large proteoglycan but increased the production of small proteoglycan in comparison with cultures lacking MU. This small proteoglycan was identified by immunoblotting as decorin. The structures of decorin synthesized in the presence and absence of MU were compared by gel filtration chromatography, and the data indicated that cells incubated with MU produced a larger decorin molecule than cells incubated without MU. Furthermore, the two decorins had galactosaminoglycan chains of different sizes. These results suggest that MU inhibits the synthesis of hyaluronan and accelerates production of the larger decorin in the extracellular matrix. PMID- 19444761 TI - Expression profiling of genes involved in collagen turnover in tendons from cerebral palsy patients. AB - Cerebral palsy (CP) is a nonprogressive central nervous system lesion clinically characterized by impairment of voluntary movement related to spasticity, time of activation, and strength of skeletal muscle. Altered muscular control may act on tendon structure and influence extracellular matrix homeostasis, in particular, collagen. The effect of spasticity on collagen turnover in CP patients' tendons has not been described previously. We studied collagen turnover related genes in the gracilis and semitendinosus tendons of diplegic (n = 6) and quadriplegic (n = 15) patients, compared to normal subjects (n = 7). In particular, using real time RT-PCR, we analyzed the mRNA levels of the major extracellular matrix (ECM) components collagen type I (COL-I, alpha 2 chain COL1A2), the matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of MMP (TIMP-1), the enzyme responsible for collagen maturation lysyl hydroxylase 2b (LH2b), of the matricellular protein involved ECM remodelling (secreted protein acidic and rich in cysteine, SPARC), and the transforming growth factor-beta1 (TGF-beta1), a multipotent cytokine involved in collagen turnover. Our results show that gene expression profiles are quite different in CP samples compared to normal ones. In fact, spasticity induces relevant modifications of tendons at the molecular level, which modify their phenotypes to respond to the higher mechanical loading and increased functional demands. Interestingly, hypertonic quadriplegic subjects displayed the highest mRNA levels of COL1A2, LH2b, TGF-beta1, and SPARC, suggesting that their tendons undergo higher mechanical loading stimulation. PMID- 19444763 TI - Hearing Impairment in 2008: a compilation of available epidemiological studies. AB - A data bank of prevalence of hearing impairment for monitoring and implementation of programmes at national or global level and for the estimate of the global burden has been established. A systematic search was conducted of random-sample population-based studies of bilateral hearing impairment with clearly defined hearing threshold levels. Fifty-three studies from 31 countries from all WHO regions were found to meet the selection criteria. The prevalence of mild and disabling hearing impairment and other details from the studies are reported by WHO region. Although a large number of studies were found, only a small number among them were suitable surveys of prevalence of bilateral hearing impairment in the general population. Hearing impairment is a major disability that should be monitored at all ages: more population-based surveys are needed in all regions of the world. Utilization of the WHO protocol is recommended for collection and analysis of data in standard ways; especially recommended is the use of WHO threshold levels and to report the prevalence of bilateral impairment, both of which required to calculate burden. PMID- 19444764 TI - Fusion of images in multistep analysis of neovascularisation. AB - PURPOSE: The aim of our study was to develop a method for the fusion of images received after repeated staining of the same sample taking into account spatial differences between the images. MATERIAL AND METHODS: A method of objective fusion performance was investigated on the images receiving during multistep staining of the xenograft tumour cross-sections. RESULTS: It was shown that several images receiving from different steps of staining procedures may be successfully fused by fluorescent marking of slide position with Trout red blood cells before analysis. CONCLUSIONS: Proposed technique provides an accurate rigid fusion of light and fluorescent images receiving during multistep image analysis under microscope and may be applied for study of neovascularisation. PMID- 19444765 TI - Exposure to wood dust and its particle size distribution in a rubberwood sawmill in Thailand. AB - A cross-sectional study on wood dust exposure and respiratory health effects was conducted at one of the largest rubberwood sawmills in Thailand. All workers (N = 340) from all jobs on a day shift were recruited for personal sampling. Overall, the personal inhalable dust (n = 742) and respirable dust (n = 241) of full-shift samples were collected from 27 job titles. These data were used to classify workers into high, moderate, and low exposure groups based on the concentrations found in each job. Static samples were also collected to determine the particle size distribution. Geometric means (GM) are used to present the concentrations of the rubber wood dust. Inhalable dust concentrations were clearly high, ranging between 0.2 to 59.4 mg/m3 and with GM of 4.7 mg/m3. The GM of inhalable dust in each job title enabled classification of the workers into three exposure groups: (1) high exposure; >5 mg/m3, (2) moderate exposure; 2.0-5.0 mg/m3, and (3) low exposure; 0.18-1.9 mg/m3. Among the high exposure group, the highest GM inhalable dust concentrations were found in sawing green lumber (12.8 mg/m3) and cutting dry lumber (7.3 mg/m3). The respirable dust concentrations were generally low, in the range of 0.1 to 6.0 mg/m3 with a GM of 0.5 mg/m3. The largest percentage of dust in major operations belonged to the thoracic fraction; 50% cutoff diameter was smaller than 9 mum. The size distribution of wood dust indicated a high proportion in the large particle sizes. PMID- 19444766 TI - Eclampsia complicated by abdominal compartment syndrome. AB - A primigravida with eclampsia and hemolytic anemia, elevated liver enzymes, and low platelet count (HELLP syndrome) developed intra-abdominal compartment syndrome requiring a decompressive laparotomy, underlining the importance of including abdominal compartment syndrome in the differential diagnosis in pregnant women. PMID- 19444767 TI - Right tracheal bronchus in an infant with congenital diaphragmatic hernia. AB - Neonates with congenital diaphragmatic hernia (CDH) often have other major malformations. Anatomic airway anomalies associated with CDH include congenital stenosis, pulmonary hypoplasia, and abnormal bronchial branching. We describe an infant with CDH who, after developing recurrent upper-lobe atelectasis, was found to have a right tracheal bronchus. This clinically significant anomaly can have important and potentially preventable adverse consequences. PMID- 19444768 TI - [Chronic obstructive pulmonary disease (COPD) as a systemic disease]. AB - Chronic obstructive pulmonary disease (COPD) is defined as a progressive, usually only partially reversible, obstruction of the airways The disease is associated with an inflammatory response of the lungs to noxious particles, particularly cigarette smoke. Numerous epidemiological studies have shown a significant association between impaired lung function and the presence of cardiovascular, metabolic or other extrapulmonary comorbidities. Systemic inflammation may be the missing link between COPD and its extrapulmonary manifestations, although the exact mechanism of this relationship remains unclear. The development and validation of score systems that classify COPD severity, not only by changes in lung function, is an important step. The BODE score (body-mass index, airways obstruction, dyspnea, exercise capacity) is such a system. Based on the concept of COPD as a systemic disease, a concept is needed which describes in detail the pharmacological treatment of the pulmonary and extrapulmonary manifestations of the disease. In addition, the part of the disease that is treatable with physiotherapy and rehabilitation must be fully taken into account. Such multimodal treatment regimens have so far not been implemented into clinical guidelines. PMID- 19444769 TI - Herbal medicines in the management of urolithiasis: alternative or complementary? AB - Kidney stone formation or urolithiasis is a complex process that results from a succession of several physicochemical events including supersaturation, nucleation, growth, aggregation, and retention within the kidneys. Epidemiological data have shown that calcium oxalate is the predominant mineral in a majority of kidney stones. Among the treatments used are extracorporeal shock wave lithotripsy (ESWL) and drug treatment. Even improved and besides the high cost that imposes, compelling data now suggest that exposure to shock waves in therapeutic doses may cause acute renal injury, decrease in renal function and an increase in stone recurrence. In addition, persistent residual stone fragments and the possibility of infection after ESWL represent a serious problem in the treatment of stones. Furthermore, in spite of substantial progress in the study of the biological and physical manifestations of kidney stones, there is no satisfactory drug to use in clinical therapy. Data from IN VITRO, IN VIVO and clinical trials reveal that phytotherapeutic agents could be useful as either an alternative or an adjunctive therapy in the management of urolithiasis. The present review therefore critically evaluates the potential usefulness of herbal medicines in the management of urolithiasis. PMID- 19444770 TI - Salidroside, the main active compound of Rhodiola plants, inhibits high glucose induced mesangial cell proliferation. AB - Because Rhodiola plants are known to have a protective effect on diabetic nephropathy, this study aimed to investigate the inhibitory effect of salidroside, the main active component of Rhodiola plants, on high glucose induced mesangial cell proliferation and its possible mechanism. Salidroside (1 approximately 100 microM) dose dependently inhibited high glucose-induced mesangial cell early proliferation. Exposure of mesangial cells to high glucose for 24 h significantly induced reactive oxygen species (ROS) accumulation, ERK1/2 phosphorylation, and p27 (Kip1) expression, and these changes were dramatically inhibited by salidroside in a dose-dependent manner. High glucose-promoted TGF- beta1 secretion was also significantly attenuated by treatment of mesangial cells with salidroside. These results indicated that salidroside had the ability to inhibit high glucose-induced mesangial cell proliferation, which is in correlation with salidroside suppressing TGF- beta1 production and ERK1/2 phosphorylation. PMID- 19444771 TI - Diterpenoids from Casearia sylvestris. AB - Two highly oxygenated clerodane diterpenes casearins U (1) and V (2) and two ent kaurane diterpene glucosides sylvestrisides A (3) and B (4) were isolated from the leaves of Casearia sylvestris, together with 13 known compounds. Their structures were established on the basis of 1D and 2D NMR spectroscopic analyses and comparison with literature data. PMID- 19444772 TI - Antimycobacterial activity of Exocarpos latifolius is due to exocarpic acid. AB - Lipophilic fractions of stem extracts from Exocarpos latifolius, native to Papua New Guinea, showed significant activity against Mycobacterium tuberculosis H37Ra. Bioactivity-guided fractionation yielded exocarpic acid (E-octadeca-13-ene-9,11 diynoic-acid) as the major active component. Several new exocarpic acid analogs were also shown to be active. Exocarpic acid has previously been reported active against gram-positive, but not gram-negative bacteria. Work presented here demonstrates the selective activity of exocarpic acid against Mycobacterium tuberculosis H37Ra. PMID- 19444773 TI - An extract from berries of Aronia melanocarpa modulates the generation of superoxide anion radicals in blood platelets from breast cancer patients. AB - Plant antioxidants protect cells against oxidative stress. Because oxidative stress (measured by different biomarkers) is observed in breast cancer patients, the aim of this study was to establish the effects of a polyphenol-rich extract of Aronia melanocarpa (final concentration of 50 microg/mL, 5 min, 37 degrees C) on superoxide anion radicals (O(2)(-*)) and glutathione (GSH) in platelets from patients with breast cancer and in a healthy group in vitro. Generation of O(2)( *) in platelets before and after incubation with the extract was measured by cytochrome C reduction. Using HPLC, we determined the level of glutathione in blood platelets. We observed a statistically significant increase of biomarkers of oxidative stress such as O(2)(-*) and a decrease in GSH in platelets from patients with breast cancer compared with the healthy group. We showed that the extract from A. melanocarpa added to blood platelets significantly reduced the production of O(2)(-*) in platelets not only from the healthy group but also from patients with breast cancer. Considering the data presented in this study, we have demonstrated the protective role of the extract from A. melanocarpa in patients with breast cancer in vitro. PMID- 19444774 TI - [Over-indebtedness and additional payments to the German health-care system - discrimination upon destitution in expenditure]. AB - AIM OF THE STUDY: In the past few years, the number of over-indebted private households in Germany has steadily increased and is currently estimated to have reached 3.13 million. Financial difficulties culminating in private insolvencies of the persons concerned may lead to a restrained usage of health-care services that require additional payment. For the first time ever this study has examined whether over-indebted individuals refrain from seeking medical treatment or from buying prescribed medicine because of their financial situation. METHODS: The cross-sectional study covered over-indebted persons in Rhineland-Palatinate and was conducted between July 2006 and March 2007. In cooperation with 53 debt counselling agencies in Rhineland-Palatinate and in cooperation with the specialized debtor counselling centre of the Johannes Gutenberg-University of Mainz a singular, anonymous questionnaire-based survey in written form was conducted. RESULTS: Altogether 666 persons (51% female) between 18 and 79 years old (mean value: 41,0 years, standard deviation: 11,2 years; median: 41 years) participated in this evaluation, which amounts to a participation rate of 35.5%. The majority of participants stated to refrain from buying prescribed medication (65.2%) as well as from seeking medical advice and paying euro 10.00 own contribution (60.8%) because of their financial situation. The multivariate, binary logistic end-model showed age, family situation, insolvency proceedings, medical conditions and the self-reported attitude towards health alertness to be relevant factors of influence for both target variables. CONCLUSION: The enacted own financial contribution when seeking health care or when receiving medication in Germany might cause a discrimination of indebted persons or households with regard to health care and medical treatment. Because of the obligation of additional payment, health services are not independent of an individual's financial resources, meaning that especially destitution in expenditure affects equal opportunities in the health care system. PMID- 19444775 TI - Frontochoanal polyp: case report. AB - Choanal polyps are solitary benign growths that can cause unilateral nasal obstruction. A frontochoanal polyp originates from the frontal sinus and extends to the nasopharynx. These lesions are rare and are usually diagnosed by endoscopic examination and computed tomography. A 20-year-old man presented with unilateral nasal obstruction and headache. Findings on endoscopy and computed tomography suggested frontochoanal polyp, and endoscopic treatment was successful. We discuss the case and review the pertinent literature. PMID- 19444776 TI - Technique selection for orbital decompression: combined endoscopic and transconjunctival versus combined endoscopic and transantral approach. AB - Surgical orbital decompression is indicated for patients with compressive optic neuropathy, exposure keratopathy, an uncontrolled elevation of intraocular pressure, globe subluxation, and disfiguring proptosis secondary to Graves ophthalmopathy. Controversy exists, however, regarding the selection of surgical technique to achieve orbital decompression. We compared the results of our combined transnasal endoscopic and transconjunctival approach with those of our combined transnasal endoscopic and transantral approach to orbital decompression. We conducted a retrospective chart review of patients who had undergone medial- and inferior-wall orbital decompression from January 1994 through January 2004. During that time, 189 combined medial- and inferior-wall orbital decompressions were performed on 124 patients; 51 combined endoscopic and transantral decompressions were performed on 28 patients, and 138 combined endoscopic and transconjunctival decompressions were performed on 96 patients. Patient demographics and the degree of preoperative proptosis were statistically equal in the 2 groups. The incidence of optic neuropathy in the transantral group was significantly higher than the incidence in the entire group (p = 0.03), and the incidence of exposure keratopathy was significantly lower in the transantral group than in the entire group (p = 0.03). Postoperatively, the reduction in proptosis in the 2 groups was statistically equivalent, but the transconjunctival group had a significantly lower incidence of both infraorbital hypesthesia (p< 0.0001) and early rhinosinusitis (p = 0.008). Three cases of globe ptosis and 2 of infraorbital neuralgia occurred. No cases of visual loss, worsened optic neuropathy, diplopia in patients without preexisting diplopia, cerebrospinal fluid leak, significant epistaxis, or periorbital hematoma were noted. We conclude that combined endoscopic and transconjunctival orbital decompression offers equivalent efficacy with less postoperative infraorbital hypesthesia and early rhinosinusitis than does combined endoscopic and transantral orbital decompression. PMID- 19444777 TI - A survey of current practices of physicians who treat adductor spasmodic dysphonia in the U.S. AB - We conducted a survey to determine the current practices of a subset of physicians in the United States who treat patients with adductor spasmodic dysphonia. Surveys were sent to 169 physicians listed in the National Spasmodic Dysphonia Association database, and responses were returned by 43 (25.4%). Almost all respondents (95.4%) indicated that they use botulinum toxin type A injections, either alone or in combination with other treatments, to treat adductor spasmodic dysphonia, and most (69.8%) inject the toxin under electromyographic guidance. However, there were wide variations in the amount of sterile saline used to reconstitute the toxin, the size of the initial dose, and the use of other treatment strategies. PMID- 19444778 TI - Infratemporal fossa abscess: a diagnostic dilemma. AB - An abscess in the infratemporal fossa is a rare complication of dental extraction. Although it is a recognized entity, only a handful of cases have been reported in the literature. We describe a case of abscess in the infratemporal fossa of a 55-year-old woman with noninsulin-dependent (type 2) diabetes who presented with left-sided facial pain and marked trismus. The abscess was managed successfully with external drainage. We have made an attempt to comprehensively review the literature on this rare condition, with special emphasis on its anatomic complexity and varied clinical presentation, and we provide a detailed discussion of the diagnosis and management of this condition. PMID- 19444779 TI - Tracheal amyloidosis-an unusual cause of stridor. AB - Amyloidosis confined to the trachea is an exceedingly rare entity. We describe the case of a 63-year-old man who presented with a history of dysphonia and stridor. Rigid bronchoscopy revealed a segment of abnormal tissue at the midtracheal level, resembling granulation tissue. A stent was placed in an attempt to secure the patient's airway, which was >50% narrowed. Although the patient's stridor disappeared completely, 5 days postoperatively it recurred, worsening within hours. Emergency bronchoscopy revealed that the tracheal stent was almost completely obstructed with amyloid and granulation tissue, despite high-dose steroid therapy, and had to be removed. Tracheostomy was performed to bypass the diseased trachea. We also highlight some of the problems encountered with tracheal stenting in benign tracheal disease. PMID- 19444780 TI - Thyroidectomy in a community hospital: findings of 100 consecutive cases. AB - The objective of this study was to determine the characteristics and surgical outcomes of 100 consecutive cases of thyroidectomy (in 98 patients) at a community hospital from October 2005 to mid-November 2006. Preoperative laryngoscopy was performed in 94% of patients and postoperative laryngoscopy in 100%. Patients' thyroid nodules had been found incidentally in 28% of cases. The two most common indications for surgery were results of fine-needle aspiration biopsy (FNA) in 55% and size of the thyroid in 22% of cases. Of the 98 patients, 79 (81%) had benign diagnoses, 7 (7%) had microcarcinomas, and 12 (12%) had well differentiated thyroid cancer. Overall, 5 patients (5%) had temporary recurrent laryngeal nerve paralysis, but this occurred in only 1 (1%) patient in the group with smaller lesions, a statistically significant difference (p< 0.02); none had permanent paralysis. Of 36 patients at risk for hypocalcemia, 3 (8%) and 1 (3%) had temporary and long-term hypocalcemia, respectively. There was no incidence of significant hemorrhage. FNA results were very accurate. We show that thyroidectomy can be performed with minimal laryngeal nerve paralysis or other complications. Larger lesions had significantly higher rates of temporary laryngeal nerve paralysis. PMID- 19444781 TI - A huge sphenoid sinus mucocele: report of a case. AB - Sphenoid sinus mucoceles are exceedingly rare. Most have occurred in men between the ages of 30 and 40 years. We report a case of sphenoid sinus mucocele that was unusual not only for the age of the patient (13 yr), but for the massive size of the lesion (59 x 53 mm). The patient presented with a 20-day history of unilateral proptosis, decreased vision, diplopia, and photophobia. He also complained of severe bilateral nasal obstruction, nasal stuffiness, and a mucoid nasal discharge. Endoscopic decompression of the left sphenoid sinus was performed, and approximately 200 ml of thick, sterile mucoid secretion was aspirated. Despite the size of the mucocele, no significant destruction of the sphenoid walls was evident. Postoperatively, the patient's symptoms improved significantly. PMID- 19444782 TI - Cervical unicentric Castleman disease presenting as a neck mass: case report and review of the literature. AB - Castleman disease is an uncommon lymphoproliferative disorder that usually presents asymptomatically at a single site, most commonly the mediastinum; it is rare in the head and neck. Although Castleman disease may be mistaken for a malignant process such as lymphoma, it is a benign condition that is curable with complete surgical resection. We report the case of a 43-year-old man with the hyaline vascular type of unicentric Castleman disease who presented with an isolated neck mass. PMID- 19444783 TI - Restrictions on business relationships with industries, and their unintended adverse consequences. PMID- 19444784 TI - Three-dimensional computed tomography for detection and management of ingested foreign bodies. PMID- 19444785 TI - Neurofibromatosis type 1 causing conductive hearing loss. PMID- 19444786 TI - Oncocytoma of the parotid gland. PMID- 19444787 TI - Dizziness in a SCUBA diver. PMID- 19444788 TI - Iatrogenic nasal saddling - a consequence of aphakia. PMID- 19444789 TI - The role of angiography in managing patients with temporal bone fractures: a retrospective study of 64 cases. AB - We conducted a retrospective study of the utility of angiography in the evaluation of patients with temporal bone fractures. Our study population was made up of 64 patients-58 males and 6 females, aged 14 to 75 years (mean: 35.3) with a temporal bone fracture who had presented to a level I trauma center over a 1-year period. Records were reviewed and data were obtained on the mechanism of injury; the type of fracture; associated injuries, particularly neurocranial injuries detected on computed tomography (CT) of the head; and any angiographic findings that might have been obtained. The primary outcomes measures were the type of treatment administered (conservative vs. surgical) and mortality. Patients were assigned to 1 of 4 groups according to CT results and angiographic findings, if any: normal CT and no angiogram (group 1; n = 12), abnormal CT and no angiogram (group 2; n = 28), abnormal CT and an abnormal angiogram (group 3; n = 9), and abnormal CT and a normal angiogram (group 4; n = 15). Conservative treatment was administered to all 12 patients in group 1 and to 9 patients (60%) in group 4; surgical treatment was provided to two-thirds of the patients in both group 2 and group 3. Mortality was low in group 1 (n = 0), group 3 (n = 1; 11%), and group 4 (n = 1; 7%), but high in group 2 (n = 10; 36%). In fact, the key finding of this study was that mortality in the group with an abnormal CT and no angiogram (group 2) was significantly higher than mortality in the group with an abnormal CT and an abnormal angiogram (group 3) (p = 0.02), even though the injuries in the 2 groups were similarly severe and their management was similarly aggressive. We conclude that current guidelines for angiography may need to be expanded to include all patients who have CT evidence of neurocranial injury in order to detect those vascular injuries that need aggressive management and thus lower overall mortality. PMID- 19444790 TI - Patient history and CT findings in predicting surgical outcomes for patients with rhinogenic headache. AB - The concept of rhinogenic headaches remains a subject of much debate. While many authors have reported good results in treating these headaches with endoscopic sinus surgery, few have attempted to establish objective criteria for identifying the best surgical candidates. We conducted a study of 33 adults with rhinogenic headaches to determine if three elements of the history and/or five aspects of computed tomography (CT) would predict which patients might benefit from the minimally invasive sinus technique (MIST) as the primary treatment modality for their headaches. Postoperative follow-up interviews revealed that endoscopic surgery was widely successful, as 28 patients (84.8%) reported improvement. However, we were unable to find any statistically significant history or CT parameters that predicted surgical outcomes. PMID- 19444791 TI - Aggressive fibromatosis of the oropharynx: a multidisciplinary approach to a benign disease. AB - We present the case of a 23-year-old woman with aggressive fibromatosis of the oropharynx that was initially treated elsewhere as a peritonsillar abscess. We discuss the characteristics of this rare tumor and review the literature, stressing the importance of postoperative follow-up for peritonsillar abscesses to avoid missing other important diagnoses, such as the one described here. PMID- 19444792 TI - Overview of gene targeting by homologous recombination. AB - Formerly UNIT 9.15, this unit has been moved to the opening spot of our new chapter on Embryonic Stem Cell technology. The unit has also been updated, and now includes information about the Cre-lox and FlP/FRT recombinase systems. PMID- 19444793 TI - Graphic and haptic modelling of the oesophagus for VR-based medical simulation. AB - BACKGROUND: Medical simulators with vision and haptic feedback have been applied to many medical procedures in recent years, due to their safe and repetitive nature for training. Among the many technical components of the simulators, realistic and interactive organ modelling stands out as a key issue for judging the fidelity of the simulation. This paper describes the modelling of an oesophagus for a real-time laparoscopic surgical simulator. METHODS: For realistic simulation, organ deformation and tissue cutting in the oesophagus are implemented with geometric organ models segmented from the Visible Human Dataset. The tissue mechanical parameters were obtained from in vivo animal experiments and integrated with graphic and haptic devices into the laparoscopic surgical simulation system inside an abdominal mannequin. RESULTS: This platform can be used to demonstrate deformation and incision of the oesophagus by surgical instruments, where the user can haptically interact with the virtual soft tissues and simultaneously see the corresponding organ deformation on the visual display. CONCLUSIONS: Current laparoscopic surgical training has been transformed from the traditional apprenticeship model to simulation-based methods. The outcome of the model could replace conventional training systems and could be useful in effectively transferring surgical skills to novice surgeons. PMID- 19444794 TI - Liquid chromatography mass spectrometry for the determination of salvianolic acid B, a natural compound from the herb Danshen in rat plasma and application to pharmacokinetic study. AB - A sensitive and specific liquid chromatographic-electrospray ionization mass spectrometric method was developed for quantification of salvianolic acid B in rat plasma with resveratrol as the internal standard. The analytes were separated on a reversed-phase column with acetonitrile (40%) and water (60%) containing 0.75% formic acid as mobile phase at a flow rate of 1 mL/min. Liquid-liquid extraction was adopted for the sample preparation, and the analytes were determined using electrospray negative ionization mass spectrometry in the selective monitoring mode. The method was validated over the concentration range 0.1-40 microg/mL using 0.1 mL of plasma with coefficients of correlation >0.999. The intra- and inter-day precisions of analysis were <10%, and accuracy ranged from 94 to 101%. This method was successfully applied to a pharmacokinetics of salvianolic acid B in rats. PMID- 19444795 TI - Determination of ferruginol in rat plasma via high-performance liquid chromatography and its application in pharmacokinetics study. AB - Ferruginol, a diterpene phenol, has recently received attention for its extensive pharmacological properties, including anti-tumor, antibacterial, cardio protective and gastroprotective effects. In the present study, a high-performance liquid chromatographic (HPLC) method was developed for determination of ferruginol in rat plasma and applied for the pharmacokinetics study. The HPLC assay was performed with a VP ODS-C(18) column. The mobile phaseconsisted of methanol and 1% acetic acid solution (90:10, v/v). The flow rate was 1.0 mL/min, and the wavelength was set at 270 nm. This method was linear over the studied range of 0.1-10.0 microg/mL( )for ferruginol. The correlation coefficient was 0.9998. The intra-day and inter-day precisions were better than 4 and 5%, respectively. The extraction recovery and accuracy were greater than 97 and 96%, respectively. The detection limit was 30 ng/mL. The mean maximum concentration of ferruginol in rat plasma was 3.14 microg/mL at 40 min after oral administration at a dose of 20 mg/kg. Ferruginol was absorbed quickly p.o. with t(1/2)ka = 14.86 min and had a high rate of elimination with t(1/2) = 41.73 min. The pharmacokinetic process of ferruginol in rat was well described with a one compartment model. PMID- 19444796 TI - Simple and rapid micro-scale quantification of artemisinin in living Artemisia annua L. by improved gas chromatography with electron-capture detection. AB - Malaria threatens 300-500 million people and kills more than one million people annually. Artemisinin has been widely used as part of the artemisinin-based combination therapies against malaria. However, its supply is seriously short due to very small amounts of production of artemisinin in Artemisia annua. Molecular biologic researches aimed at increasing the artemisinin yield in plant have received more and more attention and therefore corresponding quantification methods for artemisinin analysis are urgently needed. A variety of methods for determination of artemisinin have been developed but they cannot be applied when only very little plant material is available or the material should be kept live, which often occurs in molecular biologic researches. The present work developed a simple, fast and low toxic micro-scale analysis procedure for determination of artemisinin in a single leaf or flower of living Artemisia annua using improved gas chromatography with electron-capture detection. The recovery of >95% was achieved by vortex of a piece of fresh leaf in 1 mL ethyl acetate for 2 min at room temperature. This method provides a powerful tool for biosynthesis study of artemisnin, high-throughput screening high-yield clone in an early stage, or real time quality control of Artemisia annua crop. PMID- 19444797 TI - On-line 2D-LC-ESI/MS/MS determination of rifaximin in rat serum. AB - A highly sensitive and selective on-line two-dimensional reversed-phase liquid chromatography/electrospray ionization-tandem mass spectrometry (2D-LC-ESI/MS/MS) method was developed and validated to determine rifaximin in rat serum by direct injection. The 2D-LC-ESI/MS/MS system consisted of a restricted access media column for trapping proteins as the first dimension and a Waters C(18 )column as second dimension using 0.1% aqueous acetic acid:acetonitrile as mobile phase in a gradient elution mode. Rifampacin was used as an internal standard. The linear dynamic range was 0.5-10 ng/mL (r(2) > 0.998). Acceptable precision and accuracy were obtained over the calibration range. The assay was successfully used in analysis of rat serum to support pharmacokinetic studies. PMID- 19444798 TI - A validated SIM GC/MS method for the simultaneous determination of dextromethorphan and its metabolites dextrorphan, 3-methoxymorphinan and 3 hydroxymorphinan in biological matrices and its application to in vitro CYP2D6 and CYP3A4 inhibition study. AB - Dextromethorphan is used as a probe drug for assessing CYP2D6 and CYP3A4 activity in vivo and in vitro. A SIM GC/MS method without derivatization for the simultaneous determination of dextromethorphan and its metabolites, dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan, in human plasma, urine and in vitro incubation matrix was developed and validated. Calibration curves indicated good linearity with a coefficient of variation (r) better than 0.995. The lower limit of quantitation was found to be 10 ng/mL for all analytes in all matrices. Intra day and inter-day precision for dextromethorphan and its metabolites was better than 9.02 and 9.91%, respectively and accuracy ranged between 91.76 and 106.27%. Recovery for dextromethorphan, its metabolites and internal standard levallorphan was greater than 72.68%. The method has been successfully applied for the in vitro inhibition of metabolism of dextromethorphan by CYP2D6 and CYP3A4 using known inhibitors of CYPs such as quinidine and verapamil. PMID- 19444799 TI - Optimization and validation of an ion-pair RP-HPLC-UV method for the determination of total free iodine in rabbit plasma: application to a pharmacokinetic study. AB - An ion-pair reverse-phase high performance liquid chromatographic method with UV vis detection has been developed for the determination of total free iodine in rabbit plasma after vaginal administration of povidone-iodine (PVP-I). Sample preparation was done by protein precipitation with acetonitrile in 96-well format and aspirin was used as the internal standard. The 100 microL sodium thiosulfate solution (5 g L(-1)) was added to 100 microL plasma sample before protein precipitation, to convert the total free iodine in plasma to iodide (I(-)). Separation was performed on a C(18) column (200 x 4.6 mm i.d., 5 microm). The mobile phase consisting of a mixture of water phase (containing 10 mmol L(-1) 18 crown-6 ether, 5 mmol L(-1) octylamine and 5 mmol L(-1) sodium dihydrogen phosphate, pH adjusted to 6.0 with phosphoric acid) and acetonitrile in the ratio 70:30 (v/v) was delivered isocraticly at a flow rate of 1.0 mL min(-1). The method was sensitive with a lower limit of quantification of 0.005 microg mL(-1), with good linearity (r(2) > 0.9990) over the linear range of 0.005-2 microg mL( 1). All the validation data, such as linearity, accuracy and precision, were within the required limits. The method was successfully applied to study the pharmacokinetic of PVP-I in rabbits after vaginal administration. PMID- 19444800 TI - Measurement of bisphenol A and bisphenol B levels in human blood sera from healthy and endometriotic women. AB - A sensitive HPLC method with fluorescence detection was developed for the determination of bisphenol A (BPA) and bisphenol B (BPB) in human blood serum. The detection limits of the method were 0.18 and 0.20 ng/mL for BPA and BPB, respectively. A single-step liquid-liquid extraction was used for the pre treatment of serum samples. The recoveries of BPA and BPB spiked to sera were 85.6 and 87.7%, respectively. The analyses of sera from both healthy and endometriotic women emphasized the absence of bisphenols in all the control cases (11 women), whereas BPA was found in 30 sera (51.7%) and BPB was found in 16 sera (27.6%) in the group of 58 patients with endometriosis; in nine of such sera BPA and BPB were present simultaneously. Only relatively to the sera quantitated, BPA concentrations ranged from 0.79 to 7.12 ng/mL (mean concentration 2.91 +/- 1.74 ng/mL), whereas BPB concentrations ranged from 0.88 to 11.94 ng/mL (mean concentration 5.15 +/- 4.16 ng/mL). Therefore, the presence of at least one of the two bisphenols was verified in a percentage as high as 63.8% in the sera from endometriotic women, suggesting the existence of a relationship between endometriosis and BPA and/or BPB exposure. Indeed, it is well known that bisphenols can work as xenoestrogens, owing to their structural similarity to natural and synthetic estrogens (e.g. estradiol and dietilstilbestrol). However, further studies are necessary to confirm this hypothesis and to assess the actual dose at which exposures to bisphenols are able to increase the sensitivity of the endometriotic cells to estradiol. PMID- 19444801 TI - Coupling of solid-phase microextraction with micellar desorption and high performance liquid chromatography for the determination of pharmaceutical residues in environmental liquid samples. AB - A residue analytical method combining solid-phase microextraction (SPME) with external micellar desorption (MD) and high-performance liquid chromatography with diode array detector (HPLC-DAD) has been developed and validated for the simultaneous determination of six pharmaceutical compounds, belonging to various therapeutic categories in water samples. Target compounds include antiinflamatory drugs (ibuprofen, ketoprofen and naproxen), an analgesic (phenazone), a lipid regulator (bezafibrate) and an antiepileptic (carbamazepine). A detailed study of the experimental conditions of extraction and desorption with different surfactants was performed in order to obtain the best results during instrumental analysis. Of the different fibers and surfactants investigated, 65 microm polydimethysiloxane-divinilbenzene (PDMS-DVB) fiber and polyoxyethylene 10 lauryl ether (POLE) and polyoxyethylene 6 lauryl ether (C(12)E(6)) as desorbing agents produced the optimal response to pharmaceutical residues. Recoveries obtained were generally higher than 80% and the variability of the method was below 16% for all compounds in both surfactants. Method detection limits were 0.05-12 ng mL(-1) for POLE and 0.1-5 ng mL(-1) for C(12)E(6). The developed method was compared using external desorption with organic solvent and it was successfully applied to the determination of these pharmaceutical compounds in water samples from different origin. Solid-phase microextraction with micellar desorption (SPME MD) represents a new approach for the extraction of different pharmaceutical compounds in natural waters because it combines shorter handling time, better efficiency, safety and more environmentally friendly process than the traditional methods. PMID- 19444802 TI - An improved HPLC method for the investigation of L-selenomethionine metabolism in rat gut contents. AB - Selenomethionine (SeMet) is a widely used nutritional supplement that has potential benefit for people living in selenium-deficient areas. Previous research has shown that selenium administered as SeMet undergoes significant enterohepatic recycling which may involve the gut microflora. In order to investigate this we have developed a simple method for the quantitation of l SeMet in rat gut content suspensions prepared from jejunum, ileum, caecum and colon. After incubation of l-SeMet with gut content suspensions, samples were deproteinized with sulfosalicylic acid and derivatized with o-phthaldialdehyde (OPA) and N-acetyl-l-cysteine (NAC). Mass spectrometry confirmed the formation of a 1:1:1 derivative of l-SeMet with OPA and NAC. Samples were analysed by reversed phase high-performance liquid chromatography with fluorescence detection. The assay was linear in the concentration range 0.5-100 microg/mL (r(2) = 0.9992) with a limit of detection of 0.025 microg/mL (signal-to-noise ratio of 5). Intra day and inter-day accuracies were 91.1-92.8 and 91.7-95.5%, respectively with corresponding precisions as relative standard deviation of <5%. Incubation of l SeMet with gut content suspensions from different parts of the rat intestine showed that l-SeMet metabolism occurs mainly in the caecum. PMID- 19444803 TI - A proteomic approach identifies early pregnancy biomarkers for preeclampsia: novel linkages between a predisposition to preeclampsia and cardiovascular disease. AB - Preeclampsia (PE) is a common, potentially life-threatening pregnancy syndrome triggered by placental factors released into the maternal circulation, resulting in maternal vascular dysfunction along with activated inflammation and coagulation. Currently there is no screening test for PE. We sought to identify differentially expressed plasma proteins in women who subsequently develop PE that may perform as predictive biomarkers. In seven DIGE experiments, we compared the plasma proteome at 20 wk gestation in women who later developed PE with an appropriate birth weight for gestational age baby (n=27) or a small for gestational age baby (n=12) to healthy controls with uncomplicated pregnancies (n=57). Of the 49 differentially expressed spots associated with PE-appropriate for gestational age, PE-small for gestational age or both (p<0.05, false discovery rate corrected), 39 were identified by LC-MS/MS. Two protein clusters that accurately (>90%) classified women at risk of developing PE were identified. Immunoblots confirmed the overexpression of fibrinogen gamma chain and alpha-1 antichymotrypsin in plasma prior to PE. The proteins identified are involved in lipid metabolism, coagulation, complement regulation, extracellular matrix remodeling, protease inhibitor activity and acute-phase responses, indicating novel synergism between pathways involved in the pathogenesis of PE. Our findings are remarkably similar to recently identified proteins complexed to high-density lipoprotein and linked to cardiovascular disease. PMID- 19444805 TI - Characterisation of QoI-resistant field isolates of Botrytis cinerea from citrus and strawberry. AB - BACKGROUND: In 2004, field isolates of Botrytis cinerea Pers. ex Fr., resistant to strobilurin fungicides (QoIs), were first found in commercial citrus orchards in Wakayama Prefecture, Japan. Subsequently, QoI-resistant isolates of this fungus were also detected in plastic strawberry greenhouses in Saga, Ibaraki and Chiba prefectures, Japan. Biological and molecular characterisation of resistant isolates was conducted in this study. RESULTS: QoI-resistant isolates of B. cinerea grew well on PDA plates containing kresoxim-methyl or azoxystrobin at 1 mg L(-1), supplemented with 1 mM of n-propyl gallate, an inhibitor of alternative oxidase, whereas the growth of sensitive isolates was strongly suppressed. Results from this in vitro test were in good agreement with those of fungus inoculation tests in vivo. In resistant isolates, the mutation at amino acid position 143 of the cytochrome b gene, known to be the cause of high QoI resistance in various fungal pathogens, was found, but only occasionally. The heteroplasmy of cytochrome b gene was confirmed, and the wild-type sequence often present in the majority of resistant isolates, indicating that the proportion of mutated cytochrome b gene was very low. CONCLUSION: The conventional RFLP and sequence analyses of PCR-amplified cytochrome b gene are insufficient for molecular identification of QoI resistance in B. cinerea. PMID- 19444806 TI - Decomposition of 3'-azido-2',3'-dideoxythymidine 5'-monophosphate (AZTMP) prodrugs in biological media studied by on-line solid-phase extraction coupled to liquid chromatography mass spectrometry. AB - Using a column-switching HPLC method previously described, we studied the behavior of some mononucleotide prodrugs (pronucleotides) of 3'-azido-2',3' dideoxythymidine in various biological media. From UV data, this method allowed quantification of transient metabolites resulting from prodrug bioconversion. The kinetic data related to the successive steps were calculated according to pseudo first-order kinetic models and optimized using mono- or poly-exponential regressions. Various metabolites were identified by co-injection with authentic samples and/or ESI-MS coupling. The results led us to propose, for each considered pronucleotide, a global decomposition pathway ending in the selective delivery of the corresponding mononucleotide. Associated to the determination of other parameters (lipophilicity, aqueous solubility), the present study contributes to the search of suitable pharmacological properties for further in vivo evaluations. PMID- 19444807 TI - Racial and ethnic disparities in low birth weight delivery associated with maternal occupational characteristics. AB - OBJECTIVES: Work characteristics and maternal education have both been associated with low birth weight (LBW) delivery. We sought to examine the relative contribution of these two factors to LBW delivery and determine whether ethnic/racial differentials in educational attainment and work characteristics might play a role in well-described disparities in LBW. METHODS: Scores for work substantive complexity (SC) derived from the O*NET were imputed to maternal occupation for Connecticut singleton births in 2000. Risks for LBW were estimated separately for black, Hispanic, and white mothers using logistic regression controlling for maternal covariates. RESULTS: Using white mothers as a referent, working is associated with reduced LBW risk in black mothers compared to those not in work (OR 2.06 vs. 3.07). LBW in working black women was strongly associated with less that a high school education (OR 4.80, 95% CI 1.68-13.7), and with low work SC in blacks in those with a college education or greater (OR 4.48, 95% CI 1.24-16.2). Examination of work SC scores, controlling for age and educational level, showed lower values for blacks; increased work SC was seen in Hispanics after adjustment for lower educational attainment. A decrease in risk for LBW was seen in black mothers, compared with whites, as work SC increased. By contrast, college-educated black mothers had a greater risk for LBW than those with high school or some college education. CONCLUSIONS: Maternal employment and work in a job with greater SC were associated with a reduced risk of LBW in black mothers. Improved LBW risk was also seen with employment in Hispanics. Low work SC in those with higher educational attainment was strongly associated with LBW in blacks, but not whites or Hispanics. Education/work mismatch may play a role in racial disparities in birth outcomes. PMID- 19444808 TI - Musculoskeletal injuries resulting from patient handling tasks among hospital workers. AB - BACKGROUND: The purpose of this study was to evaluate musculoskeletal injuries and disorders resulting from patient handling prior to the implementation of a "minimal manual lift" policy at a large tertiary care medical center. We sought to define the circumstances surrounding patient handling injuries and to identify potential preventive measures. METHODS: Human resources data were used to define the cohort and their time at work. Workers' compensation records (1997-2003) were utilized to identify work-related musculoskeletal claims, while the workers' description of injury was used to identify those that resulted from patient handling. Adjusted rate ratios were generated using Poisson regression. RESULTS: One-third (n = 876) of all musculoskeletal injuries resulted from patient handling activities. Most (83%) of the injury burden was incurred by inpatient nurses, nurses' aides and radiology technicians, while injury rates were highest for nurses' aides (8.8/100 full-time equivalent, FTEs) and smaller workgroups including emergency medical technicians (10.3/100 FTEs), patient transporters (4.3/100 FTEs), operating room technicians (3.1/100 FTEs), and morgue technicians (2.2/100 FTEs). Forty percent of injuries due to lifting/transferring patients may have been prevented through the use of mechanical lift equipment, while 32% of injuries resulting from repositioning/turning patients, pulling patients up in bed, or catching falling patients may not have been prevented by the use of lift equipment. CONCLUSIONS: The use of mechanical lift equipment could significantly reduce the risk of some patient handling injuries but additional interventions need to be considered that address other patient handling tasks. Smaller high risk workgroups should not be neglected in prevention efforts. PMID- 19444809 TI - Attitudes towards antimicrobial drugs among general population in Croatia, Fyrom, Greece, Hungary, Serbia and Slovenia. AB - PURPOSE: A pilot study to assess patients' attitudes towards antimicrobials (ABs) in six European countries (Croatia, Former Yugoslav Republic of Macedonia (FYROM), Greece, Hungary, Slovenia and Serbia), as a step preceding educational intervention on the importance of patients' compliance with instructions on taking ABs and consequences of their inappropriate use. METHODS: Patients' knowledge, emotions and behaviour regarding ABs were assessed using a structured questionnaire, constructed by a psychologist and intended for general population in six European countries. Questionnaires were filled out by individuals who visited pharmacies and general practitioners. RESULTS: A total of 838 questionnaires were filled in. Respondents from Slovenia showed the best knowledge about ABs, followed by Croatians. The highest willingness for self medication reported respondents from FYROM. The most positive emotions about ABs were expressed by respondents in Greece and Hungary, and the most negative in Slovenia. All components of attitudes towards antibiotics were influenced by country and level of education. CONCLUSIONS: Behaviour regarding ABs complied with emotions and knowledge in all countries. The results of this study may lay a basis for conducting national public campaigns, as a step forward in education of patients on rational AB use. PMID- 19444812 TI - Aberrant T-lymphocytes in refractory coeliac disease are not strictly confined to a small intestinal intraepithelial localization. AB - BACKGROUND: Refractory coeliac disease (RCD) is characterized by persisting mucosal pathology in spite of a strict gluten free diet (GFD). In RCD type II, phenotypically aberrant (CD7+CD3-CD4/8-cytoplasmicCD3+) T-lymphocytes are present within the intraepitelial lymphocyte (IEL) population in the small intestine, and 50-60% of these patients develops an enteropathy associated T-cell lymphoma (EATL). AIM: To investigate whether aberrant T-lymphocytes in RCD II can be detected in other parts of the small intestinal mucosa besides the intraepithelial compartment. Additionally, the presence of aberrant T-lymphocytes was analyzed in two RCD II patients that developed atypical skin lesions. METHODS: Multiparameter flow cytometric immunophenotyping was performed on both IEL and lamina propria lymphocyte (LPL) cell suspensions, isolated from small bowel biopsy specimens of RCD II patients (n = 14), and on cutaneous lymphocytes isolated from skin-lesion biopsy specimens of RCD II patients (n = 2). In addition, immunofluorescence analysis of frozen RCD II derived small intestinal biopsies was performed. RESULTS: Our results clearly show that aberrant T lymphocytes may be present in both the IEL and the LPL compartments of RCD II derived small intestinal biopsies. Although the highest percentages are always present in the IEL compartment, aberrant LPL can exceed 20% of total LPL in half the RCD II patients. Interestingly, cutaneous lymphocytes isolated from atypical skin lesions that developed in some RCD II patients showed a similar aberrant immunophenotype as found in the intestinal mucosa. CONCLUSIONS: In RCD II, the aberrant T-lymphocytes may also reside in the subepithelial layer of the small intestinal mucosa, in the lamina propria, and even in extraintestinal localizations including the skin. Whether this phenomenon represents a passive overflow from the intestinal epithelium or active trafficking towards other anatomical localizations remains to be elucidated. RCD II appears to be a disseminated disease, which may impose the risk of EATL development outside the intestine. PMID- 19444813 TI - Specific IKKbeta inhibitor IV blocks Streptonigrin-induced NF-kappaB activity and potentiates its cytotoxic effect on cancer cells. AB - Many anticancer agents activate NF-kappaB, which plays an important role in the survival of cancer cells. Inhibition of NF-kappaB activity may therefore potentiate the efficacy of anticancer agents. We found that a previously used anticancer agent Streptonigrin (SN) was also a potent NF-kappaB inducer. Using a specific IKKbeta inhibitor IV (Podolin et al., J Pharmacol Exp Ther 2005; 312: 373-381), we revealed that the activation of NF-kappaB was mediated through DNA damage-induced activation of IKK complex. Furthermore, we demonstrated that SN induced DNA damage was unrelated to reactive oxygen species but to the hydroquinone form of SN converted by the NAD(P)H:quinine oxidoreductase (NQO1). The study suggests that the combination of SN with IKK inhibitor may improve efficacy over the use of single agent. PMID- 19444814 TI - Symptom occurrence and associated clinical factors in nursing home residents with cancer. AB - Little is known about the factors that contribute to symptoms in nursing home residents with cancer. We compared rates of symptoms in residents with (n = 1,022) and without cancer (n = 9,910) and examined physiologic, psychologic and situational factors potentially related to symptoms in residents with cancer. Pain, shortness of breath, vomiting, weight loss, and diarrhea were significantly (p < .05) more prevalent in residents with cancer. Cancer treatments, comorbid illnesses, and situational factors were not consistently correlated with symptoms. Improved symptom control was especially needed for the 30% of residents with cancer who clinically deteriorated within 3 months of admission; physical dependence and deteriorating clinical status were associated with pain, shortness of breath, and weight loss. PMID- 19444815 TI - Patient expectations for surgical outcome in extremity soft tissue sarcoma. AB - BACKGROUND AND OBJECTIVES: Patients' expectations regarding their surgical recovery can significantly influence health outcomes. This study examines the relationship between pre-treatment outcome expectations and post-operative function and health-related quality of life (HRQoL) in patients with extremity soft tissue sarcoma (ESTS). Additionally, we evaluate predictors of patients' outcome expectations. METHODS: Data were prospectively collected on 157 ESTS patients (62% male, mean age 56 years) treated with limb-preservation surgery between January 2001 and February 2005. Associations between patients' outcome expectations and 1-year function and HRQoL outcomes were evaluated using multivariable regression analyses. Factors predicting patient expectations were investigated using multinomial logistic regression. RESULTS: Patients expecting a difficult recovery and patients with uncertain expectations had worse functional outcomes than patients anticipating an easy recovery. Education, dispositional optimism, tumor location, AJCC stage, and baseline function/HRQoL were significant predictors of patient expectations. For example, patients with primary school education more frequently reported uncertain expectations regarding length of recovery (OR = 20; 95% CI, 3.7-108.6) and complications (OR = 12; 95% CI, 2.7-58.0) than patients with post-secondary education. CONCLUSIONS: Patient expectations significantly influence functional outcome in ESTS. Patients at risk for uncertain expectations may benefit from additional, individualized education so as to optimize their treatment outcomes. PMID- 19444817 TI - Society of surgical oncology fellowship training: where we have been, where we are now, and where we are going. PMID- 19444818 TI - Use of serum progesterone measurements to reduce need for follow-up in women with pregnancies of unknown location. AB - OBJECTIVE: To assess the efficacy of a progesterone-based algorithm for the management of women with pregnancies of unknown location (PULs) and explore the feasibility of developing a single-visit strategy in those with a low risk of requiring medical intervention. METHODS: All clinically stable women in whom pregnancy could not be identified on ultrasound scan were managed by a pre defined protocol based on measurement of serum progesterone and beta-human chorionic gonadotropin (beta-hCG). Intervention in the form of surgery or medical treatment with methotrexate was offered to all women with persistent or worsening symptoms and non-declining serum beta-hCG. Decision-tree analysis was used to develop a protocol for the management of women with resolving pregnancies who are at low risk of requiring medical intervention. RESULTS: 1110 women were included in the data analysis: normal intrauterine pregnancy was diagnosed in 248 (22.3%; 95% CI, 19.9-24.8) women. 761 (68.6%; 95% CI, 65.8-71.3) abnormal pregnancies resolved spontaneously on expectant management, while the remaining 101 (9.1%; 95% CI, 7.4-10.8) women with abnormal pregnancies required some form of medical intervention. Intervention rates in patients presenting with initial serum progesterone levels of 0.05). It seems that the significant antigenotoxicity effects of auraptene may be due to the prenyl moiety and also the suppression of superoxide anion (O(2) (-)) generation. This study suggests that the antigenotoxic property of auraptene is of great pharmacological importance and might be beneficial for cancer prevention. PMID- 19444821 TI - Effect of CYSTUS052 and green tea on subjective symptoms in patients with infection of the upper respiratory tract. AB - Examples of medicinal herbs that have been perpetuated along several generations based simply on a folk tradition are Cistus and green tea. The principal active constituents of the genus Cistus and green tea are polyphenolic compounds. Polyphenols exhibit a wide range of antibacterial, antifungal and antiinflammatory effects. The present work aimed to investigate the clinical effect of a Cistus extract (CYSTUS052) in comparison with green tea on 300 patients with infections of the upper respiratory tract. Due to the lack of clinical study data on their efficacy in patients, this is a report of the findings of our study on the clinical efficacy of CYSTUS052 in patients with the upper respiratory tract infections (URTIs). This study observed a total of 300 patients (277 completers) treated with CYSTUS052 given in lozenges compared with treatment with an extract of green tea. The patients scored the subjective severity of target symptoms using a predefined scale. The score of subjective symptoms decreased over the course of treatment with CYSTUS052, whereas treatment with green tea resulted in a less significant decrease of symptoms. CYSTUS052 therefore proved to be an effective adjuvant for the treatment of respiratory infections. PMID- 19444822 TI - Can prenatal ultrasound detect the effects of in-utero alcohol exposure? A pilot study. AB - OBJECTIVES: The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol-mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions. METHODS: We performed a longitudinal prospective pilot study from 2004 to 2006 at two sites in Ukraine. A sample of pregnant women who reported consuming moderate-to-heavy amounts of alcohol participated in a comprehensive maternal interview, and received ultrasound evaluation of fetal growth and specific fetal brain measurements during the second and third trimesters. These measurements were compared with those collected from a group of pregnant women who consumed little-to-no alcohol during pregnancy, and who were recruited and followed in the same manner. RESULTS: From 6745 screened women, 84 moderate-to-heavy alcohol users and 82 comparison women were identified and ultrasound examinations performed. After controlling for maternal smoking, alcohol-exposed fetuses had shorter mean femur length, caval calvarial distance and frontothalamic measurements in the second trimester (P < 0.05), and alcohol-exposed fetuses also had shorter frontothalamic distance measurements in the third trimester relative to comparison fetuses (P < 0.05). In addition, after controlling for maternal smoking, both mean orbital diameter and biparietal diameter measurements were significantly smaller on average in the alcohol-exposed group in the third trimester relative to comparison fetuses (P < 0.05). CONCLUSIONS: Significant differences in selected somatic and brain measurements were noted between alcohol-exposed and comparison fetuses, suggesting these markers may be further explored for clinical utility in prenatal identification of affected children. Further study correlating these findings with alcohol-related physical features of the newborn and subsequent comparisons of neuro-developmental outcomes will help define potential uses of prenatal ultrasound for intervention and prevention of FASD. PMID- 19444823 TI - Asymmetric allylation of methyl ketones by using chiral phenyl carbinols. AB - Novel chiral auxiliaries for the stereoselective allylation of aliphatic methyl ketones with allyltrimethylsilane and their use in the synthesis of homoallylic ethers are described. In a multicomponent domino process catalyzed by trifluoromethanesulfonic acid, the allyl moiety and the auxiliary are transferred onto the substrate to yield tertiary homoallylic ethers. The most useful auxiliary for a general application turned out to be the trimethylsilyl ether of phenyl benzyl carbinol with an induced diastereoselectivity of 90:10 using ethyl methyl ketone and 94:6 using isopropyl methyl ketone as substrates. The transferred substituted benzyl moiety has good protecting properties in subsequent transformations and can easily be removed under reductive conditions to provide the corresponding homoallylic alcohol. The origin of the high selectivity could be elucidated by identifying the relevant transition states using quantum-chemical calculations. An excellent agreement between calculated and experimentally observed selectivities was obtained assuming an oxocarbenium ion as intermediate. PMID- 19444816 TI - CHARMM: the biomolecular simulation program. AB - CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983. PMID- 19444824 TI - Calculational study of fluoroammonium and related cations and dications. AB - Structures as well as (15)N and (19)F NMR chemical shifts of a series of fluoroammonium ions were studied by ab initio/GIAO-SCF, GIAO-MP2 and GIAO-CCSD(T) methods. Calculated (15)N and (19)F NMR chemical shifts correlate well with the experimental data. The relative stabilities as well as the charge of the central nitrogen atom of fluoro-substituted tetrahedral ammonium ions were found to increase linearly with the increasing number of fluorine substituents due to their strong electron-withdrawing inductive effect. Similarly the magnitude of (15)N NMR chemical shifts also increase linearly with the increasing number of fluorine substituents in accord with the strong deshielding effect of fluorine. Structures as well as (15)N and (19)F NMR chemical shifts of yet experimentally unknown fluoroammonium dications were also computed. PMID- 19444825 TI - Use of an osmium complex as a universal luminescent probe for enzymatic reactions. AB - The water-soluble bis(bipyridine)chloro(4-picolinic acid) osmium complex, [Os(III)(bpy)2Cl(PyCOOH)]2+ (bpy=2,2'-bipyridine, Py=pyridine), is fluorescent in aqueous solution, whereas the reduced form of the complex, [Os(II)(bpy)2Cl(PyCOOH)]+, shows no significant fluorescence under the same conditions. Such reversible redox control of the fluorescence of the complex can be easily adapted to follow any enzymatic reaction to yield oxidising or reducing products that are capable of interacting with [Os(III)(bpy)2Cl(PyCOOH)]2+ or [Os(II)(bpy)2Cl(PyCOOH)]+. Based on the redox reaction between products of biocatalytic reactions and the osmium complex, we have designed a simple bioanalytical assay for the detection of nerve gases, alpha-ketoglutarate, hydrogen peroxide and glucose. PMID- 19444826 TI - Controlled synthesis of large-area and patterned electrochemically reduced graphene oxide films. PMID- 19444827 TI - High-yield synthesis of uniform star polymers--is controlled radical polymerization always needed? PMID- 19444828 TI - Interplay of interactions governing the dynamic conversions of acyclic and macrocyclic helicates. AB - A rigid, helical macrocycle that contains two copper(I) ions has been synthesized through subcomponent self-assembly. Although it does not obey the "rule of coordinative saturation", this macrocycle could be prepared through subcomponent substitution starting from a tri(copper(I)) helicate, in a reaction in which copper(I) was ejected. The macrocycle was observed to readily participate in a sequence of transformations between helical structures mediated by the electronic effects of substituents, entropic effects, the conformational preferences of organic building blocks, and the coordinative preferences of the metal ion. The thermodynamic parameters governing the interconversion of an "open" helicate and the "closed" macrocycle were determined through van 't Hoff analysis, allowing quantification of the entropic driving force for macrocyclization. PMID- 19444829 TI - Microsphere-mediated protein delivery into cells. PMID- 19444830 TI - Structures of HIV TAR RNA-ligand complexes reveal higher binding stoichiometries. AB - Target TAR by NMR: Tripeptides containing arginines as terminal residues and non natural amino acids as central residues are good leads for drug design to target the HIV trans-activation response element (TAR). The structural characterization of the RNA-ligand complex by NMR spectroscopy reveals two specific binding sites that are located at bulge residue U23 and around the pyrimidine-stretch U40-C41 U42 directly adjacent to the bulge. PMID- 19444831 TI - Triple-stem DNA probe: a new conformationally constrained probe for SNP typing. PMID- 19444832 TI - Urea route to homoleptic cyanates--characterization and luminescence properties of [M(OCN)2(urea)] and M(OCN)2 with M=Sr, Eu. AB - A novel approach for the synthesis of urea complexes and homoleptic cyanates of alkaline earth metals and europium is described. Direct reaction of urea with elemental Sr or Eu in closed ampoules at temperatures above 120 degrees C yields [M(OCN)2(urea)] with M=Sr, Eu. According to single-crystal X-ray diffraction, the isotypic complexes exhibit a layer structure ([Eu(OCN)2(urea)]: P2(1)/c, a=7.826(2), b=7.130(1), c=12.916(3) A, beta=99.76(3) degrees , Z=4, V=710.3(2) A3). Furthermore, they were characterized by vibrational spectroscopy, thermal analysis, magnetic measurements, and photoluminescence studies. Thermal treatment of the compounds [M(OCN)2(urea)] to 160-240 degrees C affords evaporation of urea and the subsequent formation of solvent-free homoleptic cyanates of Sr and Eu. The crystal structures of Sr(OCN)2 and Eu(OCN)2 were determined from X-ray powder diffraction data and refined by the Rietveld method. Both compounds crystallize in the orthorhombic space group Fddd and adopt the Sr(N3)2 type structure (Sr(OCN)2: a=6.1510(4), b=11.268(1), c=11.848(1) A, V=821.1(2) A3; Eu(OCN)2: a=6.1514(6), b=11.2863(12), c=11.8201(12) A, V=820.63(15) A3). The cyanates are stable up to 450 degrees C. Above 500 degrees C beta-Sr(CN)2 and Eu2O2(CN)2 are formed. Excitation and emission spectra of [Eu(OCN)2(urea)], [Sr(OCN)2(urea)]:Eu2+, Eu(OCN)2, Sr(OCN)2:Eu2+ at different temperatures are reported. A strong green emission for all examined Eu-containing compounds due to a 4f(6)5d(1)-4f(7) transition is observed at low temperatures. The luminescence properties are discussed in detail and are comparable to those of thiocyanates. Compared to the latter, a blue shift of the emission bands is observed due to the higher ionicity. PMID- 19444833 TI - A new deterministic code for society to worry about: if we are to believe the media hype surrounding epigenetics, the sins of the great, great grandparents may be visited on the great, great grandchildren. PMID- 19444834 TI - B-cell acute lymphoblastic leukaemia: towards understanding its cellular origin. AB - B-cell acute lymphoblastic leukaemia (B-ALL) is a clonal malignant disease originated in a single cell and characterized by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B-cell differentiation. B ALL origin has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin, although most B-ALLs probably start off with chromosomal changes in haematopoietic stem cells. However, the cells responsible for maintaining the disease appear to differ between the different types of B ALLs and this remains an intriguing and exciting topic of research, since these cells have been posited to be responsible for resistance to conventional therapies, recurrence and dissemination. During the last years this problem has been addressed primarily by transplantation of purified subpopulations of human B ALL cells into immunodeficient mice. The results from these different reconstitution experiments and their interpretations are compared in this review in the context of normal B-cell developmental plasticity. While the results from different research groups might appear mutually exclusive, we discuss how they could be reconciled with the biology of normal B-cells and propose research avenues for addressing these issues in the future. PMID- 19444835 TI - Laser-modulated ordering of gold nanoparticles at the air/water interface. AB - Beam me up, Scotty! Laser irradiation of Langmuir monolayers of gold nanoparticles (NPs) and elaidic acid led to dramatic reorganization that was dependent on the laser power (see picture, scale bar = 100 microm). Variable temperature experiments indicate that localized surface heating in an extremely small temperature range, induced by the laser beam, causes ordering of the NPs. PMID- 19444836 TI - Ageing as a price of cooperation and complexity: self-organization of complex systems causes the gradual deterioration of constituent networks. AB - The network concept is increasingly used for the description of complex systems. Here, we summarize key aspects of the evolvability and robustness of the hierarchical network set of macromolecules, cells, organisms and ecosystems. Listing the costs and benefits of cooperation as a necessary behaviour to build this network hierarchy, we outline the major hypothesis of the paper: the emergence of hierarchical complexity needs cooperation leading to the ageing (i.e. gradual deterioration) of the constituent networks. A stable environment develops cooperation leading to over-optimization, and forming an 'always-old' network, which accumulates damage, and dies in an apoptosis-like process. A rapidly changing environment develops competition forming a 'forever-young' network, which may suffer an occasional over-perturbation exhausting system resources, and causing death in a necrosis-like process. Giving a number of examples we demonstrate how cooperation evokes the gradual accumulation of damage typical to ageing. Finally, we show how various forms of cooperation and consequent ageing emerge as key elements in all major steps of evolution from the formation of protocells to the establishment of the globalized, modern human society. PMID- 19444838 TI - Conjugated polyelectrolytes: synthesis, photophysics, and applications. AB - Organic optoelectronic polymers have evolved to the point where fine structural control of the conjugated main chain, coupled with solubilizing and property modifying pendant substituents, provides an entirely new class of materials. Conjugated polyelectrolytes (CPEs) provide a unique set of properties, including water solubility and processability, main-chain-controlled exciton and charge transport, variable band gap light absorption and fluorescence, ionic interactions, and aggregation phenomena. These characteristics allow these materials to be considered for use in applications ranging from light-emitting diodes and electrochromic color-changing displays, to photovoltaic devices and photodetectors, along with chemical and biological sensors. This Review describes the evolution of CPE structures from simple polymers to complex materials, describes numerous photophysical aspects, including amplified quenching in macromolecules and aggregates, and illustrates how the physical and electronic properties lead to useful applications in devices. PMID- 19444842 TI - Simplifying the creation of hollow metallic nanostructures: one-pot synthesis of hollow palladium/platinum single-crystalline nanocubes. AB - Efficiency simplified: A synthetic strategy has been developed to prepare single crystalline hollow Pd/Pt nanocubes (right, see picture; left: nanocubes). Compared to the solid Pd/Pt nanocubes of similar sizes, the hollow Pd/Pt nanocubes increase accessible surface area and therefore improve electrocatalytic activity in formic acid oxidation. PMID- 19444841 TI - Efficient replication bypass of size-expanded DNA base pairs in bacterial cells. AB - Supersize me! Size-expanded DNA bases (xDNA) are able to encode natural DNA sequences in replication. In vitro experiments with a DNA polymerase show nucleotide incorporation opposite the xDNA bases with correct pairing. In vivo experiments using E. coli show that two xDNA bases (xA and xC, see picture) encode the correct replication partners. PMID- 19444843 TI - Low-temperature atomic layer deposition of copper metal thin films: self-limiting surface reaction of copper dimethylamino-2-propoxide with diethylzinc. AB - A uniform, conformal, pure copper metal thin film was grown at very low substrate temperatures (100-120 degrees C) on Si(100) substrates by atomic layer deposition involving the ligand exchange of [Cu(OCHMeCH(2)NMe(2))(2)] with Et(2)Zn (see scheme). Patterned copper thin films of Cu nanotubes (diameter 150 nm, length 12 microm) were fabricated. PMID- 19444844 TI - Nickel-catalyzed formation of a carbon-nitrogen bond at the beta position of saturated ketones. AB - Gone fishing: When propiophenone and related ethyl ketones are treated with morpholine in the presence of K(3)PO(4), chlorobenzene, and [Ni(cod)(2)]/PMe(3) catalyst, a carbon-nitrogen bond is formed selectively at the beta position (see scheme; cod = cycloocta-1,5-diene). Secondary amines were employed as substrates to give the corresponding beta-enaminones. PMID- 19444845 TI - Subliming the unsublimable: how to deposit nanographenes. AB - Quite sublime: Thin-layer fabrication of unsublimable large polycyclic aromatic hydrocarbons (PAHs) by pulsed laser deposition was used to prepare samples for scanning tunneling microscopy. Giant PAHs with up to 222 carbon atoms can be visualized-a size that was previously not possible because of the lack of suitable deposition methods. PMID- 19444846 TI - Taking fingerprints of DNA polymerases: multiplex enzyme profiling on DNA arrays. AB - A novel screening approach based on an oligonucleotide-addressing enzyme assay enables multiplexed simultaneous profiling of DNA polymerases in nanoliter volumes in terms of their different properties. This approach was used to identify enzymes with altered properties out of a library of protein mutants. PMID- 19444847 TI - Self-mediated stereoselective oxidation of thia-capped cyclodextrins. AB - Self-control: endo-Sulfoxide products can be synthesized selectively by the oxidation of thia-capped cyclodextrins using m-chloroperoxybenzoic acid (m-CPBA) in water. The reaction occurs by the formation of an oxidant-cyclodextrin inclusion complex. Operating in organic media preferentially leads to exo sulfoxide products. PMID- 19444848 TI - Low-energy-electron-induced hydroamination of an alkene. AB - The smallest catalyst: A new strategy to control chemical synthesis by exposure to low-energy electrons relies on the electrostatic attraction caused by the soft ionization of one of the reaction partners. This approach was used to induce a reaction between C(2)H(4) and NH(3) yielding aminoethane. The reaction resembles a hydroamination except that the electron beam replaces the catalyst used in the organic synthesis. PMID- 19444849 TI - Regio- and stereoselective generation of alkenylindium compounds from indium tribromide, alkynes, and ketene silyl acetals. AB - InBr(3) promotes the addition of ketene silyl acetals to monosubstituted alkynes to afford 2,2-disubstituted alkenylindium compounds in high regio- and stereoselectivity (see scheme). In addition, the alkenylindium derivatives have been subsequently coupled with iodobenzene in the presence of a palladium catalyst. PMID- 19444850 TI - Indoles from simple anilines and alkynes: palladium-catalyzed C-H activation using dioxygen as the oxidant. AB - Pd doles it out: A palladium-catalyzed approach to indoles using the title reaction was achieved (see scheme). The oxidant used in this catalytic cycle was O(2). Both N-nonsubstituted and N-alkyl monosubstituted anilines can be successfully transformed into the corresponding indoles by this method. PMID- 19444851 TI - Signaling networks and transcription factors regulating mechanotransduction in bone. AB - Mechanical stimulation has a critical role in the development and maintenance of the skeleton. This function requires the perception of extracellular stimuli as well as their conversion into intracellular biochemical responses. This process is called mechanotransduction and is mediated by a plethora of molecular events that regulate bone metabolism. Indeed, mechanoreceptors, such as integrins, G protein-coupled receptors, receptor protein tyrosine kinases, and stretch activated Ca(2+) channels, together with their downstream effectors coordinate the transmission of load-induced signals to the nucleus and the expression of bone-related genes. During the past decade, scientists have gained increasing insight into the molecular networks implicated in bone mechanotransduction. In the present paper, we consider the major signaling cascades and transcription factors that control bone and cartilage mechanobiology and discuss the influence of the mechanical microenvironment on the determination of skeletal morphology. PMID- 19444852 TI - Chemical redox modulation of the surface chemistry of CdTe quantum dots for probing ascorbic acid in biological fluids. AB - Most of the fluorescence resonance energy transfer (FRET)-based sensors employing quantum dots (QDs) usually use organic fluorophores and gold nanoparticles as the quenchers. However, complex processes for the modification/immobilization of the QDs are always necessary, as the generation of FRET requires strict distance between the donor and acceptor. Herein, a simple chemical redox strategy for modulating the surface chemistry of the QDs to develop a QD-based turn-on fluorescent probe is reported. The principle of the strategy is demonstrated by employing CdTe QDs with KMnO(4) as the quencher and ascorbic acid as the target analyte. The fluorescence of CdTe QDs is quenched with a blue-shift upon addition of KMnO(4) due to the oxidation of the Te atoms on the surface of the QDs. The quenched fluorescence of the QDs is then recovered upon addition of ascorbic acid due to the reduction of CdTeO(3)/TeO(2) on the surface of the QDs to CdTe. The recovered fluorescence of the QDs increases linearly with the concentration of ascorbic acid from 0.3 to 10 microM. Thus, a novel QD-based turn-on fluorescent probe with a detection limit as low as 74 nM is developed for the sensitive and selective detection of ascorbic acid in biological fluids. The present approach avoids the complex modification/immobilization of the QDs involved in FRET-based sensors, and opens a simple pathway to developing cost-effective, sensitive, and selective QD-based fluorescence turn-on sensors/probes for biologically significant antioxidants. PMID- 19444853 TI - Evaluation of cytotoxic concentration-time response in A549 cells exposed to respirable alpha-quartz. AB - A causal pathway between quartz, silicosis and lung cancer has been postulated. The aim of our study was to assess cytotoxic effects induced in a human lung epithelial cell line (A549) by exposure to alpha-quartz. Cells were exposed to respirable alpha-quartz (SRM1878a, NIST) at 25, 50 or 100 microg ml(-1 )for 24 h and at 50 or 100 microg ml(-1) for 48 h. Cytotoxic effects were analyzed by scanning electron microscopy (SEM), apoptotic morphology analysis with Hoechst staining and lactate dehydrogenase (LDH) release assay. In cells exposed to alpha quartz for 24 h, a concentration-dependent bleb development and in particular the localization of blebs at the cell edge at higher concentrations were observed. The blebbing phenomenon was more evident after 48 h of exposure to 50 or to 100 microg ml(-1) of alpha-quartz and large blebs were localized at the cell edge. At the same concentrations surface smoothing was also observed. Moreover the presence of holes and tears was detected at the highest concentration both at 24 and 48 h. Results of morphological analysis with Hoechst stain evidenced an increase concentration-time dependent of apoptotic cell percentage that was more marked after 48 h exposure to 100 microg ml(-1) and a prevalence of late apoptosis stage with the increase of exposure time and concentration. Cells exposed to 50 or 100 microg ml(-1) of alpha-quartz for 24 and 48 h produced a significant increase in LDH release. The concentration-time-dependent bleb induction evidenced by SEM correlates with the increase of apoptotic cells and LDH activity release, demonstrating the onset of cytotoxic effects in human lung cells exposed to alpha-quartz. PMID- 19444854 TI - Silver ion-induced suicidal erythrocyte death. AB - Owing to its antibiotic activity, silver is used for water purification, wound care and a wide variety of implants. Silver metal and silver compounds ionize in solution, and silver ions interfere with the function of a wide variety of proteins. In mammalian cells, silver ions may trigger apoptosis by stimulation of cytochrome c release from mitochondria. The present study explored the effect of AgNO3 on eryptosis, the suicidal death of erythrocytes, cells devoid of mitochondria. Similar to apoptosis of nucleated cells, eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Eryptosis is triggered by energy depletion, cellular depletion of nitric oxide (NO) and activation of protein kinase C (PKC). Phosphatidylserine exposure was determined by annexin V-binding, cell volume by forward scatter, cellular ATP by a luciferin-luciferase assay kit, and hemolysis by photometry. A 48 h exposure to AgNO3 (> or =100 nm) but not to NaNO3 significantly enhanced the percentage of annexin V-binding cells, slightly but significantly decreased forward scatter and significantly decreased cytosolic ATP. Furthermore, inhibition of PKC by staurosporine and donation of NO by sodium nitroprusside significantly blunted silver-induced eryptosis. In conclusion, AgNO3 triggers cell membrane scrambling, an effect attributed to ATP depletion, PKC activation and decrease of cellular NO. PMID- 19444855 TI - Proton NMR studies of dihalogenated phenyl benzamides: two-dimensional higher quantum methodologies. AB - The scalar coupled proton NMR spectra of many organic molecules possessing more than one phenyl ring are generally complex due to degeneracy of transitions arising from the closely resonating protons, in addition to several short- and long-range couplings experienced by each proton. Analogous situations are generally encountered in derivatives of halogenated benzanilides. Extraction of information from such spectra is challenging and demands the differentiation of spectrum pertaining to each phenyl ring and the simplification of their spectral complexity. The present study employs the blend of independent spin system filtering and the spin-state selective detection of single quantum (SQ) transitions by the two-dimensional multiple quantum (MQ) methodology in achieving this goal. The precise values of the scalar couplings of very small magnitudes have been derived by double quantum resolved experiments. The experiments also provide the relative signs of heteronuclear couplings. Studies on four isomers of dihalogenated benzanilides are reported in this work. PMID- 19444857 TI - Comparative study of matrices for their use in the rapid screening of anabolic steroids by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry. AB - New data on sample preparation and matrix selection for the fast screening of androgenic anabolic steroids (AAS) by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) is presented. The rapid screening of 15 steroids included in the World Anti-Doping Agency (WADA) prohibited list using MALDI was evaluated. Nine organic and two inorganic matrices were assessed in order to determine the best matrix for steroid identification in terms of ionisation yield and interference by characteristic matrix ions. The best results were achieved for the organic matrices 2-(4-hydroxyphenylazo)benzoic acid (HABA) and trans-3-indoleacrylic acid (IAA). Good signals for all the steroids studied were obtained for concentrations as low as 0.010 and 0.050 microg/mL on the MALDI sample plate for the HABA and IAA matrices, respectively. For these two matrices, the sensitivity achieved by MALDI is comparable with the sensitivity achieved by gas chromatography/mass spectrometry (GC/MS), which is the conventional technique used for AAS detection. Furthermore, the accuracy and precision obtained with MALDI are very good, since an internal mass calibration is performed with the matrix ions. For the inorganic matrices, laser fluences higher than those used with organic matrices are required to obtain good MALDI signals. When inorganic matrices were used in combination with glycerol as a dispersing agent, an important reduction of the background noise was observed. Urine samples spiked with the study compounds were processed by solid-phase extraction (SPE) and the screening was consistently positive. PMID- 19444856 TI - Expression level and DNA methylation status of glutathione-S-transferase genes in normal murine prostate and TRAMP tumors. AB - BACKGROUND: Glutathione-S-transferase (Gst) genes are downregulated in human prostate cancer, and GSTP1 silencing is mediated by promoter DNA hypermethylation in this malignancy. We examined Gst gene expression and Gst promoter DNA methylation in normal murine prostates and Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors. METHODS: Primary and metastatic tumors were obtained from TRAMP mice, and normal prostates were obtained from strain-matched WT mice (n = 15/group). Quantitative real-time RT-PCR was used to measure GstA4, GstK1, GstM1, GstO1, and GstP1 mRNA expression, and Western blotting and immunohistochemical staining was used to measure GstM1 and GstP1 protein expression. MassARRAY Quantitative Methylation Analysis was used to measure DNA methylation of the 5' CpG islands of GstA4, GstK1, GstM1, GstO1, and GstP1. TRAMP C2 cells were treated with the epigenetic remodeling drugs decitabine and trichostatin A (TSA) alone and in combination, and Gst gene expression was measured. RESULTS: Of the genes analyzed, GstM1 and GstP1 were expressed at highest levels in normal prostate. All five Gst genes showed greatly reduced expression in primary tumors compared to normal prostate, but not in tumor metastases. Gst promoter methylation was unchanged in TRAMP tumors compared to normal prostate. Combined decitabine + TSA treatment significantly enhanced the expression of 4/5 Gst genes in TRAMP-C2 cells. CONCLUSIONS: Gst genes are extensively downregulated in primary but not metastatic TRAMP tumors. Promoter DNA hypermethylation does not appear to drive Gst gene repression in TRAMP primary tumors; however, pharmacological studies using TRAMP cells suggest the involvement of epigenetic mechanisms in Gst gene repression. PMID- 19444858 TI - Synthesis of rhodium(III) complexes with tris/tetrakis-benzimidazoles and benzothiazoles--quick identification of cyclometallation by nuclear magnetic resonance spectroscopy. AB - Reactions of rhodium(III) halides with multidentate N,S-heterocycles, (LH3) 1,3,5 tris(benzimidazolyl)benzene (L1H3; 1), 1,3,5-tris(N-methylbenzimidazolyl) benzene (L2H3; 2) and 1,3,5-tris(benzothiazolyl)benzene (L3H3; 3), in the molar ratio 1:1 in methanol-chloroform produced mononuclear cyclometallated products of the composition [RhX2(LH2)(H2O)] (X = Cl, Br, I; LH2 = L1H2, L2H2, L3H2). When the metal to ligand (1-3 or 1,2,4,5-tetrakis(benzothiazolyl)benzene [L4H2; 4]) molar ratio was 2:1, the reactions yielded binuclear complexes of the compositions [Rh2Cl5(LH2)(H2O)3] (LH2 = L1H2, L2H2, L3H2) and [Rh2X4(L4)(H2O)2] (X = Cl, Br, I). Elemental analysis, IR and 1H nuclear magnetic resonance (NMR) chemical shifts supported the binuclear nature of the complexes. Cyclometallation was detected by conventional 13C NMR spectra that showed a doublet around approximately 190 ppm. Cyclometallation was also detected by gradient-enhanced heteronuclear multiple bond correlation (g-HMBC) experiment that showed cross peaks between the cyclometallated carbon and the central benzene ring protons of 1-3. Cyclometallation was substantiated by two-dimensional 1H-1H correlated experiments (gradient-correlation spectroscopy and rotating frame Overhauser effect spectroscopy) and 1H-13C single bond correlated two-dimensional NMR experiments (gradient-enhanced heteronuclear single quantum coherence). The 1H 15N g-HMBC experiment suggested the coordination of the heterocycles to the metal ion via tertiary nitrogen. PMID- 19444859 TI - Matrix-less laser desorption/ionisation mass spectrometry of polyphenols in red wine. AB - Matrix-assisted laser desorption/ionisation (MALDI) of small molecules is challenging and in most cases impossible due to interferences from matrix ions precluding analysis of molecules <300-500 Da. A common matrix such as ferulic acid belongs to an important class of compounds associated with antioxidant activity. If the shared phenolic structure is related to the propensity as an active MALDI matrix then it follows that direct laser desorption/ionisation should be possible for polyphenols. Indeed matrix-less laser desorption/ionisation mass spectrometry is achieved whereby the analyte functions as a matrix and was used to monitor low molecular weight compounds in wine samples. Sensitivity ranging from 0.12-87 pmol/spot was achieved for eight phenolic acids (4-coumaric, 4-hydroxybenzoic, caffeic, ferulic, gallic, protocatechuic, syringic, vanillic) and 0.02 pmol/spot for trans-resveratrol. Additionally, 4-coumaric, 4-hydroxybenzoic, caffeic, ferulic, gallic, syringic, vanillic acids and trans-resveratrol were identified in wine samples using accurate mass measurements consistent with reported profiles based on liquid chromatography (LC)/MS. Minimal sample pre-treatment make the technique potentially appropriate for fingerprinting, screening and quality control of wine samples. PMID- 19444860 TI - Confocal microscopy reveals Myzitiras and Vthela morphotypes as new signatures of malignancy progression. AB - G3S1 cells are a new line derived from EM-G3 breast cancer cells by chronic nutritional stress and treatments with 12-O-tetradecanoylphorbol-13-acetate. These cells are capable of growing in standard medium. G3S1 cells exhibited elevated invasiveness in Matrigel invasion chambers as compared with parental EM G3 cells. Elevated invasiveness of G3S1 cells was accompanied by higher incidence of myzitiras morphotype (sucker-like) and newly observed vthela morphotype (leech like) both inducible in Hanks' Balanced Salt Solution test. Time-lapse phase contrast microscopy showed a capacity of G3S1 cells to form lobopodial protrusions already 20 min after seeding on gelatin. These protrusions could make contact with the dish and possibly produce the vthela shape. The possible relationship of mysitiras and vthela morphotypes to an increase in malignant potential marked by enhanced invasiveness was thus indicated. PMID- 19444861 TI - Gene expression profiles in liver of mouse after chronic exposure to drinking water. AB - cDNA micorarray approach was applied to hepatic transcriptional profile analysis in male mouse (Mus musculus, ICR) to assess the potential health effects of drinking water in Nanjing, China. Mice were treated with continuous exposure to drinking water for 90 days. Hepatic gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 arrays, and pathway analysis was carried out by Molecule Annotation System 2.0 and KEGG pathway database. A total of 836 genes were found to be significantly altered (1.5-fold, P < or = 0.05), including 294 up-regulated genes and 542 down-regulated genes. According to biological pathway analysis, drinking water exposure resulted in aberration of gene expression and biological pathways linked to xenobiotic metabolism, signal transduction, cell cycle and oxidative stress response. Further, deregulation of several genes associated with carcinogenesis or tumor progression including Ccnd1, Egfr, Map2k3, Mcm2, Orc2l and Smad2 was observed. Although transcription changes in identified genes are unlikely to be used as a sole indicator of adverse health effects, the results of this study could enhance our understanding of early toxic effects of drinking water exposure and support future studies on drinking water safety. PMID- 19444862 TI - Solid-state NMR spectroscopic studies on the interaction of sorbic acid with phospholipid membranes at different pH levels. AB - 2H, 31P, and 1H-magic-angle-spinning (MAS) solid-state NMR spectroscopic methods were used to elucidate the interaction between sorbic acid, a widely used weak acid food preservative, and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers under both acidic and neutral pH conditions. The linewidth broadening observed in the 31P NMR powder pattern spectra and the changes in the 31P longitudinal relaxation time (T1) indicate interaction with the phospholipid headgroup upon titration of sorbic acid or decanoic acid into DMPC bilayers over the pH range from 3.0 to 7.4. The peak intensities of sorbic acid decrease upon addition of paramagnetic Mn2+ ions in DMPC bilayers as recorded in the 1H MAS NMR spectra, suggesting that sorbic acid molecules are in close proximity with the membrane/aqueous surface. No significant 2H quadrupolar splitting (DeltanuQ) changes are observed in the 2H NMR spectra of DMPC-d54 upon titration of sorbic acid, and the change of pH has a slight effect on DeltanuQ, indicating that sorbic acid has weak influence on the orientation order of the DMPC acyl chains in the fluid phase over the pH range from 3.0 to 7.4. This finding is in contrast to the results of the decanoic acid/DMPC-d54 systems, where DeltanuQ increases as the concentration of decanoic acid increases. Thus, in the membrane association process, sorbic acids are most likely interacting with the headgroups and shallowly embedded near the top of the phospholipid headgroups, rather than inserting deep into the acyl chains. Thus, antimicrobial mode of action for sorbic acid may be different from that of long-chain fatty acids. PMID- 19444863 TI - Development of an in vitro model to test the efficacy of novel therapies for IVD degeneration. AB - Low back pain (LBP) is a major cause of disability worldwide that has been linked to intervertebral disc (IVD) degeneration. An improved understanding of the pathogenesis of disc degeneration is now developing, which is leading to the development of a number of possible future therapies targeted at the underlying pathology and regeneration strategies. Although results thus far are promising, the investigation of such therapies in an environment that mimics the mechanical environment of the human disc in vivo is problematic. The development of an in vitro model system that can maintain metabolically active IVD tissue within a loading environment pertaining to that of the human spine is crucial for testing the efficacy of future cell-based and tissue-engineering therapies for IVD degeneration. Here, using our novel loading rig, capable of mimicking the loading environment experienced within the human spine, we have cultured nucleus pulposus tissue explants, applied a daily hydrostatic loading regime for up to 2 weeks and investigated proteoglycan retention, metabolic activity and cellular phenotype. IVD tissue cultured under a loading environment pertaining to the in vivo loading environment maintained metabolic cell activity, proteoglycan content and cellular phenotype. Indeed, all parameters were improved in IVD tissue cultured with load compared to unloaded controls. Such a model is invaluable for investigations assessing the feasibility and efficacy of future therapeutic approaches to inhibiting degeneration or stimulating regeneration of the IVD, where the in vivo loading environment may be crucial to their success or failure. PMID- 19444864 TI - Human articular chondrocytes on macroporous gelatin microcarriers form structurally stable constructs with blood-derived biological glues in vitro. AB - Biodegradable macroporous gelatin microcarriers fixed with blood-derived biodegradable glue are proposed as a delivery system for human autologous chondrocytes. Cell-seeded microcarriers were embedded in four biological glues recalcified citrated whole blood, recalcified citrated plasma with or without platelets, and a commercially available fibrin glue-and cultured in an in vitro model under static conditions for 16 weeks. No differences could be verified between the commercial fibrin glue and the blood-derived alternatives. Five further experiments were conducted with recalcified citrated platelet-rich plasma alone as microcarrier sealant, using two different in vitro culture models and chondrocytes from three additional donors. The microcarriers supported chondrocyte adhesion and expansion as well as extracellular matrix (ECM) synthesis. Matrix formation occurred predominantly at sample surfaces under the static conditions. The presence of microcarriers proved essential for the glues to support the structural takeover of ECM proteins produced by the embedded chondrocytes, as exclusion of the microcarriers resulted in unstable structures that dissolved before matrix formation could occur. Immunohistochemical analysis revealed the presence of SOX-9- and S-100-positive chondrocytes as well as the production of aggrecan and collagen type I, but not of the cartilage-specific collagen type II. These results imply that blood-derived glues are indeed potentially applicable for encapsulation of chondrocyte-seeded microcarriers. However, the static in vitro models used in this study proved incapable of supporting cartilage formation throughout the engineered constructs. PMID- 19444865 TI - Glucose abnormalities in non-alcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload. AB - Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection are major causes of liver disease frequently described in outpatient patients with glucose abnormalities. Hyperferritinemia, which suggests that iron overload plays a decisive role in the pathophysiology of insulin resistance and hyperglycemia, is a common finding in both disorders. However, the role of the hepatic iron deposition differs from one to the other. In NAFLD, a moderate liver iron accumulation has been observed and molecular mechanisms, including the downregulation of the liver iron exporter ferroportin-1, have been described. Iron overload will enhance intrahepatic oxidative stress that promotes hepatic fibrosis, interfere with insulin signalling at various levels and may hamper hepatic insulin extraction. Therefore, liver fibrosis, hyperglycemia and hyperinsulinemia will lead to increased levels of insulin resistance and the development of glucose abnormalities. Furthermore, iron depletion by phlebotomy removes liver iron content and reduces serum glucose and insulin resistance in NAFLD patients. Therefore, it seems that iron overload participates in those glucose abnormalities associated with NAFLD. Concerning chronic HCV infection, it has been classically assumed that iron overload contributes to insulin resistance associated with virus infection. However, recent evidence argues against the presence of iron overload in these patients and points to inflammation associated with diabetes as the main contributor to the elevated ferritin levels. Therefore, glucose abnormalities, and specially type 2 diabetes, should be taken into account when evaluating serum ferritin levels in patients with HCV infection. PMID- 19444866 TI - Inhibitory effects on bacterial growth and beta-ketoacyl-ACP reductase by different species of maple leaf extracts and tannic acid. AB - It is important to develop new antibiotics aimed at novel targets. The investigation found that the leaf extracts from five maples (Acer platanoides, Acer campestre, Acer rubrum, Acer saccharum and Acer truncatum Bunge collected in Denmark, Canada and China) and their component tannic acid displayed antibacterial ability against 24 standard bacteria strains with the minimum inhibitory concentration of 0.3-8.0 mg/mL. Unlike the standard antibiotic levofloxacin (LFX), these samples inhibited Gram-positive bacteria more effectively than they inhibited Gram-negative bacteria. These samples effectively inhibited two antidrug bacterial strains. The results show that these samples inhibit bacteria by a different mechanism from LFX. These samples potently inhibited b-ketoacyl-ACP reductase (FabG), which is an important enzyme in bacterial fatty acid synthesis. Tannic acid showed the strongest inhibition on FabG with a half inhibition concentration of 0.78 microM (0.81 microg/mL). Furthermore, tannic acid and two maple leaf extracts showed time-dependent irreversible inhibition of FabG. These three samples also exhibited better inhibition on bacteria. It is suggested that FabG is the antibacteria target of maple leaf extracts and tannic acid, and both reversible and irreversible inhibitions of FabG are important for the antibacterial effect. PMID- 19444867 TI - Does tubal ectopic pregnancy with hemoperitoneum always require surgery? AB - OBJECTIVE: Hemoperitoneum is accepted as an indication for surgery in women with tubal ectopic pregnancy. The aim of this pilot study was to evaluate the feasibility of managing such women non-surgically. METHODS: This was a prospective observational study. Women with tubal ectopic pregnancy and hemoperitoneum detected on transvaginal sonography (TVS) were managed as inpatients either expectantly or with methotrexate (MTX). Inclusion criteria for conservative management were: compliance, clinical stability, absence of acute abdomen, stable hemoglobin level on two measurements (0 and 12-24 h apart), serum human chorionic gonadotropin (hCG) < 5000 IU/L, absence of fetal cardiac activity on TVS and absence of significant hemoperitoneum, defined as blood above the level of the uterine fundus and/or in Morison's pouch (hepatorenal space). Subsequent management was based upon the hCG ratio at 48 h. All the women were managed as inpatients until the abdominal pain settled and the serum hCG levels were falling. RESULTS: Forty-one women with tubal ectopic pregnancy presented between November 2006 and March 2008. Eight women (20%) fulfilled the entry criteria. The median gestational age at diagnosis was 49 (interquartile range, 38 52.5) days. All women presented with lower abdominal pain/right iliac fossa or left iliac fossa pain. Hemoglobin levels ranged from 11.2 to 14.2 g/dL at presentation and from 12.0 to 14.8 g/dL after 12-24 h. 6/8 (75%) women were managed expectantly and 2/8 (25%) received MTX. All women had resolution of their ectopic pregnancy within 3 weeks with no complications. CONCLUSIONS: This pilot study suggests that the finding of hemoperitoneum on ultrasound examination may not be an absolute contraindication to conservative management of tubal ectopic pregnancy. PMID- 19444869 TI - Differentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation. AB - Cyclic adenosine monophosphate (cAMP) is generated by adenylyl cyclases (ACs), a group of enzymes with different tissue specificity and regulation. We hypothesized that AC isoforms are heterogeneously expressed along the biliary tree, are associated with specific secretory stimuli, and are differentially modulated in cholestasis. Small duct and large duct cholangiocytes were isolated from controls and from lipopolysaccharide-treated or alpha-naphthylisothiocyanate treated rats. AC isoform expression was assessed via real-time polymerase chain reaction. Secretion and cAMP levels were measured in intrahepatic bile duct units after stimulation with secretin, forskolin, HCO(3)(-)/CO(2), cholinergic agonists, and beta-adrenergic agonists, with or without selected inhibitors or after silencing of AC8 or soluble adenylyl cyclase (sAC) with small interfering RNA. Gene expression of the Ca(2+)-insensitive isoforms (AC4, AC7) was higher in small duct cholangiocytes, whereas that of the Ca(2+)-inhibitable (AC5, AC6, AC9), the Ca(2+)/calmodulin-stimulated AC8, and the soluble sAC was higher in large duct cholangiocytes. Ca(2+)/calmodulin inhibitors and AC8 gene silencing inhibited choleresis and cAMP production stimulated by secretin and acetylcholine, but not by forskolin. Secretion stimulated by isoproterenol and calcineurin inibitors was cAMP-dependent and gamma-aminobutyric acid-inhibitable, consistent with activation of AC9. Cholangiocyte secretion stimulated by isohydric changes in [HCO(3)(-)](i) was cAMP-dependent and inhibited by sAC inhibitor and sAC gene silencing. Treatment with lipopolysaccharide or alpha naphthylisothiocyanate increased expression of AC7 and sAC but decreased expression of the other ACs. CONCLUSION: These studies demonstrate a previously unrecognized role of ACs in biliary pathophysiology. In fact: (1) AC isoforms are differentially expressed in cholangiocyte subpopulations; (2) AC8, AC9, and sAC mediate cholangiocyte secretion in response to secretin, beta-adrenergic agonists, or changes in [HCO(3)(-)](i), respectively; and (3) AC gene expression is modulated in experimental cholestasis. PMID- 19444870 TI - Independent effects of physical activity in patients with nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease, characterized by elevated liver enzymes, central obesity, and insulin resistance, is becoming increasingly prevalent. The effects of changes in physical activity on the metabolic profile of this group have not been reported. We assessed at 3 months the impact of a behavior change based lifestyle intervention on physical activity and the effects of this change on the metabolic profile of people with fatty liver disease. In all, 141 participants with nonalcoholic fatty liver disease were prospectively enrolled into either a low- or moderate-intensity lifestyle intervention or to a control group. Physical activity was assessed using a validated reporting tool and physical fitness was measured using the YMCA protocol on a cycle ergometer. Individualized counseling to increase physical activity was provided. Overall, 96% of participants attended the 3-month follow-up assessment. Participants in the moderate- and low-intensity intervention groups were 9 times more likely to increase physical activity by an hour or more per week compared to controls. Patients increasing or maintaining their reported physical activity to > or =150 minutes/week, and those who increased their objective levels of fitness, had the greatest improvements in liver enzymes and other metabolic indices compared to those who were least active. This effect was independent of weight loss and was corroborated by an objective measure of fitness. There was no dose-response effect on liver enzymes with incremental increases in physical activity above 60 minutes/week. CONCLUSION: Lifestyle counseling interventions are effective in improving physical activity behavior. Maintaining or increasing physical activity provides health benefits for patients with fatty liver, independent of changes in weight. PMID- 19444871 TI - Novel mechanism of C-reactive protein for enhancing mouse liver innate immunity. AB - Although C-reactive protein (CRP) is a representative acute-phase protein produced by hepatocytes, the role of CRP in liver innate immunity remains unclear. Using C57BL/6 mice, the present study investigated how CRP affects the functions of liver macrophages, Kupffer cells, and natural killer / natural killer T (NK/NKT) cells under various conditions, including Escherichia coli infection, septic shock, and multiorgan dysfunction induced by interleukin (IL) 12/lipopolysaccharide (LPS) (generalized Shwartzman reaction [GSR]), and LPS induced lethal hepatitis in Propionibacterium acnes-primed mice. When mice were challenged with a lethal dose of E. coli, synthetic CRP peptide decreased the mortality without decreasing serum tumor necrosis factor (TNF), presumably by enhancing the phagocytic activity of Kupffer cells. Synthetic CRP greatly decreased the production of TNF and reactive oxygen species from Kupffer cells and thereby rescued mice after lethal LPS challenge. CRP also decreased the mortality from GSR and lethal hepatitis by inhibiting TNF production from Kupffer cells, especially phagocytosing Kupffer cells. However, interferon-gamma production from NK/NKT cells was generally not so affected. CRP reportedly binds to FcgammaRI and FcgammaRII, and the injection of anti-FcgammaRII/III Ab into mice abrogated TNF production from, but increased the phagocytic activity of, Kupffer cells. Furthermore, CRP pretreatment restored the decreased phagocytic activity of Kupffer cells in burn-injured mice and decreased TNF production by Kupffer cells and thereby inhibited mortality after sublethal E. coli infection. If CRP was injected into mice at 1 hour after lethal E. coli challenge, it slightly but significantly increased the survival rate. CONCLUSION: CRP thus enhances the phagocytosis of Kupffer cells but decreases their TNF production in a complex manner in which the pathway by way of FcgammaRII may be involved. PMID- 19444872 TI - Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1 antitrypsin deficiency. AB - Inappropriate accumulation of the misfolded Z variant of alpha1-antitrypsin in the hepatocyte endoplasmic reticulum (ER) is a risk factor for the development of end-stage liver disease. However, the genetic and environmental factors that contribute to its etiology are poorly understood. ER mannosidase I (ERManI) is a quality control factor that plays a critical role in the sorting and targeting of misfolded glycoproteins for proteasome-mediated degradation. In this study, we tested whether genetic variations in the human ERManI gene influence the age at onset of end-stage liver disease in patients homozygous for the Z allele (ZZ). We sequenced all 13 exons in a group of unrelated Caucasian ZZ transplant recipients with different age at onset of the end-stage liver disease. Homozygosity for the minor A allele at 2484G/A (refSNP ID number rs4567) in the 3'-untranslated region was prevalent in the infant ZZ patients. Functional studies indicated that rs4567(A), but not rs4567(G), suppresses ERManI translation under ER stress conditions. CONCLUSION: These findings suggest that the identified single nucleotide polymorphism can accelerate the onset of the end-stage liver disease associated with alpha1-antitrypsin deficiency and underscore the contribution of biosynthetic quality control as a modifier of genetic disease. PMID- 19444873 TI - Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. AB - Steatosis in the liver is a common feature of obesity and type 2 diabetes and the precursor to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. It has been shown previously that inhibiting glycosphingolipid (GSL) synthesis increases insulin sensitivity and lowers glucose levels in diabetic rodent models. Here we demonstrate that inhibiting GSL synthesis in ob/ob mice not only improved glucose homeostasis but also markedly reduced the development of hepatic steatosis. The ob/ob mice were treated for 7 weeks with a specific inhibitor of glucosylceramide synthase, the initial enzyme involved in the synthesis of GSLs. Besides lowering glucose and hemoglobin A1c (HbA1c) levels, drug treatment also significantly reduced the liver/body weight ratio, decreased the accumulation of triglycerides, and improved several markers of liver pathology. Drug treatment reduced liver glucosylceramide (GL1) levels in the ob/ob mouse. Treatment also reduced the expression of several genes associated with hepatic steatosis, including those involved in lipogenesis, gluconeogenesis, and inflammation. In addition, inhibiting GSL synthesis in diet induced obese mice both prevented the development of steatosis and partially reversed preexisting steatosis. CONCLUSION: These data indicate that inhibiting GSL synthesis ameliorates the liver pathology associated with obesity and diabetes, and may represent a novel strategy for treating fatty liver disease and NASH. PMID- 19444874 TI - S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model. AB - Hepatocellular carcinoma (HCC) remains a common cancer worldwide that lacks effective chemoprevention or treatment. Chronic liver disease often leads to impaired hepatic S-adenosylmethionine (SAMe) biosynthesis, and mice with SAMe deficiency develop HCC spontaneously. SAMe is antiapoptotic in normal hepatocytes but proapoptotic in cancerous hepatocytes. The present study investigated SAMe's effectiveness in prevention and treatment of HCC. Two weeks after injecting 2.5 million H4IIE cells into the liver parenchyma of ACI rats, they typically form a 1-cm tumor. When SAMe (150 mg/kg/day) was delivered through continuous intravenous infusion, hepatic SAMe levels reached 0.7 mM (over 10-fold) 24 hours later. This regimen, started 1 day after injecting H4IIE cells and continued for 10 days, was able to reduce tumor establishment and growth. However, if intravenous SAMe was started after HCC had already developed, it was ineffective in reducing tumor growth for 24 days. Although plasma SAMe levels remained elevated, hepatic SAMe levels were minimally increased (30% higher). Chronic SAMe administration led to induction of hepatic methyltransferases, which prevented SAMe accumulation. To see if SAMe's preventive effect on tumor establishment involves angiogenesis, the effect of SAMe on angiogenesis genes was studied. SAMe treatment of H4IIE cells altered the expression of several genes with the net effect of inhibiting angiogenesis. These changes were confirmed at the protein level and functionally in human umbilical vein endothelial cells. CONCLUSION: SAMe is effective in preventing HCC establishment but ineffective in treating established HCC because of induction of hepatic methyltransferases, which prevents SAMe level to reach high enough to kill liver cancer cells. SAMe's chemopreventive effect may be related to its proapoptotic action and its ability to inhibit angiogenesis. PMID- 19444875 TI - Three-dimensional patellar motion at the natural knee during passive flexion/extension. An in vitro study. AB - Patellar maltracking may result in many patellofemoral joint (PFJ) disorders in the natural and replaced knee. The literature providing quantitative reference for normal PFJ kinematics according to which patellar maltracking could be identified is still limited. The aim of this study was to measure in vitro accurately all six-degrees-of-freedom of patellar motion with respect to the femur and tibia on 20 normal specimens. A state-of-the-art knee navigation system, suitably adapted for this study aim, was used. Anatomical reference frames were defined for the femur, tibia, and patella according to international recommendations. PFJ flexion, tilt, rotation, and translations were calculated in addition to standard tibiofemoral joint (TFJ) kinematics. All motion patterns were found to be generally repeatable intra-/interspecimens. PFJ flexion was 62% of the corresponding TFJ flexion range; tilt and translations along femoral mediolateral and tibial proximodistal axes during TFJ flexion were found with medial, lateral, and distal trends and within 12 degrees , 6 and 9 mm, respectively. No clear pattern for PFJ rotation was observed. These results concur with comparable reports from the literature and contribute to the controversial knowledge on normal PFJ kinematics. Their consistence provides fundamental information to understand orthopedic treatment of the knee and for possible relevant measurements intraoperatively. PMID- 19444876 TI - Optimal use of intraoperative PTH levels in parathyroidectomy. AB - OBJECTIVES/HYPOTHESIS: Localization and the intraoperative parathyroid hormone assay (IOPTH) have facilitated minimally invasive parathyroidectomy. The precise algorithm governing use of IOPTH has been debated. Numerous authors advocate acquisition of a so-called pre-excision (P-E) baseline level (obtained after dissection of the adenoma, but prior to excision) in addition to a preincision baseline, to guard against spurious elevation in the baseline that might confuse interpretation of postexcision levels. We sought to clarify the optimal timing of PTH level determination. STUDY DESIGN: Consecutive single-surgeon case series with planned data collection from patients undergoing parathyroid surgery at a university hospital. METHODS: Demographic data and intraoperative laboratory and surgical findings from patients undergoing parathyroidectomy were prospectively gathered and analyzed. Attention was paid to the value of P-E and 5-minute postexcision levels and their impact on intraoperative decision-making. RESULTS: One hundred twelve patients underwent parathyroidectomy. Thirty were for secondary or tertiary hyperparathyroidism and were excluded. Seventy-nine (96.3%) of the 82 patients with primary hyperparathyroidism were rendered eucalcemic. In no case did the P-E value change what was otherwise destined to be a successful result. In 65.3% of cases, operative time was conserved as the procedure was correctly stopped after the 5-minute level, without the need to wait until the 10 minute postexcision level was reported. CONCLUSIONS: Pre-excision baseline IOPTH levels, although logical in their original proposal, appear to play little role in determining the completeness of an exploration. A 5-minute postexcision level adds value in nearly two thirds of cases by allowing earlier termination of the operation. PMID- 19444877 TI - Development and persistence of posttraumatic stress disorder and the 5-HTTLPR polymorphism. AB - Association between 5-HTTLPR polymorphism and development of acute and persistence of chronic posttraumatic stress disorder (PTSD) was prospectively investigated. DNA was extracted from 41 motor-vehicle accident victims evaluated for development and persistence of PTSD, 1 and 12 months posttrauma. At Time 1, a nonsignificant trend for higher acute PTSD rate in ll homozygotes (82%) was observed compared to those with ss and sl genotypes (50%). At Time 2, higher chronic PTSD rate was found in ll homozygotes (55%) compared to those with ss and sl genotypes (20%), with an odds ratio of 4.8 (95% CI = 1.09-21.22). Contrary to previous findings, these data are suggestive of a protective role for the s allele of 5-HTTLPR in chronic PTSD. PMID- 19444878 TI - Larynx-preserving esophagectomy and jejunal transfer for cervical esophageal carcinoma. AB - OBJECTIVES/HYPOTHESIS: To examine the efficacy and safety of free jejunal transfer after larynx-preserving esophagectomy in patients with cervical esophageal carcinoma, especially with a high tumor involving the hypopharynx. STUDY DESIGN: A retrospective analysis of patients with cervical esophageal carcinoma who underwent free jejunal transfer after larynx-preserving esophagectomy. METHODS: The subjects were 32 patients who underwent larynx preserving cervical esophagectomy and microvascular jejunal transfer. Fifteen patients had a high cervical esophageal carcinoma that involved the hypopharynx (high-tumor group), and 17 patients had a low cervical esophageal carcinoma that did not involve the hypopharynx (low-tumor group). For each group, mortality, morbidity (anastomotic leakage, wound infection, stricture, and recurrent laryngeal nerve palsy), functional outcomes (time to start oral intake, achieve complete oral intake, decannulation, and rate of larynx preservation), and oncologic outcomes (survival and local control rate) were reviewed and compared. RESULTS: No perioperative deaths occurred in either group. The incidence of postoperative complications did not differ between the groups. Oral intake started significantly later in the high-tumor group (14.9 days) than in the low tumor group (10.4 days), but all patients in the high-tumor group could finally achieve oral intake without aspiration. Decannulation was possible in patients who underwent tracheostomy, and laryngeal function was completely preserved in the high-tumor group. Both survival and local control rate did not differ between the groups. CONCLUSIONS: Free jejunal grafts in larynx-preserving surgery can be performed safely and reliably in patients with low cervical esophageal carcinomas and in selected patients with high tumors involving the hypopharynx. PMID- 19444879 TI - Cartilage grafts in dorsal nasal augmentation of traumatic saddle nose deformity: a long-term follow-up. AB - OBJECTIVES/HYPOTHESIS: To document the long-term advantages and disadvantages of cartilage grafts used to correct traumatic saddle nose deformity. Additionally, to demonstrate functional improvement and cosmetic satisfaction with the use of this graft. STUDY DESIGN: Retrospective chart review and prospective follow-up telephone survey of 20 patients after dorsal augmentation of saddle nose deformity secondary to trauma. METHODS: This is a single-surgeon, single institution investigation within an academic tertiary care medical center. All patients presented for correction of saddle nose deformity after trauma, and cartilage grafts were used for augmentation of the dorsum. Minimum postoperative follow-up period of 1 year was required. A modified and expanded Nasal Obstructive Symptoms Evaluation survey, which included questions pertaining to the appearance of their nose, was used to assess both functional and cosmetic changes after surgery. RESULTS: Only 1 of the 20 patients was dissatisfied with the overall outcome. Three (15%) were extremely satisfied, 12 (60%) were very satisfied, three (15%) were somewhat satisfied, and one (5%) was indifferent. In terms of function, four (20%) experienced excellent relief in nasal obstruction, five (25%) moderate relief, four (20%) mild relief, and seven (35%) noted no difference. Regarding cosmesis, two (10%) noted excellent improvement, three (15%) moderate improvement, nine (45%) mild improvement, and five (25%) noted no significant change. One (5%) patient reported worsening due to tip edema. Mean follow-up time was 6.8 years. CONCLUSIONS: Autogenous cartilage grafts are useful in the correction of mild to moderate traumatic saddle nose deformity. The graft is readily available, preserves long-term structural stability, and achieves functional and cosmetic satisfaction in most patients. PMID- 19444880 TI - Prognostic significance of vascular endothelial growth factor-C expression and lymphatic vessel density in supraglottic squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Regional lymph node metastases are very common findings of supraglottic cancer. The mechanism of lymphatic metastasis is as yet unknown because there have been no specific markers that could definitely distinguish lymphatic vessels from blood vessels. The aim of this study is to identify the prognostic significance of vascular endothelial growth factor-C (VEGF-C) expression and lymphatic vessel density (LVD) in supraglottic cancer. STUDY DESIGN: The prognostic value of the VEGF-C and LVD was retrospectively evaluated in an unselected series of patients treated with curative intent for supraglottic cancer. METHODS: We investigated lymphatic vessels in 43 subjects who had previously been diagnosed with supraglottic cancer. Immunohistochemical staining was performed with VEGF-C, D2-40, and CD31 monoclonal antibodies on the paraffin embedded tissues obtained from these patients. The association among the semiquantitative score of VEGF-C stained cancer cells, the density of immunohistochemically stained microvessels, and the prognostic factors of supraglottic cancers were investigated to evaluate the prognostic significance. RESULTS: VEGF-C and LVD showed a statistically significant difference according to the presence of lymph node metastasis and regional recurrence (P < .05). VEGF C was only associated with disease-free survival and regional recurrence in multivariate analysis (P < .05). CONCLUSIONS: VEGF-C and LVD might be useful as predictors of the risk of lymph node metastasis and regional recurrence. PMID- 19444881 TI - Middle turbinate hinge flap for frontal recess obliteration following prior cranialization. AB - Frontal sinus cranialization is an established procedure utilized in instances wherein the posterior table has been irreversibly compromised. A known complication of this procedure is pneumocephalus, which may develop if the frontal recess has not been fully separated from the cranialized sinus. We report 3 cases wherein massive pneumocephalus developed after cranialization of the frontal sinus. In each case, a novel endoscopic repair was undertaken utilizing a middle turbinate hinge flap to obliterate the frontal recess. In each instance, obliteration of the frontal recess resulted in durable resolution of pneumocephalus. PMID- 19444882 TI - Imagery rehearsal therapy for posttraumatic nightmares in U.S. veterans. AB - Imagery rehearsal therapy (IRT) may help reduce residual nightmares and posttraumatic stress disorder (PTSD) symptoms in veterans after trauma-focused PTSD treatment. Fifteen male U.S. veterans with PTSD and trauma-related nightmares, who had not previously completed trauma-focused PTSD treatment, attended 6 IRT group sessions. No benefits were observed immediately posttreatment. At 3- and 6-month follow-up, however, trauma-related nightmare frequency (nights/week) decreased (p < .01). The number of trauma-related nightmares/week (p < .01), number of total nightmares/week (p < .05), and PTSD symptoms (p < .05) also decreased at 3 months. The overall F test for time was significant (p < .05) for nightmare severity and fear of sleep. No effects were found on measures of the impact of nightmares, sleep quality, or depression. Clinical and research implications are discussed. PMID- 19444883 TI - Parasympathetic reactivity to recalled traumatic and pleasant events in trauma exposed individuals. AB - Parasympathetic and heart rate (HR) reactivity to memories of traumatic and pleasant events were investigated in trauma-exposed individuals (n = 40). Vagal tone and HR were recorded before, during, and following recall of traumatic and pleasant events. Posttraumatic stress (PTS) was related to blunted parasympathetic reactivity among trauma-exposed individuals. Specifically, PTS severity was related to lower parasympathetic activation and lower recovery following trauma recall, and to lower parasympathetic activation (but not recovery) in response to a pleasant event recall. No association was observed between PTS severity and initial parasympathetic tone. However, PTS severity was associated with initial HR. Assessment of parasympathetic reactivity may enhance our understanding of the normative and pathological reactions to trauma and stress. PMID- 19444884 TI - A comparison of PTSD symptom patterns in three types of civilian trauma. AB - Posttraumatic stress disorder (PTSD) is assumed to be an equivalent syndrome regardless of the type of traumatic event that precipitated it. However, the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) and previous research suggest that the clinical presentation of PTSD varies by trauma type. This study compared PTSD symptom profiles in three types of civilian trauma: sexual assault (n = 86), motor vehicle accident (n = 162), and sudden loss of a loved one (n = 185). Groups differed in overall PTSD severity and displayed distinct PTSD symptom patterns. Results suggest that different trauma types lead to unique variants of the PTSD syndrome, which may result from different etiological factors and may require different treatment approaches. PMID- 19444885 TI - Illumination guided balloon sinuplasty. PMID- 19444886 TI - Morphometric bronchoscopy in adults with central airway obstruction: case illustrations and review of the literature. AB - The severity of airway narrowing impacts ventilatory function, quality of life, and choice of therapy for patients with central airway obstruction. The quantification of airway caliber remains a subjective estimate that depends on patient positioning, technique, and operator experience. In this article, we describe how morphometric bronchoscopy, a software processing method whereby bronchoscopic digital images are analyzed in order to measure airway lumen diameter, can be used to objectively quantify the degree of airway narrowing in adult patients with central airway obstruction. PMID- 19444887 TI - The effect of treatment on survival in patients with advanced laryngeal carcinoma. AB - OBJECTIVES/HYPOTHESIS: Over the last 2 decades, survival from laryngeal cancer has decreased. We sought to identify factors associated with decreased survival in laryngeal cancer. METHODS: Patients diagnosed with laryngeal squamous cell carcinoma from 1985 to 2002 were retrospectively reviewed. RESULTS: A total of 451 patients met study criteria. Five-year survival rates were 85% for stage I, 77% for stage II, 51% for stage III, and 35% for stage IV disease. Survival for patients with stage I-III disease was similar for patients treated operatively or nonoperatively (P = .4). However, patients with stage III disease treated nonoperatively had worse survival with radiation alone (XRT) compared to chemoradiation (CR) (P = .006). Patients with stage IV disease had significantly better survival with surgery (49%) than CR (21%) or XRT alone (14%) (P < .0001). Analysis by primary tumor stage demonstrated that survival for T1-T3 disease was independent of treatment modality (P = .2); however, for T4 patients, operative treatment was associated with significantly better survival (55%) than CR (25%) or XRT (0%) (P < .0001). Proportional hazards models confirmed significantly worse survival for stage IV, T4, N2 or N3 disease, and nonoperative treatment. For T4 disease, after controlling for nodal status, nonoperative treatment was the only significant predictor of worse survival. CONCLUSIONS: Primary surgical treatment is associated with improved survival for patients with stage IV disease and specifically T4 primary tumors. These data suggest that the observed national decrease in survival from laryngeal cancer may be due to a shift toward nonoperative treatment in that subset of patients with advanced primary disease. PMID- 19444888 TI - Diagnostic and surgical dilemmas in hereditary medullary thyroid carcinoma. AB - Medullary thyroid carcinoma (MTC) is a rare malignancy arising from the parafollicular C cells within the thyroid gland. The majority of cases are sporadic, but at least 30% are hereditary in nature. Inherited forms of MTC occur as familial MTC or as a manifestation of multiple endocrine neoplasia type 2. Early diagnosis and aggressive surgical management, including prophylactic thyroidectomy, improve the prognosis of patients with hereditary MTC. Several issues regarding the diagnosis and treatment of MTC remain controversial. Genetic penetrance and virulence are variable. We present an index case of familial MTC to illustrate common difficulties in the initial diagnosis and dilemmas in the surgical approach, followed by a review of current literature relevant to the management of hereditary MTC. PMID- 19444889 TI - Spectral power Doppler ultrasound parameters: are they really significant? PMID- 19444891 TI - Treatment of esthesioneuroblastoma: a 16-year meta-analysis of 361 patients. AB - OBJECTIVES/HYPOTHESIS: This study reviews the published outcomes related to surgical (open, endoscopic, and endoscopic-assisted) and nonsurgical treatment for esthesioneuroblastoma. STUDY DESIGN: Literature meta-analysis. METHODS: A meta-analysis of individual patient data for esthesioneuroblastoma publications between 1992 (the earliest identified description of endoscopic resection) and 2008 was conducted. A total of 49 journal articles, comprising 1,170 cases of esthesioneuroblastoma, were included in the study. Criteria for meta-analysis inclusion were five or more patients in a study with sufficient patient data resolution for analysis. Twenty-three studies comprising 361 patients met all inclusion criteria. The overall treatment and outcome at final follow-up of each patient was recorded. Patients were pooled according to treatment techniques and compared to one another using a Kaplan-Meier survival curve and the Mann-Whitney U test to examine differences in follow-up times and publication years. RESULTS: Log-rank tests showed a greater published survival rate for endoscopic surgery compared to open surgery (P = .0019), even when stratifying for publication year (P = .0018). There was no significant difference in follow-up time. Review of Kadish tumor staging for each modality showed larger tumors were more often treated with an open approach, but open and endoscopic survival measures were comparable. CONCLUSIONS: These results suggest that endoscopic surgery is a valid treatment method with comparable survival to open surgery. Further prospective analysis will be beneficial. PMID- 19444892 TI - Proteomic identification of serum biomarkers for head and neck cancer surveillance. AB - OBJECTIVES/HYPOTHESIS: Serum protein profiling by SELDI-TOF-MS distinguishes pretreatment and post-treatment samples from patients with head and neck squamous cell cancer (HNSCC) by disease status (disease-free or recurrence) with a high degree of sensitivity and specificity. We sought to identify biomarkers for recurrence with potential utility for surveillance and incorporated 2-D DIGE and MALDI-TOF-MS techniques to overcome the limitations of SELDI-TOF-MS in determining biomarker identity. METHODS: Serum samples were collected prospectively from 143 HNSCC patients and analyzed based on disease status following treatment. RESULTS: Recurrent HNSCC occurred in 46 patients. MALDI-TOF MS following immunodepletion of major plasma proteins followed by 2-D DIGE identified 181 proteins with differential expression between pretreatment and post-treatment samples collected 6 months or more following treatment. Classification by disease status revealed significant differential expression of 16 proteins, with recurrent HNSCC associated with underexpression of kininogen and serine protease inhibitors C-1 inhibitor, kininogen, angiotensinogen, serine/cysteine proteinase inhibitor clade G member 1, and overexpression of thiol-specific antioxidant proteins (TSA), apolipoprotein A1 and proapolipoprotein, and epidermal cytokeratin 2. CONCLUSIONS: Serum protein profiling using 2D DIGE/MALDI-TOF-MS identifies proteins with significant differential expression in HNSCC based on disease status. Recurrent HNSCC was associated with underexpression of several protease inhibitors and kininogen, which has antiangiogenic properties, and overexpression of TSA, which is a free radical scavenger, as well as several forms of apolipoprotein A1 that may serve as a carrier molecule but may also indirectly promote tumor survival through kinase activation. This profile is consistent with a more aggressive disease variant and warrants further investigation. PMID- 19444893 TI - National laryngopharyngectomy and reconstructive surgery survey. AB - OBJECTIVES/HYPOTHESIS: To understand the various methods available to reconstruct total laryngopharyngectomy defects and to understand which, and to what degree, various factors influence the surgeon in choosing a particular reconstructive method. METHODS: Otolaryngologists and plastic surgeons who perform head and neck reconstruction were surveyed regarding preference of laryngopharyngectomy reconstruction. Numerical and rank-order data was analyzed using T statistics and Fisher exact test. RESULTS: Two hundred surveys were mailed and 72 physicians (36% response rate) provided data, with otolaryngologists comprising 54% of the respondents. Otolaryngologists were more likely to consider voice (P = .003) and swallowing (P = .02) outcomes compared to plastic surgeons. In contrast, plastic surgeons more often included cosmesis (P = .05) among those factors influencing their reconstructive choice. However, rank-order analysis demonstrated no statistical difference between plastic surgeons and otolaryngologists with respect to each factor. CONCLUSIONS: Our study sought to examine what motivates surgeons from several specialties to choose one reconstructive method over another for laryngopharyngeal defects. Otolaryngologists were more likely to consider voice and swallowing function in contrast to plastic surgeons, who more frequently included cosmesis as a factor. However, when physicians were asked to rank the importance of each of the eight factors from most to least important in influencing their reconstructive option, there was no statistical difference between plastic surgeons and otolaryngologists with respect to each factor. Further research is necessary to provide an evidence base for which reconstructive method offers the optimal functional restoration. PMID- 19444894 TI - Prostaglandin E2 is activated by airway injury and regulates fibroblast cytoskeletal dynamics. AB - OBJECTIVES/HYPOTHESIS: To characterize the activation of cyclooxygenase (COX) 2/prostaglandin (PG) E2 signaling during airway mucosal repair and its subsequent role during the wound healing process. STUDY DESIGN: Prospective animal study. METHODS: The subglottis was approached via cricothyroidotomy. Sham airways were closed, and wounded airways were subjected to laser injury and closed. Subglottic tissue was harvested at 12 hours, 24 hours, 48 hours, and 72 hours postinjury. Secretions were collected preoperatively and at time of sacrifice. Inflammatory gene expression was analyzed using quantitative reverse transcriptase polymerase chain reaction. Subglottic/tracheal explants were exposed to exogenous IL-1beta in the presence or absence of COX inhibitors. Explant-produced PGE2 levels were assayed using enzyme linked immunoassays. Human airway fibroblast migration and collagen contraction were assayed in the presence or absence of prostaglandin E2. RESULTS: Laser injury triggers a rapid, dose-dependent increase in mucosal IL 1beta and COX-2 gene expression, with an anatomical distribution proportional to the distance from the site of injury. Gene upregulation correlates with dose dependent increases in PGE2 mucosal secretion levels. Ex vivo analysis indicates IL-1beta is responsible for the activation of the COX-2 / PGE2 pathway. Prostaglandin E2 differentially inhibits airway fibroblast migration and contraction in a specific, dose-dependent manner. CONCLUSIONS: PGE2 is activated during mucosal inflammation and acts to decrease fibroplastic activity in the mucosal wound bed. During subglottic stenosis (SGS) development, the levels of PGE2 generated in response to injury may be insufficient to blunt the intrinsically fibroplastic phenotype of SGS fibroblasts, resulting in excessive scarring. PMID- 19444895 TI - Regulation of cellular contractile force in response to mechanical stretch by diphosphorylation of myosin regulatory light chain via RhoA signaling cascade. AB - Fibroblasts regulate their contractile force in response to external stretch; however, the detailed mechanism by which the force is regulated is unclear. Here, we show that diphosphorylation and dephosphorylation of myosin regulatory light chain (MRLC) are involved in the stretch-induced force response. Cellular stiffness, which reflects the cellular contractile force, under external stretch was measured by mechanical-scanning probe microscopy. Fibroblasts (NIH-3T3) expressing green fluorescent protein (GFP)-tagged mutant-type MRLC (MRLC(T18A) GFP), which cannot be diphosphorylated, did not show any stretch-induced stiffness response, whereas the stiffness in cells expressing GFP-tagged wild type MRLC (MRLC(WT)-GFP) increased immediately after the stretch and subsequently decreased after 1-2 h. Urea-PAGE western blot analysis showed that the proportion of diphosphorylated MRLC (PP-MRLC) transiently increased after the stretch and decreased after 1-2 h. Dominant-negative RhoA (RhoA(N19))-expressing cells did not show the stiffness response to the stretch, whereas wild-type RhoA-expressing cells did. It was concluded that the cellular force response originates in the stretch-induced diphosphorylation and dephosphorylation of MRLC and is regulated via the RhoA signaling cascade. PMID- 19444896 TI - Missed appointments in a genetics and birth defects clinic. PMID- 19444898 TI - Victor A. McKusick, M.D.: a clinician's clinician. PMID- 19444897 TI - The Erlenmeyer flask bone deformity in the skeletal dysplasias. AB - Erlenmeyer flask bone deformity (EFD) is a long-standing term used to describe a specific abnormality of the distal femora. The deformity consists of lack of modeling of the di-metaphysis with abnormal cortical thinning and lack of the concave di-metaphyseal curve resulting in an Erlenmeyer flask-like appearance. Utilizing a literature review and cohort study of 12 disorders we found 20 distinct disorders were associated with EFD. We interrogated the International Skeletal Dysplasia Registry (ISDR) radiographic database (1988-2007) to determine which skeletal dysplasias or syndromes were highly associated with EFD, whether it was a uniform finding in these disorders, and if forms of EFD could be differentiated. EFD was classified into three groups. The first catogory was the typical EFD shaped bone (EFD-T) resultant from absent normal di-metaphyseal modeling with relatively normal appearing radiographic trabecular bone. EFD-T was identified in: frontometaphyseal dysplasia, craniometaphyseal dysplasia, craniodiaphyseal dysplasia, diaphyseal dysplasia-Engelmann type, metaphyseal dysplasia-Pyle type, Melnick-Needles osteodysplasty, and otopalatodigital syndrome type I. The second group was the atypical type (EFD-A) due to absence of normal di-metaphyseal modeling with abnormal radiographic appearance of trabecular bone and was seen in dysosteosclerosis and osteopetrosis. The third group was EFD-marrow expansion type (EFD-ME) in which bone marrow hyperplasia or infiltration leads to abnormal modeling (e.g., Gaucher disease). Further, radiographic review determined that it was not always a consistent finding and that there was variability in both appearance and location within the skeleton. This analysis and classification aided in differentiating disorders with the finding of EFD. PMID- 19444899 TI - Preoperative sonographic diagnosis of appendiceal intussusception: a case report. AB - Appendiceal intussusception is an uncommon form of intussusception. Most of the literature regarding appendiceal intussusception discusses the colonoscopic diagnosis or surgical treatment of the condition. Sonographic findings have rarely been described. We present a case of preoperative sonographic diagnosis of appendiceal intussusception. PMID- 19444900 TI - Salivary simulation with ascorbic acid enhances sonographic diagnosis of obstructive sialadenitis. AB - PURPOSE: High-frequency ultrasound (US) is routinely used to evaluate various diseases of the salivary glands. Normally, the duct network of the submandibular and parotid glands is not visible during US assessment. In obstructive sialadenitis of the parotid and submandibular glands, localization of the obstacle is often difficult. METHODS: In a case-control study, the sonographic visibility of the duct before and after stimulation with oral ascorbic acid (vitamin C) was compared with sialendoscopy as the gold standard. Twenty male and 23 female patients suffering from salivary gland diseases were included in this study and compared with 25 healthy volunteers. US examination of the parotid and submandibular glands was performed before and after oral ascorbic acid stimulation. Changes in visibility of the main excretory duct were recorded and US diagnoses were compared with results of sialendoscopy. RESULTS: In 7 of 25 controls, the main duct became partially visible after stimulation. In the group of 43 patients, the main duct was depicted before stimulation in 27 patients (63%). After ascorbic acid stimulation, the main duct became visible in 41 patients (95%). Grading the stimulated duct dilation by measuring diameters at different points revealed no correlation with the underlying type of pathology. CONCLUSIONS: Application of ascorbic acid prior to diagnostic US examination facilitates the sonographic evaluation of obstructive salivary gland diseases. PMID- 19444901 TI - Early diagnosis, follow-up, and prenatal treatment of a case of TRAP sequence occurring in a dichorionic triamniotic triplet pregnancy. AB - We are reporting a case of twin reversed arterial perfusion (TRAP) sequence occurring in a dichorionic triamniotic triplet pregnancy with successful percutaneous prenatal treatment and excellent neonatal outcome. TRAP sequence was diagnosed at 11 weeks in a spontaneous dichorionic-triamniotic triplet. Sonographic assessment showed persistent arterial flow and development of hydrops in the acardiac twin. Percutaneous cord interstitial laser coagulation was performed, and the co-twin subsequently developed growth restriction. The 9-month old twins have a normal developmental course. This report confirms that fetal intervention is indicated in cases of TRAP sequence in which the acardiac twin presents a significant enlargement on follow-up sonographic examinations. PMID- 19444902 TI - In vivo genetic manipulation of the rat trophoblast cell lineage using lentiviral vector delivery. AB - In this report, we have adapted a lentiviral gene delivery technique for genetic modification of the rat trophoblast cell lineage. Blastocysts were incubated with lentiviral particles and transferred into the uteri of pseudopregnant female rats, harvested at various times during gestation, and then analyzed. Two test systems were evaluated: (1) delivery of an enhanced green fluorescent protein (EGFP) gene under the control of constitutive promoters to rat blastocysts; (2) delivery of EGFP short hairpin RNA (shRNA) to rat blastocysts constitutively expressing EGFP. Lentiviral packaged gene constructs were efficiently and specifically delivered to all trophoblast cell lineages. Additionally, lentiviral mediated transfer of shRNAs was an effective strategy for modifying gene expression in trophoblast cell lineages. This technique will permit the in vivo evaluation of "gain-of-function" and "loss-of-function" manipulations in the rat trophoblast cell lineage. PMID- 19444903 TI - Medical futility and psychiatry: palliative care and hospice care as a last resort in the treatment of refractory anorexia nervosa. AB - OBJECTIVE: The concept of medical futility is accepted in general medicine, yet little attention has been paid to its application in psychiatry. We explore how medical futility and principles of palliation may contribute to the management of treatment refractory anorexia nervosa. METHOD: We review the case of a 30-year old woman with chronic anorexia nervosa, treated unsuccessfully for several years. RESULTS: Ongoing assessment, including ethical consultation, determined that further active treatment was unlikely to resolve her condition. The patient was referred for palliative care and hospice care, and ultimately died. DISCUSSION: Although circumstances requiring its use are rare, palliative care may play a role in the treatment of long suffering, treatment refractory patients. For poor prognosis patients who are unresponsive to competent treatment, continue to decline physiologically and psychologically, and appear to face an inexorably terminal course, palliative care and hospice may be a humane alternative. PMID- 19444904 TI - Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6 and RAD23B but not by polymorphisms in five other nucleotide excision repair genes. AB - Laryngeal cancer is known to be associated with smoking and high alcohol consumption. Nucleotide excision repair (NER) plays a key role in repairing DNA damage induced by these exposures and might affect laryngeal cancer susceptibility. In a population-based case-control study including 248 cases and 647 controls, the association of laryngeal cancer with 14 single nucleotide polymorphisms (SNPs) in 8 NER genes (XPC, XPA, ERCC1, ERCC2, ERCC4, ERCC5, ERCC6 and RAD23B) was analyzed with respect to smoking and alcohol exposure. For genotyping, sequence specific hybridization probes were used. Data were evaluated by conditional logistic regression analysis, stratified for age and gender, and adjusted for smoking, alcohol consumption and education. Pro-carriers of ERCC6 Arg1230Pro showed a decreased risk for laryngeal cancer (OR = 0.53, 95% CI 0.34 0.85), strongest in heavy smokers and high alcohol consumers. ERCC5 Asp1104His was associated with risk in heavy smokers (OR = 1.70, 95% CI 1.1-2.5). Val carriers of RAD23B Ala249Val had an increased cancer risk in heavy smokers (OR = 1.6, 95% CI 1.1-2.5) and high alcohol consumers (OR = 2.0, 95% CI 1.1-3.4). The combined effect of smoking and alcohol intake affected risk, at high exposure level, for ERCC6 1230Pro carriers (OR = 0.47, 95% CI 0.22-0.98) and RAD23B 249Val carriers (OR = 2.6, 95% CI 1.3-4.9). When tested for gene-gene interaction, presence of 3 risk alleles in the XPC-RAD23B complex increased the risk 2.1-fold. SNPs in the other genes did not show a significant association with laryngeal cancer risk. We conclude that common genetic variations in NER genes can significantly modify laryngeal cancer risk. PMID- 19444905 TI - Flavonoid consumption and esophageal cancer among black and white men in the United States. AB - Flavonoids and proanthocyanidins are bioactive polyphenolic components of fruits and vegetables that may account for part of the protective effect of raw fruit and vegetable consumption in esophageal cancer. We studied the relationship between esophageal cancer and dietary proanthocyanidins, flavonoids and flavonoid subclasses (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols and isoflavonoids) using recently developed USDA and Tufts flavonoid and proanthocyanidin databases. The study was a population-based, case-control analysis of 161 white men with esophageal adenocarcinoma (EAC), 114 white and 218 black men with esophageal squamous cell carcinoma (ESCC) and 678 white and 557 black male controls who lived in 3 areas of the United States. Neither total flavonoid nor proanthocyanidin intake was associated with EAC and ESCC in either white or black men. In white men, inverse associations were observed between anthocyanidin intake and EAC (4th vs. 1st quartile odds ratio [OR], 0.47, 95% confidence interval [CI], 0.24-0.91; p(trend) = 0.04) and between isoflavonoid intake and ESCC (4th vs. 1st quartile OR, 0.43, 95% CI, 0.20-0.93; p(trend) = 0.01). None of the associations remained significant after adjusting for dietary fiber, which is strongly correlated with flavonoid consumption. We conclude that total flavonoids and proanthocyanidins do not have strong protective effects in either EAC or ESCC. Some protective effects were evident in flavonoid subclasses and population subgroups. In white men, foods rich in anthocyanidins may have chemopreventive effects in EAC and those rich in isoflavonoids may do so in ESCC. PMID- 19444906 TI - Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk. AB - Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20-1.00] and 0.26 (95% CI: 0.10-0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. PMID- 19444907 TI - Dietary and stored iron as predictors of breast cancer risk: A nested case control study in Shanghai. AB - Increases in risk of breast cancer in successive generations of migrants to the United States from China and rapid temporal changes in incidence rates in China following social and economic changes clearly implicate environmental factors in the etiology of this disease. Case-control and cohort studies have provided evidence that at least some of these factors may be dietary. Iron, an essential element necessary for cell function, has also been demonstrated to have potential carcinogenic and co-carcinogenic activities. Iron overload, which was previously uncommon, has become more common in the United States than iron deficiency and may be increasing in China concurrently with dramatic increases in meat consumption. A case-control study nested in a cohort of women in Shanghai, China, was conducted to evaluate possible associations between risk of proliferative and nonproliferative fibrocystic changes as well as breast cancer and dietary iron intake and plasma ferritin levels. Plasma ferritin levels and reported dietary iron intake were compared in 346 women with fibrocystic changes, 248 breast cancer cases and 1,040 controls. Increasing ferritin levels were significantly associated with increasing risk of nonproliferative fibrocystic changes (OR: 2.51, 95% CI: 1.16-5.45, p trend = 0.04). Similar, but weaker, trends were observed for proliferative changes and for breast cancer. Risk of breast cancer relative to the risk of fibrocystic changes was associated with dietary iron intake in women with nonproliferative fibrocystic changes (OR: 2.63, 95% CI: 1.04 6.68, p = 0.02). In conclusion, this study finds significant associations between iron (stored and dietary) and fibrocystic disease and breast cancer. PMID- 19444908 TI - Allorestricted T lymphocytes with a high avidity T-cell receptor towards NY-ESO-1 have potent anti-tumor activity. AB - The cancer-testis antigen NY-ESO-1 has been targeted as a tumor-associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T-cell-based therapy is the induction of T cells capable of recognizing the NY-ESO-1-expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY-ESO-1(157-165) epitope known to be naturally presented with HLA-A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY-ESO-1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA-A2-positive, NY-ESO-1 expressing tumor cell lines derived from different origins, e.g. melanoma and myeloma. The allorestricted NY-ESO-1-specific T lymphocytes displayed TCRs with the highest avidity and best anti-tumor recognition activity. TCRs derived from allorestricted, NY-ESO-1-specific T cells may be useful reagents for redirecting primary T cells by TCR gene transfer and, therefore, may facilitate the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of NY-ESO-1-expressing hematological malignancies and solid tumors. PMID- 19444909 TI - Life course sun exposure and risk of prostate cancer: population-based nested case-control study and meta-analysis. AB - There is currently no means of primary prevention for prostate cancer. Increased exposure to ultraviolet-radiation may be protective, but the literature is inconclusive. We investigated associations of life course exposure to sunlight with prostate cancer. The study design was a UK-wide nested case-control study, based on 1,020 prostate specific antigen-detected cases and 5,044 matched population controls and a systematic review with meta-analysis. Men with olive/brown skin (OR = 1.47; 95% CI: 1.00 to 2.17), men who burnt rarely/never (OR = 1.11; 0.95 to 1.29) and men with the lowest levels of intense sun exposure in the 2 years prior to diagnosis (OR = 1.24; 1.03 to 1.50) had an increased prostate cancer risk. However, amongst men with prostate cancer, spending less time outside was associated with a reduced risk of advanced cancer (OR = 0.49; 0.27 to 0.89) and high Gleason grade (OR = 0.62; 0.43 to 0.91), and men who burnt rarely/never had a reduced risk of advanced cancer (OR = 0.71; 0.47 to 1.08). The meta-analysis provided weak evidence that men with the lowest (versus highest) sunlight exposure had an increased prostate cancer risk (4 studies, random effects pooled relative risk = 1.13; 0.98 to 1.29) and higher advanced or fatal prostate cancer risk (6 studies, random-effects pooled relative risk = 1.14; 0.98 to 1.33). Our data and meta-analyses provide limited support for the hypothesis that increased exposure to sunlight may reduce prostate cancer risk. The findings warrant further investigation because of their implications for vitamin D chemoprevention trials. PMID- 19444910 TI - Gene expression profiling of alpha-radiation-induced rat osteosarcomas: identification of dysregulated genes involved in radiation-induced tumorigenesis of bone. AB - To better understand the molecular basis of radiation-induced osteosarcoma (OS), we performed global gene expression profiling of rat OS tumors induced by the bone-seeking alpha emitter (238)Pu, and the expression profiles were compared with those of normal osteoblasts (OB). The expressions of 72 genes were significantly differentially expressed in the tumors related to OB. These included genes involved in the cell adhesion (e.g., Podxl, Col18a1, Cd93, Emcn and Vcl), differentiation, developmental processes (e.g., Hhex, Gata2, P2ry6, P2rx5, Cited2, Osmr and Igsf10), tumor-suppressor function (e.g., Nme3, Blcap and Rrm1), Src tyrosine kinase signaling (e.g., Hck, Shf, Arhgap29, Cttn and Akap12), and Wnt/beta-catenin signaling (e.g., Fzd6, Lzic, Dkk3 and Ctnna1) pathways. Expression changes of several genes were validated by quantitative real-time RT PCR analysis. Notably, all of the identified genes involved in the Wnt/beta catenin signaling pathway were known or proposed to be negative regulators of this pathway and were downregulated in the tumors, suggesting the activation of beta-catenin in radiation-induced OS. By using immunohistochemical and immunoblot analyses, constitutive activation of the Wnt/beta-catenin signaling pathway in the tumors was confirmed by observing nuclear and/or cytoplasmic localization of beta-catenin and a decrease in its inactive (phosphorylated) form. Furthermore, we found a significant reduction in the levels of glycogen synthase kinase 3beta (GSK-3beta) protein in the tumors relative to OB. Taken together, these findings provide new insights into the molecular basis of radiation-induced OS. PMID- 19444911 TI - Salivary acetaldehyde increase due to alcohol-containing mouthwash use: a risk factor for oral cancer. AB - Increasing evidence suggests that acetaldehyde, the first and genotoxic metabolite of ethanol, mediates the carcinogenicity of alcoholic beverages. Ethanol is also contained in a number of ready-to-use mouthwashes typically between 5 and 27% vol. An increased risk of oral cancer has been discussed for users of such mouthwashes; however, epidemiological evidence had remained inconclusive. This study is the first to investigate acetaldehyde levels in saliva after use of alcohol-containing mouthwashes. Ready-to-use mouthwashes and mouthrinses (n = 13) were rinsed in the mouth by healthy, nonsmoking volunteers (n = 4) as intended by the manufacturers (20 ml for 30 sec). Saliva was collected at 0.5, 2, 5 and 10 min after mouthwash use and analyzed using headspace gas chromatography. The acetaldehyde content in the saliva was 41 +/- 15 microM, range 9-85 microM (0.5 min), 52 +/- 14 microM, range 11-105 microM (2 min), 32 +/ 7 microM, range 9-67 microM (5 min) and 15 +/- 7 microM, range 0-37 microM (10 min). The contents were significantly above endogenous levels and corresponding to concentrations normally found after alcoholic beverage consumption. A twice daily use of alcohol-containing mouthwashes leads to a systemic acetaldehyde exposure of 0.26 microg/kg bodyweight/day on average, which corresponds to a lifetime cancer risk of 3E-6. The margin of exposure was calculated to be 217,604, which would be seen as a low public health concern. However, the local acetaldehyde contents in the saliva are reaching concentrations associated with DNA adduct formation and sister chromatid exchange in vitro, so that concerns for local carcinogenic effects in the oral cavity remain. PMID- 19444912 TI - APM2 is a novel mediator of cisplatin resistance in a variety of cancer cell types regardless of p53 or MMR status. AB - Cisplatin is one of the most widely used chemotherapeutics in the world today. Unfortunately, chemoresistance often develops hindering the effectiveness of the drug. Mismatch-repair (MMR) and p53 have previously been shown to be important determinants of cisplatin resistance and can contribute to cisplatin resistance clinically. Here, we have used cDNA microarray to identify several genes as up or downregulated in a previously described, cisplatin resistant, clone of the HCT116 cell line (HCT116-K). On follow-up, one gene, APM2, was found to promote cisplatin resistance when overexpressed in sensitive HCT116 clones. Furthermore, silencing APM2 in a panel of cell lines encompassing all combinations of p53 status and MMR proficiency (HCT116-K, HCT116, SW620, MCF7, PC-3 and OV2008) resulted in sensitization regardless of these 2 factors. In addition, silencing APM2 stably using shRNA also resulted in the sensitization of cells to cisplatin. More importantly, cisplatin inhibited the growth of APM2 silenced tumor xenografts (HCT116-K or OV2008 cells) significantly better than it inhibited the growth of xenografts carrying nontargeting control shRNAs. These findings represent a novel strategy that could be exploited to overcome cisplatin resistance in patients regardless of p53 status or ability to perform MMR. PMID- 19444913 TI - Common immune-related risk factors and incident non-Hodgkin lymphoma: the multiethnic cohort. AB - Severe immune dysfunction is an established risk factor of lymphoma, but the role of moderate alterations of immunity is not clear and prospective investigations are needed. We examined several immune-related disorders and medications in relation to non-Hodgkin lymphoma (NHL) in the Multiethnic Cohort. Over 215,000 subjects of African American, Caucasian, Japanese American, Latino and Native Hawaiian ancestry aged 45-75 years completed a questionnaire, including information on medical history, in 1993-1996. After exclusions, we performed Cox regression among 193,050 cohort members including 939 incident NHL cases while adjusting for sex, age, ethnicity, education, body mass index and alcohol intake. Self-reported diabetes was not associated with NHL overall, but was positively associated with risk among Japanese Americans [hazard ratio (HR) = 1.55; 95% confidence interval (CI): 1.10-2.17]. Participants with a history of blood transfusion were at increased risk with HR = 1.39 (95% CI: 1.06-1.84) in men and HR = 1.22 (95% CI: 0.94-1.58) in women, especially for the diffuse large B-cell lymphoma subtype. History of asthma or other allergies was associated with elevated risk only among Latinos (HR = 1.46; 95% CI: 1.07-2.00) who also showed a significant relation between current use of antihistamines and NHL (HR = 1.80; 95% CI: 1.09-2.97). Use of nonsteroidal anti-inflammatory drugs was not associated with NHL. Our findings from this large prospective study support a moderate risk for NHL related to blood transfusions, current long-term antihistamine use and diabetes, but the associations were limited to certain ethnic groups and require further replications. PMID- 19444915 TI - XRCC1 gene polymorphisms and esophageal squamous cell carcinoma risk in Chinese population: A meta-analysis of case-control studies. AB - Two non-synonymous polymorphisms Arg194Trp and Arg399Gln in the DNA-base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been implicated in risk for esophageal cancer. However, the results from different studies remain controversial. The present meta-analysis of literatures was performed to clarify these associations in Chinese population. A comprehensive literature search was conducted to identify all case-control studies of XRCC1 polymorphisms Arg194Trp and Arg399Gln and risk for esophageal squamous cell carcinoma (ESCC). A total of 9 eligible studies, including 1,538 ESCC cases and 2,472 controls, were identified to the meta-analysis. The odds ratio (OR) for the variant homozygous genotype Trp/Trp of the Arg194Trp polymorphism, compared with the wild-type homozygote Arg/Arg, was 1.59 (p = 0.0007), with 95% confidence interval (95% CI) 1.22-2.09, for ESCC risk without between-study heterogeneity. However, there was no statistically significant associations of ESCC risk in the dominant model Arg/Trp+Trp/Trp (OR 0.97; 95% CI 0.84-1.12; p = 0.69) and heterozygous genotype Arg/Trp (OR 0.90; 95% CI 0.77-1.04; p = 0.16) when comparing with wild-type genotype Arg/Arg. For Arg399Gln, there was no effect in dominant modeling (Arg/Gln+Gln/Gln vs. Arg/Arg: OR 0.92; 95% CI 0.80-1.06; p = 0.25), and the variant Gln/Gln homozygote was not associated with ESCC risk (OR 1.29; 95% CI 0.79-2.10; p = 0.31), either. In conclusion, Arg194Trp genetic polymorphism may be associated with an increased risk for developing ESCC and a study with the larger sample size is needed to further evaluate gene-environment interaction on XRCC1 polymorphisms and ESCC risk. PMID- 19444914 TI - Posttranslational regulation of Myc by promyelocytic leukemia zinc finger protein. AB - The promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, induces cellular resistance to oncogenic transformation by diverse oncoproteins. Two point mutants of PLZF that have lost the antioncogenic activity of the wild-type protein are oncogenic in chicken embryo fibroblasts; this activity is correlated with differential effects on Myc. Wild-type PLZF represses Myc transcription without affecting total Myc protein levels and reduces the levels of phosphorylated Myc. The PLZF mutants do not alter Myc transcription or protein expression but increase the levels of phosphorylated Myc. These modifications of Myc are correlated with PLZF-induced changes in Akt and the mitogen-activated protein kinase (MAPK) pathway. Wild-type PLZF downregulates the MAPK pathway and activates Akt, resulting in reduced phosphorylation on serine 62 of Myc by Erk and on threonine 58 by glycogen synthase kinase 3beta. The mutants fail to activate Akt and only slightly downregulate phospho-Erk. We postulate that the 2 PLZF mutants are oncogenic, because they function as dominant negatives of wild-type PLZF, enhancing Myc phosphorylation and increasing Myc transcriptional and oncogenic activity. In support of this suggestion, a specific inhibitor of Myc is able to revert the transformed phenotype of PLZF mutant expressing cells. PMID- 19444916 TI - Cancer incidence and risk factors after solid organ transplantation. AB - Iatrogenic immunosuppression is a unique setting for investigating immune-related mechanisms of carcinogenesis. Solid organ transplant recipients have a 3-fold excess risk of cancer relative to the age- and sex-matched general population. Population-based studies utilizing cancer registry records indicate that a wide range of cancers, mostly those with a viral etiology, occur at excess rates. To date, cancer risk has predominantly been examined in adult kidney transplant recipients in Western countries. It is yet to be established whether a similar incidence profile exists in the long-term for other solid organ, pediatric and non-Western transplant recipients. The cancer incidence profile before and after kidney transplantation strongly suggests a relatively minor contribution by both preexisting cancer risk factors and the conditions underlying end-stage kidney disease, and points to a causal role for immunosuppression. Within-cohort risk factor analyses have largely been performed on cohorts with voluntary cancer notification, and very few have incorporated biomarkers of the level of immunosuppression, the current receipt of immunosuppressive agents, or genetic risk factors. Because of their markedly high risk of certain cancers, findings from comprehensive studies in transplant recipients have the potential to raise new avenues for investigation into causal mechanisms and preventive measures against immune-related and infectious causes of cancer. PMID- 19444917 TI - Cancer-induced bone loss and associated pain-related behavior is reduced by risedronate but not its phosphonocarboxylate analog NE-10790. AB - Prostate, breast and lung cancers readily develop bone metastases which lead to fractures, hypercalcemia and pain. Malignant growth in the bones depends on osteoclast-mediated bone resorption and in this regard bisphosphonate compounds, which have high-bone affinity and inhibit osteoclast activity, have been found to alleviate bone cancer symptoms. In this study, the bisphosphonate risedronate and its phosphonocarboxylate derivative NE-10790 was tested in a murine bone cancer pain model. Risedronate decreased bone cancer-related bone destruction and pain related behavior and decreased the spinal expression of glial fibrillary acidic protein, whereas NE-10790 had no effect on these parameters. Furthermore, risedronate but not NE-10790 induced dose-dependent toxicity in NCTC-2472 cells in vitro. Furthermore, the direct toxic effect of risedronate on tumor cells observed in vitro opens the possibility that a direct toxic effect on tumor cells may also be present in vivo and be related to the efficacy of bisphosphonate compounds. In conclusion, these results suggest that risedronate treatment may lead to an increased life quality, in patient suffering from bone cancer, in terms of decreased osteolysis and pain, and merits further study. PMID- 19444918 TI - Prion protein ablation increases cellular aggregation and embolization contributing to mechanisms of metastasis. AB - Cellular Prion Protein (PrP(C)) is a cell surface protein highly expressed in the nervous system, and to a lesser extent in other tissues. PrP(C) binds to the extracellular matrix laminin and vitronectin, to mediate cell adhesion and differentiation. Herein, we investigate how PrP(C) expression modulates the aggressiveness of transformed cells. Mesenchymal embryonic cells (MEC) from wild type (Prnp(+/+)) and PrP(C)-null (Prnp(0/0)) mice were immortalized and transformed by co-expression of ras and myc. These cells presented similar growth rates and tumor formation in vivo. When injected in the tail vein, Prnp(0/0)ras/myc cells exhibited increased lung colonization compared with Prnp(+/+)ras/myc cells. Additionally, Prnp(0/0)ras/myc cells form more aggregates with blood components than Prnp(+/+)ras/myc cells, facilitating the arrest of Prnp(0/0)ras/myc cells in the lung vasculature. Integrin alpha(v)beta(3) is more expressed and activated in MEC and in transformed Prnp(0/0) cells than in the respective Prnp(+/+) cells. The blocking of integrin alpha(v)beta(3) by RGD peptide reduces lung colonization in transformed Prnp(0/0) cells to similar levels of those presented by transformed Prnp(+/+) cells. Our data indicate that PrP(C) negatively modulates the expression and activation of integrin alpha(v)beta(3) resulting in a more aggressive phenotype. These results indicate that PrP(C) may have main implications in modulating metastasis formation. PMID- 19444919 TI - Cod liver oil, other dietary supplements and survival among cancer patients with solid tumours. AB - The effect of various dietary supplements on chronic diseases and mortality has been widely studied, but few convincing results have emerged from studies in well nourished populations. In Norway, both cod liver oil and other dietary supplements are frequently used. In the Norwegian Women and Cancer cohort study, we explored if supplement use before diagnosis affected survival of cancer patients with solid tumours. We performed Cox proportional hazards analyses, adjusting for age at diagnosis, smoking and stage. Cod liver oil was the most frequently used dietary supplement, followed by multivitamins and minerals. Whole year daily use of cod liver oil was associated with lower risk of death in patients with solid tumours [RR = 0.77 (95% CI 0.61-0.97)] and in lung cancer patients [RR=0.56 (95% CI 0.34-0.92)]. Also daily and occasional use of other dietary supplements decreased the risk of death among lung cancer patients [RR = 0.70 (95% CI 0.49-0.99) and 0.55 (95% CI 0.31-0.97)]. More research is needed to clarify the association; meanwhile adjustment for dietary supplement use should be performed in survival analyses of lung cancer patients. PMID- 19444920 TI - Fusion protein of adenovirus E4orf4 and human epidermal growth factor inhibits tumor cell growth. AB - Adenovirus early region 4 open reading frame 4 (E4orf4) protein is a novel cell death factor that selectively induces apoptosis in cancer cells. This study evaluated tumor inhibitory effects of a protein made by fusion E4orf4 and human epidermal growth factor (EGF). EGF was used to ensure the selective targeting of EGF receptor (EGFR)-overexpressing tumor cells. Results showed that EGF-E4orf4 stimulated EGFR phosphorylation in a time- and dose-dependent manner. Confocal microscopy analysis showed both EGF-E4orf4 and EGF could be internalized via EGFR but they had different intercellular trafficking pathways. In vitro study showed that EGF-E4orf4 significantly inhibited the proliferation of BGC823 and in vivo study showed EGF-E4orf4 suppressed tumor growth in a dose-dependent fashion with an inhibition rate of 79% for MDA-MB-231 and 49% for BGC 823 (p < 0.05). No toxic effects were observed in the nude mice with a dose as high as 10 mg/kg of EGF E4orf4. These results indicated that EGF-E4orf4 could be a potential drug for cancer therapy. PMID- 19444921 TI - Perilla leaf extract ameliorates obesity and dyslipidemia induced by high-fat diet. AB - The objective of this study was to evaluate the antiobesity effect of perilla leaf extract (PLE) in animal models of high fat diet-induced obesity. C57BL/6J mice were fed a standard diet (STD) or high fat diet (HFD) for 5 weeks to induce obesity. The experimental groups were four groups with 10 mice per group and fed for 4 weeks: a STD group, a HFD group, a HFD containing 1% PLE (HFD+PLE 1%) group and a HFD containing 3% PLE (HFD+PLE 3%) group. The PLE supplementation significantly decreased body weight gain, food efficiency ratio, and relative liver and epididymal fat mass compared with those of the HFD group. Also, triglyceride, total cholesterol and LDL levels in the plasma were significantly reduced by PLE supplementation compared with the HFD group. Histological changes in the liver of the PLE supplemented group showed an inhibition of steatosis induced by HFD. Furthermore, PLE reversed the HFD induced changes in the expression patterns of epididymal adipose tissue genes: acetyl CoA carboxylase (ACC), glycerol-3-phosphate dehydrogenase (GPDH) and peroxisome proliferator activated receptor gamma (PPARgamma). These results suggest that the PLE supplement suppressed body weight gain and improved the blood lipid profiling, in part by down-regulating adipogenic transcription factor and other specific target genes. PMID- 19444922 TI - Aflatoxin B1 misregulates the activity of serine proteases: possible implications in the toxicity of some mycotoxin. AB - Aflatoxins are highly hazardous contaminants of common food and feed. Aflatoxin B1 in particular, the most predominant among aflatoxins, was thoroughly demonstrated to be highly toxic, mutagenic, teratogenic and carcinogenic in many animal species. Besides its established targets and effects, this work investigates on the possible direct interaction between aflatoxin B1 and three major serine proteases, namely elastase, thrombin and trypsin. These proteases belongs to a class of structurally and functionally related proteins pivotal in both direct and indirect regulation of a number of cellular events. Additionally, several pathological processes, including cancer, inflammatory processes and thrombosis, rely upon the subtle equilibrium between these enzymes and their potential modulators: in fact, their misregulation, caused by foreign molecules, could facilitate (or be the cause for) the occurrence of these pathologies. Our results provide the evidence for a reversible binding between AFB1 and these enzymes, likely to have profound implications in the manifestation of aflatoxicosis. Precisely, the toxin behaved as a moderate competitive inhibitor toward the enzymatic activity of the serine proteases in the low micromolar range. PMID- 19444923 TI - Influence of inorganic and organic iron compounds on parameters of cell growth and survival in human colon cells. AB - Increased risk for development of colon cancer is associated with red meat intake and iron toxicity is discussed for one underlying mechanism. Anyhow, for iron itself only limited evidence is found. In this study, effects of different iron compounds on proliferation of HT29 carcinoma and LT97 adenoma human colon cells were investigated. After treatment of cells with inorganic (ferrous sulfate: FeSO4 and ferric nitrilotriacetate: FeNTA) and organic (hemoglobin and hemin) iron sources (24-72 h), number of cells and metabolic activity were measured. Under normal cell culture conditions, neither iron compound elevated cell growth in either cell line with the exception of FeNTA which induced LT97 cell growth significantly. Distinct inhibition of cell proliferation was measured for organic iron. Serum-free incubation of HT29 cells revealed growth promoting properties of iron under deficiency. Even though organic iron, especially hemin, was a potent growth factor, both substances showed also dose-dependent cytotoxic effects. In conclusion, these data emphasize that not iron itself, but merely organic iron may promote carcinogenic events. Since promotion of proliferation was only detectable under deficiency, cytotoxic properties of organic iron may be of more importance in colon carcinogenesis. PMID- 19444924 TI - Cytotoxicity and mitotic alterations induced by non-genotoxic lithium salts in CHO cells in vitro. AB - Aneugenic compounds are able to cause chromosome missegregation during mitosis which results in aneuploidy in cells that are able to survive. Aneuploidy is considered a key early condition in the progression from a normal cell into a cancerous cell. The possible toxicity of therapeutic lithium has raised concern because lithium salts are currently widely prescribed as an efficient treatment of manic-depressive disorders and numerous undesirable side effects of long-term treatment have been reported to date. We have observed a dose-dependent cytotoxic effect of both Li2CO3 and LiCl in AA8 CHO cells, while no genotoxic damage was detected. Mitotic abnormalities such as multipolar anaphases and lagging chromosomes leading to the presence of micronuclei in the next interphase were frequently observed after treatment with lithium salts. Thus, the effectiveness of both lithium salts to induce alterations in the normal segregation of chromosomes could be ascribed to interference with proteins involved in the organization and/or function of the mitotic apparatus. PMID- 19444925 TI - Mechanistic assessment of peptide reactivity assay to predict skin allergens with Kathon CG isothiazolinones. AB - Assessment of skin sensitization hazard of chemicals currently depends on in vivo methods. Considering the forthcoming European Union ban on in vivo testing of cosmetic/toiletry ingredients, the search for alternative non-animal approaches is an urgent challenge for investigators today. For the skin sensitization end point the concept of protein/peptide haptenation, that could reflect the chemical modification of skin proteins, crucial to form immunogenic structures, has been used to develop in vitro assays to predict the sensitization potential of new chemicals. Using glutathione and nucleophile-containing synthetic peptides we confirmed previously the possibility to screen for skin sensitization potential by measuring peptide depletion following incubation with a set of allergens and non-allergens. In this paper, additionally to our model development work, we performed mechanistic based studies to confirm the peptide reactivity concept under the specific conditions used for haptens in the screening assay as they were somewhat different from the ones expected to happen in vivo. Following the reactivity toward the peptides of 13C labelled MI and MCI, models of true haptens, we showed that the initial step leading to the biological end-point was similar regardless the conditions used even if final adducts could be different. This confirmed the validity of the peptide reactivity concept as well as the choice made to look at peptide depletion rather than at adduct formation. PMID- 19444926 TI - The compensatory responses to upper airway obstruction in normal subjects under propofol anesthesia. AB - Upper airway obstruction during sleep can trigger compensatory neuromuscular responses and/or prolong inspiration in order to maintain adequate minute ventilation. The aim of this study was to investigate the strength of these compensatory responses during upper airway obstruction during propofol anesthesia. We assessed respiratory timing and upper airway responses to decreases in nasal pressure in nine propofol anesthetized normal subjects under condition of decreased (passive) and increased (active) neuromuscular activity. Critical closing pressure (PCRIT) and upstream resistance (RUS) were derived from pressure-flow relationships generated from each condition. The inspiratory duty cycle (IDC), maximum inspiratory flow (V1max) and respiratory rate (f) were determined at two levels of mean inspiratory airflow (VI; mild airflow limitation with VI > or = 150 ml s-1; severe airflow limitation with VI < 150 ml s-1). Compared to the passive condition, PCRIT decreased significantly (5.3 +/- 3.8 cm H2O, p < 0.05) and RUS increased (7.4 cm H2O ml-1 s, p < 0.05) in the active condition. The IDC increased progressively and comparably as decreased in both the passive and active conditions (p < 0.05). These findings imply that distinct compensatory mechanisms govern the modulation of respiratory pattern and pharyngeal patency during periods of airway obstruction under propofol anesthesia. PMID- 19444927 TI - In vitro cytotoxic and immunomodulatory profiling of low molecular weight polyethylenimines for pulmonary application. AB - Polyethylenimines (PEI) are potent non-viral nucleic acid delivery vehicles used for gene delivery and RNA interference (RNAi). For non-invasive pulmonary RNAi therapy the respiratory tissue is an attractive application route, but offers particularly unwanted side-effects like cytotoxicity as well as inflammatory and immune responses. In the current study, we determined the most crucial issues of pulmonary applications for two low molecular weight PEIs in comparison to the well-known lung toxic crystalline silica. Cytotoxic effects and inflammatory responses were evaluated in three murine pulmonary target cell lines, the alveolar epithelial (LA4), the alveolar macrophage (MH-S) and the macrophage monocyte-like (RAW 264.7) cell line. For both PEIs, cytotoxicity was detected most prominently in the alveolar epithelial cells and only at high doses. Cytokine responses, in contrast were observed already at low PEI concentrations and could be divided into three groups, induced (i) by free PEI (IL-6, TNF-alpha, G-CSF), (ii) by PEI/siRNA complexes (CCL2, -5, CXCL1, -10), or (iii) unaffected by either treatment (IL-2, -4,-7, -9, and CCL3). We conclude that even for the respiratory tissue both PEIs represent powerful siRNA delivery tools with reduced cytotoxicity and minor proinflammatory potency. However, in relation to response levels observed upon crystalline silica exposures, some PEI induced proapoptotic and proinflammatory responses might not be considered completely harmless, therefore further in vivo investigations are advisable. PMID- 19444928 TI - T-2 toxin inhibits the differentiation of human monocytes into dendritic cells and macrophages. AB - The aim of this work was to study the in vitro effect of T-2 toxin on human monocyte differentiation into macrophages and dendritic cells. Cytotoxicity of T 2 toxin on monocytes, on monocytes in differentiation process into macrophages or dendritic cells, and on immature dendritic cells and macrophages was evaluated to determine IC50. Monocytes are more sensitive to T-2 toxin than to differentiate cells. IC50 were equal to 0.11 nM for monocyte, to 45 and 30 nM for monocyte during differentiation process for 24 and 48 h of incubation, respectively, to 38 and 20 nM for immature dendritic cells after 24 and 48 h of incubation, and to 22 and 20 nM for macrophages after 24 and 48 h of incubation. T-2 toxin effects on monocyte differentiation process into macrophages have been explored: according to phenotypic expressions (CD71, CD14, CD11a, CD80, CD86, HLA-DR and CD64), endocytic capacity, phagocytosis, burst respiratory activity and TNF-alpha secretion. In the presence of 10 nM of T-2 toxin (no cytotoxic concentration), CD71 expression is downregulated compared to control. Endocytosis and phagocytosis capacities are less effective as burst respiratory activity and TNF alpha secretion. Monocyte differentiation process into dendritic cells in the presence of 10 nM T-2 toxin is also markedly disturbed. Expression of CD1a (specific dendritic cells marker) is downregulated while that of CD14 (specific monocyte marker) is upregulated. CD11a, CD80, CD86, HLA-DR and CD64 expressions did not change. These results show that T-2 toxin disturbs human monocytes differentiation process into macrophages and dendritic cells. These results could significantly contribute to immunosuppressive properties of this alimentary toxin. PMID- 19444929 TI - Evaluation of cytotoxic effects and oxidative stress with hydroxyapatite dispersions of different physicochemical properties in rat NR8383 cells and primary macrophages. AB - Enhanced cytotoxicity and oxidative stress through reactive oxygen species (ROS) formation are discussed as relevant parameters regarding potential hazardous properties of nanomaterials. In this study, the biocompatibility of five hydroxyapatite materials of different size and morphology, i.e., nano/needle shaped (HA-NN), nano/rod-like (HA-NR), nano/plate-like (HA-NP), fine/dull needle shaped (HA-FN), and a hydroxyapatite-protein-composite (HPC), was investigated in rat NR8383 and primary alveolar macrophages. Lipopolysaccharide (LPS) and DQ12 quartz served as positive controls. In the water-soluble tetrazolium salt 1 (WST 1) and lactate dehydrogenase (LDH) assays with NR8383 cells, no cytotoxicity was observed for HPC and the pure hydroxyapatite samples up to 3000 microg/ml, while HA-FN showed a significant effect at the highest dose in the LDH assay. In primary cells, no cytotoxicity was observed with all samples up to 300 microg/ml. ROS generation measured by electron paramagnetic resonance (EPR) technique was significantly enhanced with HA-NN and HPC in NR8383 cells. No effect was detected in primary cells, which are considered more relevant to physiological conditions. All hydroxyapatites elicited TNF-alpha release from the NR8383 cells, but with significantly lower potency than DQ12 quartz and LPS. In conclusion, combined findings in both cell types support a good biocompatibility of the pure hydroxyapatite samples as well as of the hydroxyapatite-protein-composite. PMID- 19444930 TI - Exposure of the murine RAW 264.7 macrophage cell line to hydroxyapatite dispersions of various composition and morphology: assessment of cytotoxicity, activation and stress response. AB - Cellular stress responses leading to the release of cytotoxic mediators are discussed as indicators of the hazard presented by particles, and in particular ultrafine particles or nanomaterials. The present study was designed to investigate effects of the following materials on RAW 264.7 macrophages: three hydroxyapatite materials of various morphologies, i.e., nano-sized with rod-like (HA-NR), plate-like (HA-NP) or needle-shaped (HA-NN) morphology, and an irregularly shaped composite of hydroxyapatite and protein (HPC) in the low micrometer range. Concentrations of 50, 100, 500, 1000 and 5000 microg/ml were applied and cells were analyzed for viability (XTT-test), cytokine production (TNF-alpha) and induction of nitric oxide (NO) after 18 and 42 h. DQ12 quartz and lipopolysaccharide (LPS) served as positive controls. Up to concentrations of 500 microg/ml, cell viability was not considerably impaired by the test samples at both timepoints. Overall, viability was about one order of magnitude higher than with comparable concentrations of quartz. TNF-alpha release was induced in all samples after 18 h, with HA-NR showing the most pronounced induction at 100 microg/ml, still clearly below the LPS signal. No or little induction was observed after 42 h. NO production was low after 18 and 42 h. The results support the conclusion that the tested materials exhibit good biocompatibility and are safe to use. PMID- 19444931 TI - In vitro selection and efficacy of topical skin protectants against the nerve agent VX. AB - Against highly toxic chemicals that are quickly absorbed in the skin, topical formulations could adequately complement specific protective suits and equipments. In this work, we evaluated in vitro and compared the skin protection efficacy against the nerve agent VX of four different topical formulations: oil in-water and water-in-oil emulsions, a perfluorinated-based cream and a hydrogel. Semi-permeable silicone membrane, pig-ear and human abdominal split-thickness skin samples mounted in diffusion cells were compared as in vitro permeation tests. The results showed that silicone membrane could be used instead of skin samples to screen for potentially effective formulations. However, the results indicated that due to potentially significant interactions between formulations and skin, relevant ranking of formulations according to their protective efficacy could require tests with skin samples. The main phase of emulsions, water or oil, was not found to be critical for skin protective efficacy against VX. Instead, specific film-forming ingredients such as perfluorinated-based polymers and silicones could significantly affect the skin protective efficacy of formulations. We showed that a hydrogel containing specific hydrophilic polymers was by far the most effective of the formulations evaluated against VX skin permeation in vitro. PMID- 19444932 TI - The antioxidant glutathione in the fish cell lines EPC and BCF-2: response to model pro-oxidants as measured by three different fluorescent dyes. AB - Reduced glutathione (GSH) protects cells against injury by oxidative stress and maintains a range of vital functions. In vitro cell cultures have been used as experimental models to study the role of GSH in chemical toxicity in mammals; however, this approach has been rarely used with fish cells to date. The present study aimed to evaluate sensitivity and specificity of three fluorescent dyes for measuring pro-oxidant-induced changes of GSH contents in fish cell lines: monochlorobimane (mBCl), 5-chloromethylfluorescein diacetate (CMFDA) and 7-amino 4-chloromethylcoumarin (CMAC-blue). Two cell lines were studied, the EPC line established from a skin tumour of carp Cyprinus carpio, and BF-2 cells established from fins of bluegill sunfish Lepomis macrochirus. The cells were exposed for 6 and 24 h to low cytotoxic concentrations of pro-oxidants including hydrogen peroxide, paraquat (PQ), copper and the GSH synthesis inhibitor, L buthionine-SR-sulfoximine (BSO). The results indicate moderate differences in the GSH response between EPC and BF-2 cells, but distinct differences in the magnitude of the GSH response for the four pro-oxidants. Further, the choice of GSH dye can critically affect the results, with CMFDA appearing to be less specific for GSH than mBCl and CMAC-blue. PMID- 19444934 TI - The role of testosterone in the metabolic syndrome: a review. AB - Over the last three decades it has become apparent that testosterone plays a significant role in the maintenance of bone and muscle mass, in erythropoiesis, and in mental functions. But testosterone is also a key player in glucose homeostasis and lipid metabolism. The metabolic syndrome is a clustering of risk factors predisposing to late onset diabetes mellitus, atherosclerosis and cardiovascular morbidity and mortality. The main components of the syndrome are visceral obesity, glucose intolerance, raised blood pressure and dyslipidaemia (elevated triglycerides, low levels of high-density lipoprotein cholesterol),and a pro-inflammatory and thrombogenic state. Cross-sectional epidemiological studies have reported a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin(SHBG) predict a higher incidence of the metabolic syndrome. There is now evidence to argue that hypotestosteronaemia should be an element in the definition of the metabolic syndrome. Administration of testosterone to hypogonadal men reverses the unfavorable risk profile for the development of diabetes and atherosclerosis. Testosterone should be regarded as a pivotal hormone for men's health. PMID- 19444935 TI - Intracrinology of sex steroids in ductal carcinoma in situ (DCIS) of human breast: comparison to invasive ductal carcinoma (IDC) and non-neoplastic breast. AB - Sex steroids, including those through intratumoral production in an intracrine manner, play important roles in the development of invasive ductal carcinoma (IDC) of human breast, but biological and/or clinical significance of intratumoral production and metabolism of sex steroids, have remained largely unknown in the ductal carcinoma in situ (DCIS), an important precursor lesion of IDC. We recently examined tissue concentration of estradiol and 5 dihydrotestosterone using liquid chromatography/electrospray tandem mass spectrometry in non-neoplastic breast, DCIS, and IDC tissues. Results of our study suggest that intratumoral concentrations of both estradiol and 5 dihydrotestosterone are increased in DCIS, which is considered due to intratumoral production of these sex steroids. Therefore, both estradiol and 5 dehydrotestosterone are considered to play important roles in the development of DCIS as well as IDC through an intracrine manner. Intratumoral metabolism and synthesis of estrogens and androgens as a result of the interactions of various enzymes are therefore also considered to play important roles in hormone dependent DCIS. Aromatase, which is one of the estrogen synthesis enzymes, plays an important role in intratumoral production of estrogen but other enzymes also play pivotal roles in intratumoral estrogen and androgen productions in human breast carcinoma. Therefore, in this review, we also focused on the importance of key intracrine enzymes such as 17beta-hydroxysteroid dehydrogenases, steroid sulfatase,estrogen sulfotransferase, 5alpha-reductases in both IDC and DCIS. PMID- 19444933 TI - Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells. AB - Resistance to endocrine therapies, whether de novo or acquired, remains a major limitation in the ability to cure many tumors that express detectable levels of the estrogen receptor alpha protein (ER). While several resistance phenotypes have been described, endocrine unresponsiveness in the context of therapy-induced tumor growth appears to be the most prevalent. The signaling that regulates endocrine resistant phenotypes is poorly understood but it involves a complex signaling network with a topology that includes redundant and degenerative features. To be relevant to clinical outcomes, the most pertinent features of this network are those that ultimately affect the endocrine-regulated components of the cell fate and cell proliferation machineries. We show that autophagy, as supported by the endocrine regulation of monodansylcadaverine staining, increased LC3 cleavage, and reduced expression of p62/SQSTM1, plays an important role in breast cancer cells responding to endocrine therapy. We further show that the cell fate machinery includes both apoptotic and autophagic functions that are potentially regulated through integrated signaling that flows through key members of the BCL2 gene family and beclin-1 (BECN1). This signaling links cellular functions in mitochondria and endoplasmic reticulum, the latter as a consequence of induction of the unfolded protein response. We have taken a seed-gene approach to begin extracting critical nodes and edges that represent central signaling events in the endocrine regulation of apoptosis and autophagy. Three seed nodes were identified from global gene or protein expression analyses and supported by subsequent functional studies that established their abilities to affect cell fate. The seed nodes of nuclear factor kappa B (NFkappaB), interferon regulatory factor-1 (IRF1), and X-box binding protein-1 (XBP1)are linked by directional edges that support signal flow through a preliminary network that is grown to include key regulators of their individual function: NEMO/IKKgamma, nucleophosmin and ER respectively. Signaling proceeds through BCL2 gene family members and BECN1 ultimately to regulate cell fate. PMID- 19444936 TI - Recent advances in 17beta-hydroxysteroid dehydrogenases. AB - The metabolism of steroids at position 17 is catalysed by a growing number of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs). Several human diseases like breast or prostate cancer, endometriosis,metabolic syndrome and mental diseases were associated with dysfunctions of 17beta-HSDs, which consequently became drug targets. This review will focus on identities of 17beta-HSDs and recent advances in analyses of their physiological roles in steroid and lipid metabolism. It will also address the potential of metabolomics in drug development. PMID- 19444937 TI - Vitamin D and aging. AB - Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1alpha-hydroxylase activity seems to be a cause of the premature aging. In several studies, we have described that a complete or partial lack of vitamin D action (VDR-/- mice and CYP27B1-/-) show almost similar phenotype as FGF23-/- or Klotho-/- mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1-/- mice do not show alopecia nor balance deficit, which might be apoVDR dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena. Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging related chronic diseases more directly than calcitriol. Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-kappaB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer. Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given. PMID- 19444938 TI - Seasonal variation of 1,25-dihydroxyvitamin D and its association with body mass index and age. AB - Under most normal conditions the serum level of 1,25-dihydroxyvitamin D is constant throughout the year, due to tight biochemical regulation. In contrast to this, the level of 25-hydroxyvitamin D is variable through the year, being largest in late summer, due to photosynthesis in the skin. The vitamin D status is usually assessed by measuring the level of the latter vitamin D derivative, rather than that of the presumably most active derivative 1,25(OH)2 vitamin D.We here show that for persons with a high body mass index (BMI) there is a significant seasonal variation, not only of 25(OH) vitamin D, but also of 1,25(OH)2 vitamin D. The variation seems to be largest for those with the poorest vitamin D status. Furthermore, there seems to be a correlation between the levels of the two vitamin D metabolites, indicating that the regulation of 1,25(OH)2 vitamin D is not always tight, notably in persons with high BMI. PMID- 19444939 TI - Quantitative plasma DNA analysis in Parkinson's disease. AB - Parkinson disease (PD) is a neurodegenerative disease resulting from the loss of the dopaminergic neurons from the substantia nigra pars compacta (SNpc). It is characterized by bradykinesia, rigidity, resting tremor and/or postural instability. The diagnosis of PD is essentially clinical and there is no reliable biological marker to assess its progression. Recently, investigations have been performed on the potential use of circulating cell-free deoxyribonucleic acid (DNA) in the plasma for clinical diagnosis, prognosis and monitoring of human diseases. The aim of this work was to assess the role of free DNA as a biological marker of PD. Forty-two patients with PD (19 men, 23 women) and 20 healthy (7 men, 13 women) subjects were enrolled in this study. Mean +/- SD plasma DNA concentration in PD patients and control subjects were, respectively, 16,487 +/- 16,378 (range: 100-62,034) kilogenomes-equivalents/L and 37,975 +/- 17,832 (range: 15,143-78,783) kilogenomes-equivalents/L. There was a significant difference between control and PD groups (p < 0.001). There was no correlation between plasma DNA levels and demographic or clinical parameters in PD patients. Free DNA does not seem to be a reliable marker of PD progression. Further research is warranted to confirm the present results to have some value as biomarkers in other neurodegenerative diseases. PMID- 19444940 TI - Occipital cortex activation studied with simultaneous recordings of functional transcranial Doppler ultrasound (fTCD) and visual evoked potential (VEP) in cognitively normal human subjects: effect of healthy aging. AB - We evaluated effect of aging, gender and eye (sighting) dominance on relationship between visual evoked flow response (VEFR) and visual evoked potential (VEP), which refers to neurovascular coupling. The VEFR was defined as a percentage increase of the ratio of mean blood flow velocity in the contralateral (according to the side of dominant eye processing) posterior cerebral artery P2 segment to those in ipsilateral middle cerebral artery from the baseline during half-field stimulation. Vasoneural coupling index (CI) was defined as "100 x VEFR/VEP P100 amplitude". Compared to the healthy elderly subjects (n: 19; female/male: 6/13, mean age: 69.7 +/- 7), younger participants (n: 28; female/male: 16/12; mean age: 31.1 +/- 4.7) had significantly higher VEFR for both sides: 18.9 +/- 6.7% versus 11.2 +/- 6.7%, p < 0.001 and 17.3 +/- 7.7% versus 11.8 +/- 5.5%, p: 0.007, for the hemisphere contralateral to dominant and nondominant eye (D and ND side), respectively. Albeit absence of any correlation between their latencies, VEP and VEFR amplitudes were well correlated. However, this was significant only for younger subjects and more evident in D side. The CI was higher in young subjects compared to those in old ones (6.49 +/- 2.79 versus 4.75 +/- 2.35, respectively, p = 0.007). But, this age-related trend remained as borderline when sides were analyzed individually: In the young subjects CI was 5.99 +/- 2.21 and 6.96 +/- 3.22 for D and ND sides, while those were 4.27 +/- 2.60 and 5.19 +/- 2.07 in old ones. This study confirmed diminished visual evoked flow in relation with advancing age, and suggested that "weakened" neurovascular coupling (as evidenced by a decreased VEP and VEFR correlation along with decreased CI) as one of the underlying mechanisms. PMID- 19444941 TI - Localization of COX-1 and COX-2 in the intracranial dura mater of the rat. AB - Primary headaches such as migraine can be aborted by systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs), potentially through the non selective inhibition of cyclooxygenase (COX) activity in the intracranial meninges. In this study we have used single and double labeling immunohistochemistry to examine the distribution of the COX-1 and COX-2 isoforms in the intracranial dura mater of the rat and identify cell types that express them. COX-1 immunoreactivity was found in medium and small dural blood vessels and was co-expressed with the endothelial cell markers vimentin and the endothelial isoform of nitric oxide synthase (ecNOS). COX-1 was also found to be present in most dural mast cells. COX-2 was mainly expressed in ED2-positive resident dural macrophages. Constitutive COX-2 expression was also found in some axonal profiles, many of which were co-labeled with the nociceptor peptide marker CGRP. The findings suggest that NSAIDs may abort headache, at least in part, by inhibiting either neuronal or non-neuronal COX activity in the dura mater. PMID- 19444942 TI - Extrusion of the device: a rare complication of the pacemaker implantation. AB - Skin erosion caused by the pacemaker is widely documented, but the complete extrusion of the device is very rare. We describe the case of a 54-year-old woman who was admitted to hospital because of skin erosion, followed by the complete extrusion of the pacemaker pulse generator out of the subcutaneous pocket. The patient underwent a lead extraction procedure and a new pacemaker, in the contralateral side, was implanted. This case demonstrates that the early stages of skin erosion favoured by the device, if neglected, may cause more serious complications that may require the removal of the hardware. PMID- 19444943 TI - Uncoupling of flow and metabolism by chloral hydrate: a rat in-vivo autoradiographic study. AB - General anesthesia is commonly used in experiments; however, its effects on cerebral circulation remain unknown. We measured cerebral blood flow using N isopropyl[methyl 1,3-14C] p-iodoamphetamine (14C-IMP) and glucose utilization using 2-[1-14C] deoxy-D-glucose during general anesthesia with pentobarbital and chloral hydrate as well as conscious controls using rats and in-vivo autoradiography. Although a substantial reduction in 14C-IMP uptake was seen in the pentobarbital group, there was a significant increase in the chloral hydrate group. The ratio of cerebral blood flow against cerebral glucose utilization was 0.58 over all regions in the pentobarbital group, similar to the value for the controls, whereas this value was significantly high (over 1.5) in the chloral hydrate group. This decoupling effect should be considered when extrapolating experimental study data to normal physiology. PMID- 19444944 TI - Transgenic mice expressing nerve growth factor in smooth muscle cells. AB - Ectopic expression of nerve growth factor (NGF) in transgenic mice leads to site specific sympathetic sprouting. Smooth muscle cells in the intestines, urinary bladder, and arteries have been shown to express NGF. To address whether enhanced NGF production among these different organ systems stimulates comparable patterns of sympathetic collateral growth, we generated transgenic mice that express NGF under the control of the smooth muscle alpha-actin promoter. In response to elevated levels of NGF protein in the colon, bladder, and arteries/arterioles, sympathetic axons displayed robust sprouting only in the colon and bladder. These data reveal that, unlike most other peripheral tissues, sympathetic efferents in adult mammalian arteries/arterioles do not undergo collateral growth in response to increased levels of smooth muscle-derived NGF. PMID- 19444945 TI - A neurophysiological study into the foundations of tonal harmony. AB - Our findings provide magnetoencephalographic evidence that the mismatch negativity response to two-note chords (dyads) is modulated by a combination of abstract cognitive differences and lower-level differences in the auditory signal. Participants were presented with series of simple-ratio sinusoidal dyads (perfect fourths and perfect fifths) in which the difference between the standard and deviant dyad exhibited an interval change, a shift in pitch space, or both. In addition, the standard-deviant pair of dyads either shared one note or both notes were changed. Only the condition that featured both abstract changes (interval change and pitch-space shift) and two novel notes showed a significantly larger magnetoencephalographic mismatch-negativity response than the other conditions in the right hemisphere. Implications for music and language processing are discussed. PMID- 19444946 TI - Prolonged insula activation during perception of aftertaste. AB - Although a critical component of taste perception, the neural basis of aftertaste perception has yet to be elucidated with neuroimaging. This functional neuroimaging study assessed the temporal dynamics of neural responses to sucrose and aspartame in eight healthy volunteers. Aspartame has a sweetness flavor profile similar to sucrose but a longer temporal profile. Participants underwent functional magnetic resonance imaging while tasting sucrose and aspartame solutions administered through a magnetic resonance imaging compatible delivery device. The insula showed significantly longer activation to aspartame than sucrose, whereas other regions activated by the task (somatosensory cortex, thalamus, amygdala, and basal ganglia) did not show a prolonged response to either tastant. These findings implicate the insula in aftertaste perception. PMID- 19444947 TI - White matter abnormalities and executive function in children with very low birth weight. AB - The aim of this study was to investigate any structural-functional relationship between changes in white matter microstructure seen on diffusion tensor imaging and results of an executive function test in adolescents with very low birth weight (VLBW). Thirty-four VLBW adolescents were examined at 15 years of age. Executive function was assessed by the Wisconsin Card Sorting Test. Diffusion tensor imaging scans were performed at 1.5 T for calculation of individual fractional anisotropy maps. Through a voxel-wise regression analysis, correlations were found between the results on Wisconsin Card Sorting Test and fractional anisotropy values in the left cingulum and both inferior fronto occipital fascicles. We speculate that impairments in executive function in VLBW children may be influenced by disturbed connectivity between posterior brain regions and the prefrontal cortex. PMID- 19444948 TI - Intact point-light walker processing in Williams syndrome: a magnetoencephalography study. AB - Williams syndrome (WS) is a rare genetic disorder that results in profound spatial cognitive deficits. Several behavioral studies have showed that point light walker (PLW) perception is intact in children and adults with WS; however, the neural responses underlying PLW perception in adults with WS have not been fully investigated. In this study,we studied an adult with WS by magnetoencephalography. We introduced a novel experimental technique to extract a neuromagnetic response relating to PLW perception, and then evaluated how this response differed from that in normal adults. The peak amplitude and latency of neuromagnetic responses were within 2 SD of the means among normal adults. PMID- 19444949 TI - Similarities in neural activations of face and Chinese character discrimination. AB - This study compared Chinese participants' visual discrimination of Chinese faces with that of Chinese characters, which are highly similar to faces on a variety of dimensions. Both Chinese faces and characters activated the bilateral middle fusiform with high levels of correlations. These findings suggest that although the expertise systems for faces and written symbols are known to be anatomically differentiated at the later stages of processing to serve face processing or written-symbol-specific processing purposes, they may share similar neural structures in the ventral occipitotemporal cortex at the stages of visual processing. PMID- 19444950 TI - Delayed visual feedback reveals distinct time scales in balance control. AB - We performed an experiment in which we challenged postural stability in 12 healthy subjects by providing artificial delayed visual feedback. A monitor at eye-height presented subjects with a visual representation of the location of their center-of-pressure (COP) and they were instructed to position their COP as accurately as possible on a small target. Visual feedback of the COP was displayed either in real-time, or delayed by 250, 500, 750, or 1000 ms. In a control condition, no visual feedback was provided. As expected, stability increased during real-time visual feedback compared to when feedback was absent. To identify time scales at which postural control during quiet stance takes place we sought to distinguish between different frequencies. Low frequencies, i.e. slow components of postural sway, showed a monotonic increase in sway amplitude with increasing delay, whereas high frequencies, i.e. fast components of postural sway, showed significantly reduced sway amplitude for delays of 500-750 ms compared to the other delay conditions. Low- and high-frequency components of postural sway thus exhibited differential susceptibility to artificial delays, thereby supporting the notion of postural control taking place on two distinct time scales. PMID- 19444951 TI - Reptin52 expression during in vitro neural differentiation of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) give rise to all somatic cell types, including neural cells such as astrocytes, oligodendrocytes and neurons. Commitment of hESC to a neural fate can be achieved via selection and expansion of developing neural stem cells, which, grown into non-adhering colonies called neurospheres, express nestin, a neurofilament marker. Analysis of hESC and hESC-derived neural stem cell nuclear extracts revealed an increased expression of Reptin52 in neurosphere nuclei. The increase in Reptin52 was evident throughout directed neuronal differentiation as assessed by western blotting, quantitative RT-PCR and immunocytochemistry. Reptin52 serves a pivotal regulatory role in nuclear activities such as transcription regulation and histone modification. In that regard, co-immunoprecipitation experiments showed that binding partners of Reptin52 (Pontin52, beta-catenin and ATF-2) associate with this regulatory protein in hESC-derived neuronal precursors. Moreover, expression of two of these proteins (beta-catenin - the end product of the Wnt signaling pathway - and ATF 2) is coordinately regulated with Reptin52. PMID- 19444952 TI - Cystatin C in cerebrospinal fluid as a biomarker of ALS. AB - Amyotrophic lateral sclerosis (ALS) is diagnosed on the basis of progressive symptoms in both the upper and lower motor neurons. Because there are no specific biomarkers for ALS, it is difficult to diagnose this disease in its early stages. Cerebrospinal fluid (CSF) samples were obtained from 14 patients in the early stages of ALS, from 13 with polyneuropathy, and from 16 with other neurological disorders. The concentration of cystatin C in the CSF was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) kit. The concentration of cystatin C in the CSF was significantly lower in ALS patients than in the control subjects who were patients with polyneuropathy or other neurological diseases (patients with ALS, polyneuropathy, and other diseases exhibited 5.5 +/- 0.3, 6.7 +/- 0.4, and 6.9 +/- 0.3 mg/L cystatin C, respectively; ALS patients vs. control subjects: p = 0.014 and ALS patients vs. polyneuropathy patients: p = 0.024). Cystatin C may be a useful biomarker of ALS and can be used to distinguish between ALS and polyneuropathy. PMID- 19444953 TI - Effects of cholinesterase inhibition on brain white matter volume in Alzheimer's disease. AB - Brain white matter volume changes were quantified by using voxel-based morphometry in 26 minimal-to-mild Alzheimer's disease patients receiving cholinesterase inhibitors over 20 weeks. Patients treated with rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, did not show those reductions in white matter volume that were observed in patients treated with acetylcholinesterase-selective agents, donepezil and galantamine. This is the first time that dual cholinesterase inhibition has been shown to influence white matter volume specifically. The findings are consistent with a thesis that dual cholinesterase inhibition may have neuroprotective potential. Attenuated loss of brain volumes and delayed/slower long-term clinical decline in patients treated with agents such as rivastigmine may be due to less extensive white matter damage and loss of corticosubcortical connectivity. PMID- 19444954 TI - Chronic imipramine downregulates cyclic AMP signaling in rat hippocampus. AB - Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are synthesized by adenylate cyclase and guanylyl cyclase and degraded by phosphodiesterases. Antidepressant treatment action is hypothesized to occur through increased cAMP signaling; however, antidepressants are also reported to increase phosphodiesterase-4 expression. We addressed this paradox by systematically studying elements of intracellular signaling in the hippocampus of rats chronically treated with imipramine. We observed decreases in cAMP levels, which were congruent with our findings of increased gene expression for phosphodiesterases and decreased adenylate cyclase. Immunoassay results showed unchanged cGMP and brain-derived neurotrophic factor levels. We conclude that in contrast with the assumption of antidepressant-mediated increases in cAMP levels, longterm imipramine treatment may have the opposite effect, namely decreased hippocampal cAMP. PMID- 19444955 TI - Sensory gating impairments in poor sleepers during presleep wakefulness. AB - The neurocognitive model of insomnia predicts information processing deficits in poor sleepers. There is some evidence for deficits in later cognitive processing, but earlier sensory processing remains to be investigated. Paired-click stimuli were delivered to good and poor sleepers in a single night. P50 amplitude to stimuli provided an index of sensory gating in presleep wake, rapid eye movement sleep and stage 2 sleep. Poor sleepers exhibited sensory gating impairments during wake. For both groups, gating was intact in rapid eye movement sleep but absent in stage 2 sleep. These data show that poor sleepers experience enhanced sensory processing in the waking period before sleep. Further study is needed to explore sensory gating in chronic primary insomnia, sleep maintenance insomnia, and across multiple recording nights. PMID- 19444956 TI - Low susceptibility to inert gases and pressure symptoms in TREK-1-deficient mice. AB - Nervous disorders may occur after an organism is saturated with inert gases, which may alter the lipid bilayer structure, according to their liposolubility coefficient. Increase in the nitrogen partial pressure induces a neurological syndrome called 'nitrogen narcosis'. By contrast, high pressures of helium induce epilepsy, an high-pressure nervous syndrome symptom. On the basis of an analogy with anaesthetic mechanisms, we used TREK-1 knockout mice, earlier described to volatile the anaesthetics resistance. These mice had a higher threshold of resistance to the narcotic effects of nitrogen and to the death after recurrent epileptic seizure induced by high pressure. TREK-1 channels seem to play a key role in modulating the anaesthetic potential of inert gases and in neuroprotection. PMID- 19444957 TI - Prenatal ozone exposure abolishes stress activation of Fos and tyrosine hydroxylase in the nucleus tractus solitarius of adult rat. AB - Ozone (O3) is widely distributed in the environment, with high levels of air pollution. However, very few studies have documented the effects on postnatal development of O3 during pregnancy. The long-term effects of prenatal O3 exposure in rats (0.5 ppm 12 h/day from embryonic day E5 to E20) were evaluated in the adult nucleus tractus solitarius (NTS) regulating respiratory control. Neuronal response was assessed by Fos protein immunolabeling (Fos-IR), and catecholaminergic neuron involvement by tyrosine hydroxylase (TH) labeling (TH IR). Adult offspring were analyzed at baseline and following immobilization stress (one hour, plus two hours' recovery); immunolabeling was observed by confocal microscopy. Prenatal O3 increased the baseline TH gray level per cell (p < 0.001). In contrast, the number of Fos-IR cells, Fos-IR/TH-IR colabeled cells and proportion of TH double-labeled with Fos remained unchanged. After stress, the TH gray level (p < 0.001), number of Fos-IR cells (p < 0.001) and of colabeled Fos-IR/TH-IR cells (p < 0.05) and percentage of colabeled Fos-IR/TH-IR neurons against TH-IR cells (p < 0.05) increased in the control group. In prenatal-O3 rats, immobilization stress abolished these increases and reduced the TH gray level (p < 0.05), indicating that prenatal O3 led to loss of adult NTS reactivity to stress. We conclude that long-lasting sequelae were detected in the offspring beyond the prenatal O3 exposure. Prenatal O3 left a print on the NTS, revealed by stress. Disruption of neuronal plasticity to new challenge might be suggested. PMID- 19444958 TI - Osmolality-induced tuning of action potentials in trigeminal ganglion neurons. AB - The present study explored the effect of anisotonicity on action potential (AP) in cultured trigeminal ganglion (TG) neurons. We demonstrate that the number of evoked APs was increased by both hypo- and hypertonic treatment. Transient Receptor Potential Vanilloid 4 receptor (TRPV4) activator increased the number of APs, but only hypotonic-response was markedly blocked in TRPV4-/- mice. Additionally, inhibition of PKC attenuated hypotonicity-induced increase, whereas antagonism of PKA attenuated hypertonicity-response. We conclude that anisotonicity increases excitability of nociceptors, which might be involved in anisotonicity-induced nociception. The increase of APs by hypo- and hypertonicity is mediated through different receptor and intracellular signaling pathways. PMID- 19444959 TI - Blood pressure assessment in haemodialysis patients: comparison between pre dialysis blood pressure and ambulatory blood pressure measurement. AB - AIM: Hypertension is common in haemodialysis (HD) patients. Determining the most appropriate method of blood pressure (BP) measurement, representative of target organ damage, is still an issue. BP variations between pre- and post-HD treatment, or between on-dialysis day and off-dialysis day, are common. The aim of this study was to examine the possible differences between pre-HD office BP (OBP) levels, inter-HD (iHD) or HDday 24 h ambulatory BP measurement (ABPM) with 48 h ABPM, where the latter was considered the gold standard. METHODS: 163 HD patients were studied. BP was monitored consecutively for 48 h with a Takeda TM2421 device, then sub-analysed into two periods of 24 h: HD and iHD day. An average of 12 sessions pre-HD OBP measurements was determined. RESULTS: OBP significantly overestimates systolic (SBP) and diastolic BP (DBP) when compared with 48 hABPM. SBP and DBP are significantly higher on iHD day than on HD day: 141.2 1 20.8 versus 137.9 1 20.9, and 77.1 1 11.1 versus 76.1 1 10.9 (P < 0.01). No differences of SBP night/day ratio were reported between 48 hABPM and iHD 24 h ABPM or HD 24 h ABPM. The highest correlations were reported between 48 h SBP/DBP with iHD or HD 24 h ABPM (r 2 = 0.95, P < 0.001), while the lowest between 48 h SBP/DBP and OBP (r 2 = 0.40,P < 0.01, r 2 = 0.12, P < 0.01). The narrowest limits of agreement using the Bland and Altman test were reported between 48 h SBP or DBP and 24 h iHD or HD day ABPM. Considering 48 h ABPM, 80.5% of patients had BP higher than the norm, compared with 61.7% of patients in the case of OBP (c2 = 13.28, P < 0.001). The sensibility for detecting hypertension for iHD day 24 h ABPM was 98.4%, with specificity of 90%. The sensibility of 24 h HDday ABPM was 90.3%, with specificity 96.6%. In the case of OBP, sensibility and specificity were considerably lower, that is, 72.6% and 83.3% respectively. CONCLUSION: Significant differences are shown between OBP and 48 h ABPM in the recognition of a hypertensive state. OBP measurement has a lower sensibility and specificity than 24 h ABPM, which remains a valid alternative approach to 48 h ABPM in HD patients. Errors of OBP estimation should be taken into account, with possible negative impact on treatment strategies and epidemiology studies PMID- 19444960 TI - The historical biogeography of the freshwater knifefishes using mitogenomic approaches: a mesozoic origin of the Asian notopterids (Actinopterygii: Osteoglossomorpha). AB - The continental distributions of freshwater fishes in the family Notopteridae (Osteoglossomorpha) across Africa, India, and Southeast Asia constitute a long standing and enigmatic problem of freshwater biogeography. The migrational pathway of the Asian notopterids has been discussed in light of two competing schemes: the first posits recent transcontinental dispersal while the second relies on distributions being shaped by ancient vicariance associated with plate tectonic events. In this study, we determined complete mitochondrial DNA sequences from 10 osteoglossomorph fishes to estimate phylogenetic relationships using partitioned Bayesian and maximum likelihood methods and divergence dates of the family Notopteridae with a partitioned Bayesian approach. We used six species representing the major lineages of the Notopteridae and seven species from the remaining osteoglossomorph families. Fourteen more-derived teleosts, nine basal actinopterygians, two coelacanths, and one shark were used as outgroups. Phylogenetic analyses indicated that the African and Asian notopterids formed a sister group to each other and that these notopterids were a sister to a clade comprising two African families (Mormyridae and Gymnarchidae). Estimated divergence time between the African and Asian notopterids dated back to the early Cretaceous when India-Madagascar separated from the African part of Gondwanaland. Thus, estimated time of divergence based on the molecular evidence is at odds with the recent dispersal model. It can be reconciled with the geological and paleontological evidence to support the vicariance model in which the Asian notopterids diverged from the African notopterids in Gondwanaland and migrated into Eurasia on the Indian subcontinent from the Cretaceous to the Tertiary. However, we could not exclude an alternative explanation that the African and Asian notopterids diverged in Pangea before its complete separation into Laurasia and Gondwanaland, to which these two lineages were later confined, respectively. PMID- 19444961 TI - African Dacus (Diptera: Tephritidae: molecular data and host plant associations do not corroborate morphology based classifications. AB - The genus Dacus Fabricius includes economically important pest fruit flies distributed in the Afrotropical and Indo-Australian regions. Two recent revisions based on morphological characters proposed new and partially discordant classifications synonymizing/revalidating several subgeneric names and forming species groups. Regardless these efforts, the phylogenetic relationships among Dacus species remained largely unresolved mainly because of the difficulties in assigning homologous character states. Therefore we investigated the phylogeny of African Dacus by sequencing 71 representatives of 32 species at two mitochondrial (COI, 16S) and one nuclear (period) gene fragments. Phylogenetic relationships were inferred through Bayesian and Maximum Parsimony methods and hypotheses about the monophyly of Dacus subgenera were tested by Shimodaira-Hasegawa tests. The congruence tests and the analyses of the single gene fragments revealed that the nuclear gene supports similar conclusions as the two mitochondrial genes. Levels of intra- and inter-specific differentiation of Dacus species were highly variable and, in some cases, largely overlapping. The analyses of the concatenated dataset resolved two major bootstrap-supported groups as well as a number of well-supported clades and subclades that often comprised representatives of different subgenera. Additionally, specimens of Dacus humeralis from Eastern and Western African localities formed separate clades, suggesting cryptic differentiation within this taxon. The comparisons between the molecular phylogeny and the morphological classification revealed a number of discrepancies and, in the vast majority of cases, the molecular data were not compatible with the monophyly of the currently recognised subgenera. Conversely, the molecular data showed that Apocynaceae feeders are a monophyletic sister group of species feeding on both Cucurbitaceae and Passifloraceae (these latter being also monophyletic). These results show a clear association between the molecular phylogeny of African Dacus and the evolution of host plant choice and provide a basis towards a more congruent taxonomy of this genus. PMID- 19444962 TI - Review article: endothelial progenitor cells in renal disease. AB - This brief overview is intended to provide basic information about endothelial progenitors, their definition and consensus markers used for their detection, describe the pathways of their mobilization and homing and highlight the mechanisms and manifestations of their incompetence that occurs in some chronic kidney diseases. Discussion is geared towards the potential role of endothelial progenitor cells in organ regeneration, in particular, in kidney regeneration. The concept we attempted to promote attributes to the incompetence of endothelial progenitor cells in failed regeneration and ensuing progression of chronic kidney disease. This field of inquiry remains insufficiently explored, especially in renal diseases. Promising areas for future exploration are emphasized. PMID- 19444963 TI - Typical and atypical antipsychotics alter acetylcholinesterase activity and ACHE expression in zebrafish (Danio rerio) brain. AB - Antipsychotic agents are widely used for the treatment of psychotic symptoms in patients with several brain disorders. Antipsychotic drugs principally affect dopamine systems with the newer ones also affecting serotonin, norepinephrine, and histamine systems. Other transmitter systems can be involved with selected antipsychotic drugs but effects on cholinergic system are less known. Considerable evidence has shown that complex interactions between dopaminergic and cholinergic systems are critical for the proper regulation of motor control and memory. These neurotransmitter systems have been studied in zebrafish, which has recently become a focus of neurobehavioral studies. Therefore, we have evaluated the in vitro and in vivo effects of sulpiride, olanzapine, and haloperidol on acetylcholinesterase activity and ache expression pattern in zebrafish brain. For in vitro studies, all drugs were able to promote a decrease on acetylcholinesterase activity. For in vivo studies, olanzapine and sulpiride exposure did not change acetylcholinesterase activity. In contrast, this enzyme activity was significantly increased at 5 and 9 microM haloperidol (29.9% and 20.4%, respectively). Haloperidol exposure was able to increase acetylcholinesterase mRNA transcripts. These findings have suggested that the alterations in zebrafish acetylcholinesterase could reveal molecular mechanisms related to cholinergic signaling induced by antipsychotic treatment. PMID- 19444964 TI - Review article: importance of the kidney proximal tubular cells in thiazolidinedione-mediated sodium and water uptake. AB - Thiazolidinediones (TZD) such as pioglitazone and rosiglitazone are proxisome proliferator-activated receptor gamma (PPARg) agonists and are widely used clinically to treat type 2 diabetes mellitus. Fluid retention still poses a significant limitation to its use. The primary renal process underlying TZD associated oedema is reduced urinary sodium and water excretion. Experimental evidence suggests that this is mainly related to the effects of PPARg agonists on the distal nephron and collecting duct. We have recently shown that PPARg agonists upregulate sodium and water transport channels in human proximal tubule cells and that Sgk-1 is involved. In this review, we focus on the importance of the proximal tubular cells in TZD-mediated sodium and water uptake. PMID- 19444965 TI - Freeze tolerance evolution among anurans: Frequency and timing of appearance. AB - Despite numerous mechanistic studies on physiological responses supporting freeze tolerance in anurans, few have addressed the evolutionary significance of this trait. We thus investigated the phylogenetic relationships among anuran species whose freeze tolerance has been assessed and in combination with new data on freezing tolerance of two closely related species of the European brown frogs (Rana temporaria and Rana dalmatina). The species we studied exhibited short survival times in frozen state (around 8 h for both species). Phylogenetic analysis suggests that freeze tolerance evolved at least two times among Ranidae and one or two times among Hylidae and never in Bufonidae. Furthermore, in order to assess the timing of divergence of this character we used a relaxed molecular clock created, and found that the most recent separation between a freeze tolerant species and a freeze intolerant species dates from 15.9 +/- 7.6 Myr (Rana arvalis and R. temporaria). The comparison between these two species thus represents the best current model to understand freeze tolerance evolution. Addressing the evolution of this trait with such large-scale approaches will not only improve our understanding of cold hardiness strategies, but might also create a framework guiding future comparative studies. PMID- 19444966 TI - Association between metabolic syndrome and chronic kidney disease in the Korean population. AB - AIM: We performed a retrospective study to examine the association between the metabolic syndrome (MS)and risk for the development of chronic kidney disease (CKD). METHODS: This cohort study included 60 921 healthy adults recruited from two health promotion centres.Anthropometric measures, blood pressure, fasting glucose, lipid profile and serum creatinine were evaluated. The glomerular filtration rate was estimated (eGFR) using the abbreviated equation developed by the Modification of Diet in Renal Disease (MDRD) formula. CKD was defined as an eGFR of <60 mL/min per 1.73 m2 or the presence of proteinuria. RESULTS: The prevalence of MS and CKD was 19.0% and 7.2% respectively. Those with MS had a higher prevalence of CKD (11.0% vs 6.3%, P < 0.001) than those without MS. As the number of MS components increased, the prevalence of CKD increased and the eGFR decreased. The multiple linear analyses showed that each of the components of the MS was negatively correlated with the eGFR. Unadjusted and multivariate adjusted associations were identified between MS and CKD. Individuals with MS had a multivariate adjusted odds ratio of 1.680 (95% confidence interval, 0.566-1.801) for CKD compared with those without MS. CONCLUSION: Our findings, which were obtained from a large Korean cohort, suggest that MS was associated with CKD. PMID- 19444967 TI - Protective effects of a carbon monoxide-releasing molecule (CORM-3) during hepatic cold preservation. AB - There is increasing evidence that carbon monoxide (CO), a signaling molecule generated during the degradation of heme by heme oxygenase-1 (HO-1) in biological systems, has a variety of cytoprotective actions, including anti-hypoxic effects at low temperatures. However, during liver cold preservation, a direct effect needs to be established. Here, we designed a study to analyze the role of CO, delivered via a carbon monoxide-releasing molecule (CO-RM) in the maintenance of liver function, and integrity in rats during cold ischemia/reperfusion (CI/R) injury. We used an isolated normothermic perfused liver system (INPL) following a clinically relevant model of ex vivo 48 h cold ischemia stored in a modified University of Wisconsin (UW) solution, to determine the specific effects of CO in a rat model. CO was generated from 50 microM tricarbonylchloro ruthenium glycinato (CORM-3), a water-soluble transition metal carbonyl that exerts pharmacological activities via the liberation of controlled amounts of CO in biological systems. The physiological effects of CORM-3 were confirmed by the parallel use of a specific inactive compound (iCORM-3), which does not liberate CO in the cellular environment. CORM-3 addition was found to prevent the injury caused by cold storage by improving significantly the perfusion flow during reperfusion (by almost 90%), and by decreasing the intrahepatic resistance (by 88%) when compared with livers cold preserved in UW alone. Also, CORM-3 supplementation preserved good metabolic capacity as indicated by hepatic oxygen consumption, glycogen content, and release of lactate dehydrogenase. Liver histology was also partially preserved by CORM-3 treatment. CONCLUSIONS: These findings suggest that CO-RM could be utilized as adjuvant therapeutics in UW solutions to limit the injury sustained by donor livers during cold storage prior to transplantation, as has been similarly proposed for the heart, and kidney. PMID- 19444968 TI - Diagnostic accuracy of blood qualitative nucleic acid testing for polyomavirus associated nephropathy in kidney recipients. AB - AIM: Polyomavirus-associated nephropathy (PVAN) is an important cause of graft loss following kidney transplantation and may only be diagnosed with kidney transplant biopsy. Early detection may improve outcomes by enabling early intervention. Serum polyomavirus polymerase chain reaction (PVPCR) has been used to identify patients at risk of PVAN, but prior studies have not assessed all patients with negative PVPCR with transplant biopsy, potentially overestimating test performance. METHODS: We assessed the diagnostic accuracy of qualitative PVPCR for detection of PVAN in a population undergoing protocol biopsies. We included all patients receiving kidney or kidney-pancreas transplants and followed at Westmead Hospital, Sydney, Australia, between May 2002 and March 2007, excluding those with graft loss prior to 1 month post transplant or without PVPCR testing in the first 12 months. We compared PVPCR to contemporaneous transplant biopsies assessed with light microscopy and immunohistochemistry. RESULTS: Of the 257 included patients, 246 (96%) underwent biopsy within 30 days of PVPCR. Eight of 36 patients with positive PVPCR had PVAN and one of 210 patients with negative PVPCR had PVAN. The point prevalence of PVAN was therefore 3.7%, with PVPCR sensitivity 89% (95% CI 57% to 99%) and specificity 88%(95% CI 83% to 92%). The negative predictive value is 99.5% (95% CI 97.3% to 100.0%). CONCLUSION: Qualitative PVPCR on serum is a reliable triage test for excluding the presence of PVAN. Screening for PVAN need not include biopsy in patients with negative PVPCR. PMID- 19444969 TI - Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations. AB - Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80-90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10-14 days; for liver biopsy, 70-100%, 1-7 days; tonsillectomy: 90 100%, 5-11 days; indwelling venous access device insertion: 100%, 3-10 days; circumcision: 50-60%, 2-4 days; dental surgery: 30-50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better-designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration. PMID- 19444970 TI - Are nanometric films of liquid undercooled interfacial water bio-relevant? AB - It is known that life processes below the melting point temperature can actively evolve and establish in micrometer-sized (and larger) veins and structures in ice and permafrost soil, filled with unfrozen water. Thermodynamic arguments and experimental results indicate the existence of much smaller nanometer sized thin films of undercooled liquid interfacial (ULI) water on surfaces of micrometer sized and larger mineral particles and microbes in icy environments far below the melting point temperature. This liquid interfacial water can be described in terms of a freezing point depression, which is due to the interfacial pressure of van der Waals forces. The physics behind the possibly also life supporting capability of nanometric films of undercooled liquid interfacial water, which also can "mantle" the surfaces of the much larger and micrometer-sized microbes, is discussed. As described, biological processes do not necessarily have to proceed in the "bulk"" of the thin interfacial water, as in "vinical" water and in the micrometer sized veins e.g., but they can be supported or are even made possible already by covering thin mantles of liquid interfacial water. These can provide liquid water for metabolic processes and act as carrier for the necessary transport of nutrients and waste. ULI water supports two different and possibly biologically relevant transport processes: 2D molecular diffusion in the interfacial film, and flow-like due to regelation. ULI-water, which is "lost" by transport into microbes, e.g., will be refilled from the neighbouring ice. In this way, the nanometric liquid environment of microbes in ULI-water is comparable to that of microbes in bulk water. Another probably also biologically relevant property of ULI is, depending on the hydrophobic or hydrophilic character of the surfaces, that it is of lower density (LDL) or higher density (HDL) than bulk water. Furthermore, capillary effects and ions in ULI-water solutions can support, enhance, and stabilize the formation of layers of interfacial water. A more detailed future investigation of the possible support of life processes by nanometric ULI water in ice is a challenge to current cryomicrobiology. Related results of Rivkina et al. [22] indeed indicate that life processes can remain active at water contents corresponding to about or less than two monolayers of ULI water. PMID- 19444971 TI - Investigation of oxidation in freeze-dried membranes using the fluorescent probe C11-BODIPY(581/591). AB - Incorporation of the fluorescent probe C11-BODIPY(581/591) in two dried membrane systems, soy bean phosphatidylcholine liposomes freeze-dried in a carbohydrate/protein matrix and Lactobacillus acidophilus (La-5) freeze-dried in a carbohydrate matrix, was successful and could be visualised by Confocal Laser Scanning Microscopy (CLSM). The C11-BODIPY(581/591) probe is a lipid oxidation reporter molecule, which is known to associate with the lipids of biological membranes and exhibit a fluorescence shift from the red range to the green range of the visible spectrum when it is oxidised together with the lipids. The present study is the first to demonstrate that the C11-BODIPY(581/591) probe can be used in dried membrane systems, and that a detection of oxidation is possible by CLSM analysis directly on the dried samples. PMID- 19444972 TI - Cold-regulated proteins with potent antifreeze and cryoprotective activities in spruces (Picea spp.). AB - Antifreeze proteins (AFPs) were obtained from intercellular spaces of spruce needles Picea abies (L.) Karst. and Picea pungens Engelm. by vacuum infiltration with ascorbic acid, followed by centrifugation to recover the infiltrate. As shown by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS- PAGE), apoplastic proteins are accumulated in these spruce species as a group of 5-9 polypeptide bands. These proteins have a molecular mass of 7-80 kDa. The spruce AFPs have the ability to modify the growth of ice and thermal hysteresis, TH, caused by these AFPs was close to 2.0 degrees C at a concentration of 400 lg/ ml. The antifreeze activity of proteins from these winter-hardy coniferous species showed a positive correlation with the concentration of proteins after cold acclimation of needle tissues. Apoplastic proteins from winter spruce needles exhibited antifreeze activity, whereas no such activity was observed in extracts from summer needles. When we examined the possible role of spruce AFPs in cryoprotection, we found that lactate dehydrogenase, LDH, activity was higher after freezing in the presence of AFPs compared with bovine serum albumin. Amino terminal sequence comparisons indicated that a 27-kDa protein from both P. abies and P. pungens was similar to some pathogenesis-related proteins namely chitinases, also from conifer species. These results show that spruces produce AFPs that are secreted into the apoplast of needles. The accumulation of AFPs in extracellular spaces caused by seasonal cold acclimation during winter indicates that these proteins may play a role in the acquisition of freezing tolerance of needle cells in coniferous species. PMID- 19444973 TI - Effects of repeated whole-body cold exposures on serum concentrations of growth hormone, thyrotropin, prolactin and thyroid hormones in healthy women. AB - Cold therapy is used to relieve pain and inflammatory symptoms. Humoral changes may account for the pain alleviation related to the cold exposures. The aim of the present study was to examine the effects of two types of cold therapy, winter swimming in ice-cold water (WS) and whole body cryotherapy (WBC), on the serum levels of the growth hormone, prolactin, thyrotropin and free fractions of thyroid hormones (fT3, fT4). One group of healthy females (n = 6) was exposed to WS (water 0-2 degrees C) for 20 s and another group (n = 6) to WBC (air 110 degrees C) for 2 min, three times a week for 12 weeks. Blood samples used for the hormone measurements were taken on weeks 1, 4 and 12 before and 35 min after the cold exposures and on the days of the respective weeks, when the cold exposures were not performed. During the WS treatments, serum thyrotropin increased significantly at 35 min on weeks 1 (p < 0.01) and 4 (p < 0.05), but the responses were within the health-related reference interval. During the WS, the serum prolactin measured at 35 min on week 12 was lower than during the control treatment, and no changes in fT3 or fT4 were observed. During the WBC, no changes in the serum levels of the studied hormones were observed during the 12 weeks. In conclusion, repeated WS and WBC treatments for healthy females do not lead to disorders related to altered secretions of the growth hormone, prolactin, thyrotropin, or thyroid hormones. PMID- 19444974 TI - The outcome of cementless total hip arthroplasty in haemophilic hip arthropathy. AB - Total hip arthroplasty (THA) in haemophilic arthropathy is reported to be less successful than in non-haemophilic indications. Although preliminary results are encouraging, the survival and functional outcome of cementless THA in haemophilia are not known. The aim of this study was to analyse mid-term results of cementless THA in haemophilia. Twenty-seven consecutive cementless THAs with 23 patients performed between June 1995 and June 2003 were reviewed. Mean age at time of operation was 36 years and mean follow-up period was 92 months (range, 60 156). Radiographic assessment was done for fixation of components, loosening, osteolysis, wear and bone responses around the implants. The factor requirements, amount of transfusion and complications associated with bleeding were studied. The mean preoperative Harris hip score changed from 57 to 95.9 at the latest follow-up. The survival at mean follow-up was 95.2%. One patient with osteolysis around acetabular cup was re-operated with bone-grafting and change of polyethylene liner. One loose cup was revised with a cemented cup. All other components were deemed stable at the latest follow-up. A standardized management protocol and dedicated team approach comprising of haematologist, physicians, physical therapist, nurses and coordinators is needed for excellent results. The present retrospective study shows that the functional results of cementless THA in haemophilia are satisfactory as it happens in osteoarthritic patients according to the current literature, mainly the younger. Thus, taking into account that the majority of haemophilia patients requiring a THA are relatively young, cementless THA is currently recommended. PMID- 19444975 TI - Doctor displacement: a political agenda or a health care imperative? Comment. PMID- 19444976 TI - IL-1 beta, IL-6, KC and MCP-1 are elevated in synovial fluid from haemophilic mice with experimentally induced haemarthrosis. AB - The hallmark of haemophilia is the joint morbidity resulting from haemarthrosis that accounts for the majority of the bleeds. The exact mechanisms underlying changes are not fully elucidated. Cytokines are speculated to be involved in the progression and in vitro studies have confirmed the presence of elevated levels of cytokines in synovial tissue and cartilage from patients with haemophilic synovitis. In this study, the presence of selected cytokines in synovial fluid from haemophilia A mice with experimentally induced haemarthroses treated with rFVIII, rFVIIa and an rFVIIa analogue were investigated. Ten cytokines previously shown to be involved in arthritic syndromes were evaluated. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-10, IL-17, Tumor Necrosis Factor-alpha (TNF- alpha), keratinocyte-derived chemokine (KC), Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) were included. In this article, we demonstrate, for the first time, that bleeding in knee joints of haemophilia A mice resulted in correlated increased levels of the pro-inflammatory cytokines: IL-1 beta, IL-6, KC and the MCP-1 in synovial fluid. These results suggest an important role of MCP-1 in the recruitment of monocytes and furthermore that the inflamed synovium releases IL-1 beta, IL-6 and KC, which in turn might contribute to further progression of the inflammatory process. PMID- 19444977 TI - Registered nurses for the home treatment of children with haemophilia who have developed inhibitors: a case report. PMID- 19444978 TI - About the rarity of haemoptysis in congenital bleeding disorders. A report of five cases. PMID- 19444979 TI - The use of combination FEIBA and rFVIIa bypassing therapy, with TEG profiling, in uncontrollable bleeding associated with acquired haemophilia A. PMID- 19444980 TI - Arthroscopic synovectomies combined with reduced weight-bearing using patella tendon-bearing braces were very effective for progressed haemophilic ankle arthropathy in three paediatric patients. PMID- 19444981 TI - Newly qualified midwives must have experience of labour ward. PMID- 19444982 TI - Hypnosis in a GP obstetric unit. PMID- 19444985 TI - Lab hazard. PMID- 19444986 TI - Intrinsic chemosensitivity: how is it measured; what does it mean; and how does it help us understand the ventilatory response to CO2? PMID- 19444987 TI - Loss of dispersion energy changes the stability and folding/unfolding equilibrium of the Trp-cage protein. AB - The structure of proteins as well as their folding/unfolding equilibrium are commonly attributed to H-bonding and hydrophobic interactions. We have used the molecular dynamic simulations in an explicit water environment based on the standard empirical potential as well as more accurately (and thus also more reliably) on the QM/MM potential. The simulations where the dispersion term was suppressed have led to a substantial change of the tryptophan-cage protein structure (unfolded structure). This structure cannot fold without the dispersion energy term, whereas, if it is covered fully, the system finds its native structure relatively quickly. This implies that after such physical factors as temperature and pH, the dispersion energy is an important factor in protein structure determination as well as in the protein folding/unfolding equilibrium. The loss of dispersion also affected the R-helical structure. On the other hand, weakening the electrostatic interactions (and thus H-bonding) affected the R helical structure only to a minor extent. PMID- 19444988 TI - Evidence of oxidative stress and mitochondrial dysfunctions in the testis of prepubertal diabetic rats. AB - Earlier, we have shown the occurrence of oxidative impairments and their progression in the testis of diabetic adult rats. This study investigated the vulnerability of immature testis to oxidative stress and mitochondrial dysfunctions in a prepubertal (PP) diabetic rat model. PP male rats (4/6-week old) rendered diabetic by an acute dose of streptozotocin were monitored for induction of oxidative stress in testis cytosol/mitochondria. Diabetic rats of both age groups showed severe hyperglycemia, testicular atrophy and marked oxidative damage as evidenced by enhanced generation of reactive oxygen species, hydroperoxide and malondialdehyde levels (4 week > 6 week). Mitochondrial dysfunctions manifested as reduction in the activities of aldehyde dehydrogenase, tricarboxylic acid cycle enzymes, enhanced activities of oxidative phosphorylation enzymes, perturbations in calcium homeostasis and membrane potential. These evidences suggest that an immature testis is vulnerable to oxidative stress under diabetes, which may play a significant role in the development of testicular degeneration, leading to impaired fertility in adulthood. PMID- 19444989 TI - Cloning and expression of koala (Phascolarctos cinereus) liver cytochrome P450 reductase. AB - The cloning, expression and characterization of hepatic NADPH-cytochrome P450 reductase (CPR) from koala (Phascolarctos cinereus) is described. Two 2059 bp koala liver CPR cDNAs, designated CPR1 and CPR2, were cloned by reverse transcription-polymerase chain reaction and rapid amplification of cDNA ends. The koala CPR cDNAs encode proteins of 678 amino acids and share 85% amino acid sequence identity to human CPR. Transfection of the koala CPR cDNAs into Cos-7 cells resulted in the expression of proteins, which were recognized by a goat antihuman CPR antibody. The koala CPR1 and 2 cDNA-expressed enzymes catalysed cytochrome c reductase at the rates of 4.9 +/- 0.5 and 2.6 +/- 0.4 nmol/min/mg protein (mean +/- SD, n = 3), respectively which were comparable to that of rat CPR cDNA-expressed enzyme. The apparent Km value for CPR activity in koala liver microsomes was 11.61 +/- 6.01 microM, which is consistent with that reported for rat CPR enzyme. Northern analysis detected a CPR mRNA band of approximately 2.6 kb. Southern analysis suggested a single PCR gene across species. The present study provides primary molecular data regarding koala CPR1 and CPR2 genes in this unique marsupial species. PMID- 19444990 TI - Progestogens cause immunosuppression of stimulated carp (Cyprinus carpio L.) leukocytes in vitro. AB - The involvement of steroid hormones in direct and indirect regulation and modulation of immune responses is well recognized in mammals. Here, we demonstrate that progestogens are capable of influencing the innate immunity in fish as well. Therefore, we confirmed the known immunosuppressive effects of natural progesterone (P4), and compared them to influences of 17alpha,20beta dihydroxy progesterone (DHP4) and the synthetic progestins, medroxyprogesterone acetate (MPA) and levonorgestrel (LEV), on NO release by in vitro-stimulated carp leukocytes derived from both, head and trunk kidney, respectively. DHP4 known as the main maturation-inducing steroid in many teleosts potently inhibited the NO release by carp leukocytes. The synthetic progestin MPA, which may also be environmentally relevant due to its world-wide use in hormonal contraception, significantly decreased NO formation by head and trunk kidney cells. In contrast, LEV showed no significant influence on NO release by head and trunk kidney leukocytes. The observed immunosuppressive actions of progestogens on NO production were compared to the known impairment by natural and synthetic glucocorticoids. Determining the potential impact of progestogens on mRNA expression of iNOS by means of semi-quantitative reverse transcription polymerase chain reactions (RT-PCR) revealed downregulation of proinflammatory type I immune response characteristics at high concentrations. These findings demonstrate for the first time that similar to the known effects of natural progesterone synthetic progestogens are also able to influence immune signaling cascades in fish, and provide evidence that these steroids are capable of influencing mRNA expression of iNOS. The induction of a regulatory type II immune response by progestogens is a striking example of interference of female steroid-mediated events with the piscine immune system. Furthermore, the identification of a partial sequence of a membrane-associated progestogen receptor (mPR) in carp leukocytes by RT-PCR indicates a specific mechanism underlying the observed effects of progestogens on these immune cells. PMID- 19444991 TI - N-Acetylcysteine provides dose-dependent protection against fenthion toxicity in the brain of Cyprinus carpio L. AB - N-Acetyl-L-cysteine, a low-molecular weight thiol compound, with two different doses was used to prevent fenthion, an organophosphorus insecticide and acaricide, related oxidative stress in the brain of a model organism, Cyprinus carpio. Fish were exposed to sub-lethal and nominal concentration of fenthion after intraperitoneal injection of 0.5 or 400 mg/kg NAC. Brain tissues were then dissected and homogenized to analyse GSH, GSSG, TBARS, and protein contents. Enzymes that constitute the first line antioxidant defence, namely SOD and CAT, GSH-related enzymes, GR and GST, together with AChE activities were also determined spectrophotometrically. Fenthion did not cause any alteration in SOD and CAT activities while increasing GSH content, GSH/GSSG ratio and GST specific enzyme activity and decreasing GSSG, TBARS, and protein contents. Although, the highest induction in SOD and GST enzymes activities and the highest increase in GSH content were observed in the 0.5 mg/kg NAC-injected fish, their protein contents showed a decrease. 400 mg/kg NAC impeded the activation of the GST enzyme and a higher decrease in lipid peroxidation was observed. Fish were also protected against protein depletion by the higher dose NAC application. AChE activity was not influenced by fenthion exposure. Xenobiotic and GSH transporters may cause mild oxidative stress conditions in brain. Cellular redox status could trigger a series of reactions that result in an increase in SOD activity and a decrease in protein content. Based on the present results, it was suggested that the usefulness of NAC against fenthion depends on applied dose and tissue characteristics. Species-specifity and concentration selection should be taken into consideration in studies dealing with anticholinesterases. PMID- 19444992 TI - The effects of chronic inorganic and organic phosphate exposure on bactericidal activity of the coelomic fluid of the sea urchin Lytechinus variegatus (Lamarck) (Echinodermata: Echinoidea). AB - The sea urchin Lytechinus variegatus can survive chronic exposure to sodium phosphate (inorganic phosphate) concentrations as high as 3.2 mg L-1, and triethyl phosphate (organic phosphate) concentrations of 1000 mg L-1. However, chronic exposure to low (0.8 mg L-1 inorganic and 10 mg L-1 organic phosphate), medium (1.6 mg L-1 inorganic and 100 mg L-1 organic phosphate) or high (3.2 mg L 1 inorganic and 1000 mg L-1 organic phosphate) sublethal concentrations of these phosphates inhibit bactericidal clearance of the marine bacterium Vibrio sp. Bacteria were exposed to coelomic fluid collected from individuals maintained in either artificial seawater, or three concentrations of either inorganic phosphate or organic phosphate. Sterile marine broth, natural seawater and cell free coelomic fluid (cfCF) were employed as controls. Bacterial survival indices were measured at 0, 24 and 48 h periods once a week for four weeks. Bacteria were readily eliminated from the whole coelomic fluid (wCF) of individuals maintained in artificial seawater. Individuals maintained in inorganic phosphates were able to clear bacteria following a two week exposure period, while individuals maintained at even low concentrations of organic phosphates failed to clear all bacteria from their coelomic fluid. Exposure to phosphates represses antimicrobial defenses and may ultimately compromise survival of L. variegatus in the nearshore environment. PMID- 19444993 TI - In the October 2008 issue of "Heart Advisor," there was an article about home monitoring of blood pressure. The illustration shows a man slouched in a chair with his legs crossed taking his pressure. Everything I have ever read in the way of instruction says you should sit up straight with both feet flat on the floor? PMID- 19444994 TI - Your article on the "A-B-C's of heart health" in the October 2008 "Women's Heart Advisor" emphasized the importance of vitamin D for heart health. I am taking Synthroid 88mcg for hypothyroidism, and I recently read in a medical report that vitamin D is known to antagonize thyroid function--that excessive vitamin D supplementation can contribute to a loss of potassium and suppress thyroid function. The article says patients should avoid sources of extra vitamin D if they have a hypothyroid condition. Can you please address this? PMID- 19444995 TI - I read about a new drug for diabetes called Januvia. Should I be interested in it? PMID- 19444996 TI - I'm overweight and have type 2 diabetes. How much weight do I need to lose to bring my diabetes under control, and what's the best way to accomplish it? PMID- 19444997 TI - I'm 66 and I've been diagnosed with pre-diabetes. I've had mild, but controlled hypertension for a few years. What kind of screening tests should I have on a regular basis and how often should I have those tests? PMID- 19444998 TI - How do aspirin and nitroglycerin differ in heart attack prevention and treatment? PMID- 19444999 TI - SSI. Woman's HIV status, depression not severe impairments. PMID- 19445000 TI - Discrimination. Company negligently revealed former employee's HIV status. PMID- 19445001 TI - Recent study shows gaps in use of rapid HIV testing. Here are the take-home points. PMID- 19445002 TI - FDA notifications. Efavirenz 100 mg scored tablets approved for pediatric treatment. PMID- 19445004 TI - Proceedings of the North Pacific Surgical Association 95th Annual Meeting. Seattle, Washington, USA. November 14-15, 2008. PMID- 19445003 TI - Sputum eosinophil count in athletes with antiasthmatic therapeutic use exemption. PMID- 19445005 TI - Proceedings of the 14th International Conference on Prenatal Diagnosis and Therapy. June 1-4, 2008. Vancouver, Canada. PMID- 19445006 TI - Avian Influenza: vectors, vaccines, public health, and product marketability. Proceedings of the First Keynote Symposium of the 2008 Poultry Science Association Centennial Meeting. July 20, 2008. Niagara Falls, Ontario, Canada. PMID- 19445007 TI - Learning to 'talk the talk: the relationship of psychopathic traits to deficits in empathy across childhood. AB - BACKGROUND: Psychopathy is characterised by profound deficits in the human tendency to feel and care about what other people feel, often known as 'affective empathy'. On the other hand, the psychopath often has intact 'cognitive' empathy skills, that is, he is able to describe what and why other people feel, even if he does not share or care about those feelings. Despite a rapidly advancing neuroscience of empathy, little is known about the developmental underpinnings of this psychopathic disconnect between affective and cognitive empathy. METHODS: The parents of N = 2760, 3-13-year-olds reported on the levels of empathy, callous-unemotional traits (CU), and antisocial behaviour (AB). Consistent with current theory and measurement practice, an index of 'psychopathic traits' was derived from the CU and AB measures. RESULTS: There are important gender and developmental differences in empathy deficits related to psychopathic traits. As expected, psychopathy is associated with severe deficits in affective empathy across all ages for males; however, no such deficits were found for females. Contrary to adult findings, psychopathic traits are associated with deficits in cognitive empathy in childhood for both sexes; however, males with high psychopathic traits appear to overcome these deficits in cognitive empathy as they move through the pubertal years. CONCLUSIONS: In contrast to cognitive empathy, low affective empathy does not appear to be associated with psychopathic traits in females. The characteristic disconnect between cognitive and affective empathy seen in adult male psychopathy crystallises in the pubertal years when they appear to learn to 'talk the talk' about other people's emotions, despite suffering severe deficits in their emotional connection (affective empathy) to others. PMID- 19445008 TI - Proceedings of the New Technologies and Procedures Symposium at the 88th Annual Meeting of the American Association for Thoracic Surgery. May 10-14, 2008. San Diego, California, USA. PMID- 19445009 TI - A developmental dissociation in compound summation following extinction. AB - Recent studies suggest that extinction may involve different processes across development. The present study attempted to further clarify the nature of the processes involved in extinction of Pavlovian conditioned fear across development by employing a compound test procedure in rats. In this procedure, a comparison is made between the responding elicited by individual versus compound presentations of two extinguished CSs. The first two experiments showed that PND25 rats exhibit reliable compound summation (i.e., greater responding to the compound than to the individual CSs), at least when a between-subjects design is employed, but that PND18 rats do not exhibit such an effect. Experiment 3 demonstrated that this developmental difference in compound summation was not simply due to PND25 rats acquiring a stronger CS-US association in the conditioning phase, and Experiment 4 showed that the results cannot be explained in terms of developmental differences in how the compound stimulus is processed at a perceptual level at test. Taken together, these results suggest that there are developmental differences in the amount of associative change that occurs to CSs during extinction training. PMID- 19445010 TI - Emergency department nurses' understanding and experiences of implementing discharge planning. AB - AIM: This paper is a report of a study conducted to describe emergency department nurses' understanding and experiences of implementing discharge planning. BACKGROUND: Discharge planning in the emergency department is an important issue because of increased healthcare costs and greater emphasis on continuity of care. When executed as a collaborative process involving a multi-disciplinary team with the patient and family, discharge planning provides continuity of care for patients, less demand on hospitals, improvement in community services and in the services of other healthcare organizations. METHOD: The qualitative approach of phenomenography was used in this study. Thirty-two emergency department nurses were recruited between July and September 2005. Semi-structured interviews were conducted. FINDINGS: From interviewees' descriptions of implementing discharge planning, six categories were established: implementing discharge planning as 'getting rid of my patients', completing routines, being involved in patient education, professionally accountable practice, autonomous practice and demonstrating professional emergency department nursing care. The referential meaning of implementing discharge planning 'in the outcome space' was the professional commitment to emergency department provision of effective discharge services. CONCLUSION: The results of this research contribute to knowledge of emergency department nurses' experience in the implementation of the discharge planning process. Key requirements for the provision of manageable discharge services both in Taiwan and worldwide highlighted by this study include adequate workloads, sufficient time, clear policies and standards of discharge planning and enhancement of professional commitment. PMID- 19445011 TI - The Internet as a research site: establishment of a web-based longitudinal study of the nursing and midwifery workforce in three countries. AB - AIM: The aim of this paper is to describe the development of a web-based longitudinal research project, The Nurses and Midwives e-cohort Study. BACKGROUND: The Internet has only recently been used for health research. However, web-based methodologies are increasingly discussed as significant and inevitable developments in research as Internet access and use rapidly increases worldwide. METHOD: In 2006, a longitudinal web-based study of nurses and midwives workforce participation patterns, health and wellbeing, and lifestyle choices was established. Participating countries are Australia, New Zealand and the United Kingdom. Data collection is handled through a dedicated website using a range of standardized tools combined into one comprehensive questionnaire. Internet specific data collection and a range of recruitment and retention strategies have been developed for this study. DISCUSSION: Internet-based technology can support the maintenance of cohorts across multiple countries and jurisdictions to explore factors influencing workforce participation. However, barriers to widespread adoption of web-based approaches include website development costs, the need for fast broadband connection for large data collection instruments, and varying degrees of Internet and computer literacy in the nursing and midwifery workforce. CONCLUSION: Many of the issues reported in this paper are transitional in nature at a time of rapid technological development. The development of on-line methods and tools is a major and exciting development in the world of research. Research via the world-wide web can support international collaborations across borders and cultures. PMID- 19445012 TI - Unsatisfactory cervical cytology screening specimens are associated with missed cervical dysplasia and cancer. PMID- 19445013 TI - The functioning antigens: beyond just as the immunological targets. AB - Antigenic peptides derived from tumor-associated antigens (TAAs) facilitate peptide cancer vaccine therapies. With the recent progress in cancer immunity research, huge amounts of antigenic peptides have already been reported. Clinical trials using such peptides are underway now all over the world. Some reports have shown the efficacy of peptide vaccine therapies. However, others ended with unfavorable results, suggesting fundamental underlying problems. One major mechanism that negates the peptide vaccine therapy is tumor escape from immunological systems caused by loss of antigens. TAAs that are used in cancer vaccine therapies may be divided into two major groups: functioning antigens and nonfunctioning antigens. A 'functioning antigen' could be defined as a TAA that is essential for tumor growth, is expressed in several kinds of malignancies and shows homogenous expression in cancerous tissues. It is not difficult to imagine that antigen loss will occur easily with non-functioning antigens as a target of cancer vaccine therapy. Thus, it is essential to use functioning antigens for successful cancer vaccine therapy. In this review, we discuss the functioning antigens and their categorization in detail. PMID- 19445014 TI - Transgenerational effects of prenatal exposure to the Dutch famine. PMID- 19445015 TI - Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. AB - Understanding tumor-specific metabolism under hypoxia is important to find novel targets for antitumor drug design. Here we found that tumor cells expressed higher levels of cytosolic acetyl-CoA synthetase (ACSS2) under hypoxia than normoxia. Knockdown of ACSS2 by RNA interference (RNAi) in tumor cells enhanced tumor cell death under long-term hypoxia in vitro. Our data also demonstrated that the ACSS2 suppression slowed tumor growth in vivo. These findings showed that ACSS2 plays a significant role in tumor cell survival under hypoxia and that ACSS2 would be a potential target for tumor treatment. Furthermore, we found that tumor cells excreted acetate and the quantity increased under hypoxia: the pattern of acetate excretion followed the expression pattern of ACSS2. Additionally, the ACSS2 knockdown led to a corresponding reduction in the acetate excretion in tumor cells. These results mean that ACSS2 can conduct the reverse reaction from acetyl-CoA to acetate in tumor cells, which indicates that ACSS2 is a bi-directional enzyme in tumor cells and that ACSS2 might play a buffering role in tumor acetyl-CoA/acetate metabolism. PMID- 19445016 TI - Relationship between autonomic innervation in crista terminalis and atrial arrhythmia. AB - BACKGROUND: The crista terminalis (CT) is known to initiate and maintain atrial arrhythmia, and is affected by autonomic tone, but the underlying mechanisms are poorly understood. This study sought to study the relation between autonomic innervation in CT and atrial arrhythmia. METHODS: Thirty adult canines were used in the present study. Tissues of the CT and the pectinate muscles (PM) were obtained from 10 dogs for electrophysiology studies. Furthermore, tissues of the superior CT, the inferior CT, and the PM were obtained from 10 dogs for immunohistochemistrical studies. Anti-growth-associated protein 43 (GAP43), anti tyrosine hydroxylase (TH), and choline acetyltransferase (ChAT) antibodies for immunocytochemical staining of cardiac nerves were performed to test the densities of autonomic nerve. Densities of I K,ACh in the superior CT, the inferior CT, and the PM cells were measured by patch clamp in the other 10 dogs. RESULTS: With the pacing cycle length decreased, the amplitude of delayed after depolarization (DAD) increased and DAD-induced triggered activity was induced in the CT but not in PM with norepinephrine administration. GAP-43 and TH-positive nerves in the superior CT and the inferior CT were all significantly higher than in the PM (GAP-43: 6,250 +/- 1,928 vs 1,247 +/- 747, 2,855 +/- 1,579 vs 1,247 +/- 747; TH: 3,140 +/- 1,240 vs 690 +/- 720, 1,210 +/- 980 vs 690 +/- 720; P < 0.01). Furthermore, the GAP-43 and TH-positive nerves in the superior CT were higher than in the inferior CT. However, there were no significant differences in ChAT positive nerves and I K,ACh in the superior CT, the inferior CT, and the PM. CONCLUSIONS: The higher densities of adrenergic nerve in the CT play an important role in the genesis of atrial arrhythmia. PMID- 19445017 TI - PROMPT education and development: saving mothers' and babies' lives in resource poor settings. PMID- 19445018 TI - Matrix metalloproteinase-2 expression in stromal tissues is a consistent prognostic factor in stage II colon cancer. AB - For patients with stage II colon cancer, the usefulness of adjuvant chemotherapy remains controversial. Therefore, it is important to identify high-risk indicators. The biological prognostic factors for recurrence might allow further insight into the optimal treatment strategy for patients with node-negative disease. Matrix metalloproteinase-2 seems to be one of the essential factors for tumor invasion and lymph node metastasis. In this study, we analyzed the expression of cyclooxygenase-2 and matrix metalloproteinase-2 by immunohistochemical staining in 109 patients with stage II colon cancer. A positive correlation was observed between tumor cyclooxygenase-2 and tumor matrix metalloproteinase-2 expression (P = 0.0006) and between tumor cyclooxygenase-2 and stromal matrix metalloproteinase-2 expression (P < 0.0001). Stromal matrix metalloproteinase-2 expression was associated with disease-free survival (P = 0.0095) and was shown to be an independent risk factor for recurrence by multivariate analysis. In addition, we carried out an invasion assay in vitro to investigate whether cyclooxygenase-2 and matrix metalloproteinase-2 affected the tumor-invasive potential of colon cancer cell lines. The invasion assay showed that every cancer cell line acquired invasive potential in coculture with stromal cell lines and the cyclooxygenase-2 inhibitor suppressed this phenomenon by downregulating the matrix metalloproteinase-2 expression of stromal cells. In conclusion, these findings suggest that matrix metalloproteinase-2 expression in stromal cells can be a high-risk indicator for recurrence in patients with stage II colon cancer. PMID- 19445019 TI - Pacemaker syndrome during managed ventricular pacing mode: what is the mechanism? PMID- 19445020 TI - High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers. AB - Downregulation of the cyclin-dependent kinase inhibitory protein p27 is frequently observed in various cancers due to enhancement of its degradation. We recently reported that p53-inducible protein with RING-H2 domain (Pirh2) is a novel ubiquitin ligase for p27, required for the ubiquitylation and consequent degradation of p27 protein. However, there is no reports about the involvement of Pirh2 in both p27 downregulation and pathogenesis in human cancers. In the present study, we investigated them using cultured cell lines and surgical specimens derived from human head and neck squamous cell carcinoma (HNSCC). Depletion of Pirh2 by short interfering RNA induced accumulation of p27 and inhibited the growth of cultured HNSCC cells. By immunohistochemical analysis in 57 cases of HNSCC specimens, higher levels of Pirh2 expression (labeling index > or = 60%) were found in 61.4% of HNSCC in comparison with 0% of normal mucosa. In addition, 83.3% of HNSCC with lower p27 expression (labeling index < 20%) displayed high Pirh2 levels. Therefore, Pirh2 expression was inversely correlated with p27 expression. Finally, Pirh2 expression was well correlated with poor prognosis. These findings suggest that Pirh2 overexpression may have an important role in the development and maintenance of HNSCC at least partially through p27 degradation, and that Pirh2 may be a potential molecular target for human HNSCC. PMID- 19445021 TI - Post-surgical irradiation causes cellular immune suppression in patients with breast cancer. AB - According to several studies, even the locoregional irradiation of patients with carcinoma can cause a severe and rather alarming cellular immune defect. We thus designed a prospective research in order to study the effect of post-operative irradiation on cellular immunity in patients suffering from breast cancer. In 35 patients with breast cancer who required post-operative irradiation, four blood samples were taken at indicated point times. Nineteen out of 35 patients received post-surgical chemotherapy before irradiation. The total lymphocytes as well as CD4 and CD8 subpopulations were measured by using flow cytometry analysis. The mean T-lymphocyte (Tol) count dropped from 1487.77 to 1227.91 (P = 0.0013) and the CD4+ count from 674.17 to 580.91 (P = 0.0189). The mean value of CD8+ dropped from 421.31 to 314.00 (P = 0.0003). Moreover, a statistically significant difference regarding the pattern of temporal change was observed between a group of patients that received irradiation only and a group that received radiation therapy (RT) with chemotherapy (P-values 0.0015, 0.01 and 0.092 for Tol, CD4+ and CD8+ respectively). The group of patients that received RT only presented a more rapid decrease of Tol concerning the decrease observed in the group that underwent chemotherapy and RT. PMID- 19445022 TI - T-lymphocyte maturation-associated protein gene as a candidate metastasis suppressor for head and neck squamous cell carcinomas. AB - Previous gene expression profiles revealed the T-lymphocyte maturation-associated protein (MAL) gene as being frequently downregulated in head and neck cancer. To define the relationship between the MAL gene and the metastatic process, we evaluated the expression status of the gene in matched primary and metastatic tumors of head and neck cancer by semiquantitative reverse transcription polymerase chain reaction. Furthermore, we aimed to identify potential genetic and epigenetic mechanisms associated with downregulation of MAL, including loss of heterozygosity (LOH), mutation, and hypermethylation. Thirty-five cell lines of University of Turko squamous cell carcinoma (UT-SCC) series derived from head and neck cancer, including nine pairs from matched primary and metastatic tumors, and 30 pairs of matched primary and metastatic tumor samples were analyzed. Twenty out of 35 (57%) cell lines showed downregulation of MAL expression, whereas no expression was found in 10 cell lines (29%). Considering matched primary and metastatic tumor-derived cell-line pairs, four pairs showed decreased expression only in metastasis-derived cells compared with their primary counterparts. Expression analysis of 21 tissue samples demonstrated decreased or no expression of MAL mRNA in 43% of metastatic tumors compared with matched primary tumors. Relating to mechanisms of downregulation, LOH was observed in 30% of primary tumors and 38% of their metastatic counterparts by a MAL-specific microsatellite marker. Furthermore, we found restoration of MAL mRNA after treatment with demethylating agent (5-aza-2'-deoxycytidine) in 9 (45%) out of 20 cell lines. No mutation was found in UT-SCC cell lines. In conclusion, our findings indicate selective downregulation of MAL expression in metastatic cells, suggesting the MAL gene as a new metastasis-suppressor candidate for head and neck cancer. LOH and hypermethylation appeared to be important mechanisms for inactivation of MAL function. PMID- 19445023 TI - Metastatic acinar cell carcinoma of the pancreas responding to gemcitabine, 5 fluorouracil and leucovorin therapy: a case report. AB - Acinar cell carcinoma of the pancreas is rare tumour with a generally poor prognosis. There are very few reports of tumour regression following chemotherapy. In this case report, a patient with metastatic acinar cell carcinoma in the liver developed progressive disease after cisplatin/etoposide and then had progressive disease after weekly paclitaxel chemotherapy. However, his tumour then responded to gemcitibine/5-flourouracil/leucovorin chemotherapy. Herein, previously described chemotherapy regimens used for this rare tumour are reviewed. This case represents the first reported metastatic acinar cell carcinoma responding to this regimen. PMID- 19445024 TI - Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. AB - Signaling through the Notch1 receptor has a pivotal role in early thymocyte development. Gain of Notch1 function results in the development of T-cell acute lymphoblastic leukemia in a number of mouse experimental models, and activating Notch1 mutations deregulate Notch1 signaling in the majority of human T-cell acute lymphoblastic leukemias. Notch2, another member of the Notch gene family, is preferentially expressed in mature B cells and is essential for marginal zone B-cell generation. Here, we report that 5 of 63 (approximately 8%) diffuse large B-cell lymphomas, a subtype of mature B-cell lymphomas, have Notch2 mutations. These mutations lead to partial or complete deletion of the proline-, glutamic acid-, serine- and threonine-rich (PEST) domain, or a single amino acid substitution at the C-terminus of Notch2 protein. Furthermore, high-density oligonucleotide microarray analysis revealed that some diffuse large B-cell lymphoma cases also have increased copies of the mutated Notch2 allele. In the Notch activation-sensitive luciferase reporter assay in vitro, mutant Notch2 receptors show increased activity compared with wild-type Notch2. These findings implicate Notch2 gain-of-function mutations in the pathogenesis of a subset of B cell lymphomas, and suggest broader roles for Notch gene mutations in human cancers. PMID- 19445025 TI - Newly synthesized curcumin analog has improved potential to prevent colorectal carcinogenesis in vivo. AB - Curcumin (diferuloylmethane) has chemopreventive and chemotherapeutic potentials against various types of cancers. We have developed a series of curcumin analogs to improve its low bioavailability by enhancing its potentials. The newly synthesized analog GO-Y030 [(1E, 4E)-1,5-bis-(3,5(-bismethoxymethoxyphenyl) penta 1,4-dien-3-one] showed a 30-fold greater growth suppression in vitro via similar molecular mechanisms to curcumin. The availability of this analog was examined by using a mouse model harboring the germ-line mutation of Apc, Apc(580D/+), in vivo. Apc(580D/+) mice had a very limited survival time with an intestinal obstruction due to polyposis. The average tumor number in mice fed GO-Y030 was reduced to 61.2% of those that were fed the basal diet (P < 0.05). Compared with Apc(580D/+) mice fed the basal diet (median survival time = 166.5 days), a significantly prolonged lifespan (213 days) was observed in Apc(580D/+) mice fed GO-Y030. The chemopreventive effect with GO-Y030 was improved, compared with curcumin (191 days). The survival benefit corresponded to the diminished intestinal tumor incidence in Apc(580D/+) mice fed GO-Y030. No adverse reactions were observed, judging from body weight or biochemical data concerning liver and renal damage. Degradation of accumulated beta-catenin with curcumin is one of the major mechanisms of chemoprevention in colorectal carcinogenesis. It was demonstrated that the number of beta-catenin-positive adenoma cells in Apc(580D/+) mice fed GO-Y030 was reduced. PMID- 19445026 TI - EBAG9 inducing hyporesponsiveness of T cells promotes tumor growth and metastasis in 4T1 murine mammary carcinoma. AB - The estrogen receptor-binding fragment-associated gene 9 (EBAG9) has been identified as an estrogen-responsive gene and was recently identified as a tumor promoting and prognostic factor for renal cell carcinoma. We investigated whether EBAG9 expression was correlated with primary tumor growth and distant tumor metastasis in a murine breast carcinoma model. Knockdown expression of EBAG9 by small interfering RNA significantly suppressed tumor growth and metastasis in vivo in a highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model. 4T1 cells stably overexpressing EBAG9 developed larger and faster tumor growth and lung metastasis compared with parental 4T1 or 4T1 expressing vector alone. Strong specific cytotoxic T lymphocyte activity and enhanced gamma-interferon and interleukin-2 productions were induced in mice that received EBAG9 small interfering RNA therapy. Gene silencing of EBAG9 prolonged the survival of tumor-bearing mice and induced more intensive infiltration of CD8+ T cells in tumor mass. EBAG9 induced apoptosis of T cells, enhanced glycogen synthase kinase 3beta phosphorylation and inhibited gamma-interferon production of T cells when T lymphocytes were cocultured with 4T1 cells overexpressing EBAG9. Furthermore, overexpression of EBAG9 in 4T1 cells was accompanied with enhanced expression of chemokine (C-X-C motif) receptor 4, which might be involved in tumor metastasis. Taken together, our results suggested that EBAG9 promoted primary 4T1 mammary carcinoma growth and distant metastasis, and EBAG9 small interfering RNA exerted overt regression of tumor growth and metastasis. These findings might provide insights into the mechanism through which tumors evade immunosurveillance and provide a strategy for therapeutic intervention of cancer metastases. PMID- 19445027 TI - Morphometric investigation of death by asphyxia. AB - The aim of this study was to investigate the possibility of distinguishing deaths by asphyxia from those due to natural causes by comparing morphometric measurements in lungs. The study population comprised 27 subjects: 14 cases of death by asphyxia (hanging or drowning) and 13 cases of sudden natural death. Eighty parenchyma sections were used for each subject. Data were collected by computerized image analysis. Measurements aimed at quantifying, as percentages, pulmonary parenchyma (mean values of positive-fraction areas [PFA] and their standard deviations). Subjects who died of natural causes and of drowning showed a relative internal homogeneity compared to those who hanged. Results show significant discrimination between drowned subjects and those dying of natural causes (mean of PFA p = 0.01) and between hanged and drowned subjects (SD of PFA p = 0.04). Attention must be paid to the possible role played by senile emphysema. The method is proposed as a complementary tool in forensic cases. PMID- 19445028 TI - Proceedings of the 5th Asian-Australian Conference on Composite Materials (ACCM 5). Hong Kong. November 27-30, 2006. PMID- 19445029 TI - Proceedings of the XI International Orthoptic Congress. Antwerp, Belgium. May 2008. PMID- 19445030 TI - Proceedings of the XIVth International Congress on Nutrition and Metabolism in Renal Disease. Marseilles, France. June 11-15, 2008. PMID- 19445031 TI - Chemotherapy and immunotherapy in metastatic colorectal cancer. PMID- 19445032 TI - Chemotherapy and immunotherapy in metastatic colorectal cancer. PMID- 19445033 TI - Chemotherapy and immunotherapy in metastatic colorectal cancer. PMID- 19445034 TI - Atypical antipsychotic drugs and the risk of sudden cardiac death. PMID- 19445035 TI - Decontamination of the digestive tract in ICU patients. PMID- 19445036 TI - Decontamination of the digestive tract in ICU patients. PMID- 19445037 TI - Decontamination of the digestive tract in ICU patients. PMID- 19445038 TI - Decontamination of the digestive tract in ICU patients. PMID- 19445039 TI - Behavioral management for anorexia nervosa. PMID- 19445040 TI - Differentiated CaCo-2 cells as an in-vitro model to evaluate de-novo apolipoprotein A-I production in the small intestine. AB - BACKGROUND: Increasing HDL cholesterol concentrations by stimulating de-novo apolipoprotein A-I (apoA-I) production in the liver and/or in the small intestine is a potential strategy to reduce coronary heart disease risk. Although there is quite some knowledge concerning regulatory effects in the liver, less is known concerning potential agents that could elevate de-novo apoA-I production in the small intestine. METHODS: Therefore, we compared side-by-side effects of various peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, retinoid-X receptor alpha, and farnesoid-X-receptor agonists on de-novo apoA-I production in differentiated CaCo-2 and HepG2 cells. RESULTS: For PPARa agonists, we showed that GW7647 elevated apoA-I concentrations in the medium of both cell models, whereas WY14643 elevated only de-novo apoA-I concentrations in differentiated CaCo-2 cells. Unexpectedly, fenofibric acid lowered apoA-I medium concentrations in both cell lines, which could not be explained by a lack of PPAR transactivation or a lack of retinoid-X-receptor a activation. For farnesoid-X receptor agonists, chenodeoxycholic acid strongly reduced apoA-I concentrations both in differentiated CaCo-2 and HepG2 cells, whereas GW4064 and taurocholate only lowered apoA-I in CaCo-2 cells (GW4064) or in HepG2 cells (taurocholate). However, overall effects of all individual components on apoA-I production in differentiated CaCo-2 and HepG2 cells were highly correlated (r = 0.68; P = 0.037; N=9). CONCLUSION: We conclude that differentiated CaCo-2 cells are suitable models to study de-novo small intestinal apoA-I production in vitro enabling the possibility to screen for potential bioactive dietary components. This cell model may also determine small-intestinal-specific effects, as some discrepancy was found between both cell models. PMID- 19445041 TI - Screening colonoscopy for colorectal cancer prevention: results from a German online registry on 269000 cases. AB - BACKGROUND: The efficacy of screening colonoscopy in general use remains to be determined. Here we report data over a 39-month study period collected in a nationwide online registry. STUDY: Data from consecutive screening colonoscopies performed on asymptomatic patients in the practices of 280 participating gastroenterologists (age 55-99 years) were collected in an online registry. The number and histology of colorectal polyps and carcinomas, complication rates of colonoscopy and polypectomy were registered. Advanced adenoma was defined as an adenoma of >or= 10 mm in diameter, villous or tubulovillous in histology, or presence of high-grade dysplasia. RESULTS: A total of 269 144 colonoscopies (male 44%) were evaluated. Tubular, villous/tubulovillous adenomas and invasive cancers were found in 15.6, 3.7, and 0.8%, respectively. Advanced adenomas amounted to 7.1%. In 95% of polyps greater than 5mm and less than 30 mm immediate polypectomy was performed. In 399 of the 575 carcinomas with complete tumor node metastasis stages, which were detected during colonoscopy, early stages dominated (UICC stages I and II in 43 and 27%, respectively). Complication rate was low and no fatalities were observed: cardiopulmonary complication in 0.10% of the colonoscopies, bleeding in 0.8% of polypectomies most of which were managed endoscopically (surgery in 0.03% of polypectomies). Perforation occurred in 0.02% of the colonoscopies and 0.09% of polypectomies. CONCLUSION: Colonic neoplasias are detected in about 20% of patients most of which are immediately removed by polypectomy at a low risk. Polypectomy of adenomas and low UICC stages in cancer patients during screening colonoscopy may be tools for fighting colorectal cancer mortality. PMID- 19445042 TI - Prediction of asymptomatic cirrhosis in chronic hepatitis C patients: accuracy of artificial neural networks compared with logistic regression models. AB - OBJECTIVE: Models based on logistic regression analysis are proposed as noninvasive tools to predict cirrhosis in chronic hepatitis C (CHC) patients. However, none showed to be sufficiently accurate to replace liver biopsy. Artificial neural networks (ANNs), providing a prediction based on nonlinear algorithms, can improve the diagnosis of cirrhosis, a syndrome characterized by complex, nonlinear biological alterations. We compared ANNs with two logistic regression analysis-based models in predicting CHC histologically proven cirrhosis. METHODS: Liver biopsy was obtained in CHC patients of two different cohorts (an internal cohort including 244 patients and an external cohort including 220 patients). One hundred and forty-four patients from the internal cohort served as a training set to construct ANNs and a logistic regression model (LOGIT). These two models and the aspartate aminotransferase-to-platelet ratio index (APRI) were tested in the remaining 100 patients (internal validation set) and in the external cohort (external validation set). Diagnostic performances were evaluated by standard indices of accuracy. RESULTS: In the internal validation set, ANNs, LOGIT, and APRI showed similar discrimination powers (0.88, 0.87, and 0.87 respectively). However, ANNs showed the best positive predictive value (0.86 vs. 0.67 and 0.56) and positive likelihood ratio (40.2 vs. 13.4 and 8.4). In the external validation set, the discrimination power of ANNs (0.76) was significantly higher than those of LOGIT (0.67) and APRI (0.67). CONCLUSION: Compared to conventional models, ANNs performance in predicting CHC cirrhosis is slightly better and more reproducible. PMID- 19445043 TI - Highly upregulated in liver cancer noncoding RNA is overexpressed in hepatic colorectal metastasis. AB - BACKGROUND: The highly upregulated in liver cancer (HULC) gene transcribes to an mRNA-like noncoding RNA (ncRNA) by the RNA polymerase II and processed by capping, splicing and polyadenylation. It is specifically expressed in the hepatocytes with striking upregulation in hepatocellular carcinoma (HCC). OBJECTIVES: To study the expression levels of HULC in normal colorectal samples, primary colorectal carcinomas and in secondary tumors formed from colorectal carcinomas that metastasize to either the liver or the lymph nodes, taken from the same patients. Also a panel of carcinoma cell lines is tested for HULC expression. BASIC METHODS: Semiquantitative reverse transcriptase-PCR technique is used to detect for HULC expression in study specimens and cell lines. RESULTS: Consistent with the previous report, HULC is neither expressed in primary colorectal carcinomas samples nor in their normal counterparts. We show for the first time those colorectal carcinomas that metastasize to the livers but not to lymph nodes experience an upregulation of HULC ncRNA in all the samples tested (n= 8), with a strong-to-moderate expression in six out of eight. Moreover HULC is not expressed in the majority of carcinoma cell lines tested and also in samples of normal bladder and bladder cancers of various grades. We also show that HULC ncRNA is upregulated in two hepatocellular carcinoma cell lines producing HBV relevant to their parental lines that do not produce HBV. CONCLUSION: Our results presented here indicate that HULC expression is not confined to HCC, but also to those colorectal carcinomas that metastasize to the liver. PMID- 19445044 TI - Treatment of particle-associated pulmonary aspiration with bronchoscopic lavage: report of two cases. PMID- 19445045 TI - Endotracheal tube cutting during neurosurgical operation. PMID- 19445047 TI - Oral Pathology Quiz #62. Case number 3. Odontogenic myxoma. PMID- 19445046 TI - [Intracranial hypertension and cerebellar syndrome]. PMID- 19445048 TI - Oral Pathology Quiz #62. Case number 4. Ameloblastic fibro-odontoma. PMID- 19445049 TI - [The incident is a clear violation]. PMID- 19445050 TI - [Lancet establishing a health alliance in Palestine]. PMID- 19445051 TI - Lichen planus associated with omalizumab administration in an adult with allergic asthma. PMID- 19445053 TI - Proceedings of the Third International Symposium on Women's Health Issues in Thrombosis and Haemostasis. February 6-8, 2009. Prague, Czech Republic. PMID- 19445052 TI - [Complex hygienic evaluation of territory in running the objects with radiation jeopardy]. AB - Complex hygienic evaluation of observation zone territory in long-standing running an object with radiation jeopardy revealed that radionuclides and heavy metals content of soil, surface water basins and ambient air is the same as background levels in reference territories. The authors point out possible use of the obtained values as reference levels for ecologic control in similar territories. PMID- 19445054 TI - Small molecule screen for compounds that affect vascular development in the zebrafish retina. AB - Blood vessel formation in the vertebrate eye is a precisely regulated process. In the human retina, both an excess and a deficiency of blood vessels may lead to a loss of vision. To gain insight into the molecular basis of vessel formation in the vertebrate retina and to develop pharmacological means of manipulating this process in a living organism, we further characterized the embryonic zebrafish eye vasculature, and performed a small molecule screen for compounds that affect blood vessel morphogenesis. The screening of approximately 2000 compounds revealed four small molecules that at specific concentrations affect retinal vessel morphology but do not produce obvious changes in trunk vessels, or in the neuronal architecture of the retina. Of these, two induce a pronounced widening of vessel diameter without a substantial loss of vessel number, one compound produces a loss of retinal blood vessels accompanied by a mild increase of their diameter, and finally one other generates a severe loss of retinal vessels. This work demonstrates the utility of zebrafish as a screening tool for small molecules that affect eye vasculature and presents several compounds of potential therapeutic importance. PMID- 19445056 TI - Proceedings of the 16th UKPHA Annual Forum. Liverpool, United KIngdom. PMID- 19445055 TI - Proceedings of the IV Congress of the World Society for Reconstructive Microsurgery (WSRM). Athens, Greece. June 22-27, 2007. PMID- 19445057 TI - Efficacy of cuff inflation media to prevent postintubation-related emergence phenomenon: air, saline and alkalinized lignocaine. AB - BACKGROUND AND OBJECTIVE: We wished to examine the efficacy of different media used for inflation of tracheal tube cuffs. METHODS: In our prospective randomized, controlled study over 3 months, there were 150 patients of either sex undergoing surgery under general anaesthesia with controlled ventilation with nitrous oxide and oxygen. The patients were divided into three equal groups (air, isotonic saline and alkalinized lignocaine as inflation media) using sealed envelope technique. The volume of the inflation medium, intracuff pressure, duration of intubation, volume of the inflation medium withdrawn from the cuff and complications like tube intolerance, coughing on tube, restlessness, hoarseness, sore throat, breathlessness and laryngospasm were analysed. Continuous data are presented as mean +/- SD, whereas categorical data are presented as frequencies and percentages. A [chi]2, analysis of variance and student's t-test were used to analyse the data. A P value less than 0.05 was considered as statistically significant. RESULTS: Age, sex, duration of intubation, intracuff pressure at the time of intubation were comparable. After intubation at all intervals, the intracuff pressure was higher in the air group with statistical significance at 5 min, 30 min, 1 h and just before extubation when air and saline groups were comparable and at all intervals after intubation up to just before extubation when air and lignocaine groups were comparable. The volume of air increased just before extubation in the air group, as compared with a fall in volume in the other groups. Tube intolerance, hoarseness and sore throat were least in the lignocaine group. CONCLUSION: We found that alkalinized 2% lignocaine and saline are better cuff inflation media, than air. PMID- 19445058 TI - Can't intubate, can't ventilate! A survey of knowledge and skills in a large teaching hospital. AB - BACKGROUND AND OBJECTIVE: The Difficult Airway Society protocol for the 'can't intubate, can't ventilate' scenario recommends the use of kink-resistant cannula cricothyroidotomy with transtracheal jet ventilation or surgical cricothyroidotomy. This survey aimed to assess the preparedness of anaesthetists and anaesthetic assistants for emergency tracheal access. METHODS: Ninety-seven anaesthetists and 63 assistants were asked the location of the two difficult airway trolleys. The anaesthetists were asked for their choice of emergency tracheal access. Those opting for cannula cricothyroidotomy with jet ventilation were asked to demonstrate cannulation of a mock trachea. After insertion of the airway cannula, the time required to attach the jet ventilator to the anaesthetic machine oxygen outlet and insufflate a dummy lung was recorded. The time to connect to a jet ventilator was also recorded for assistants. RESULTS: Five (5.2%) anaesthetists and 18 (28.6%) assistants knew the location of both airway trolleys. Sixty-one (62.9%) anaesthetists and one (1.6%) assistant did not know the location of either airway trolley. Thirty-six out of ninety-seven (37.1%) anaesthetists chose a method of tracheal access in keeping with Difficult Airway Society guidelines. Thirty-six out of ninety-seven (37.1%) anaesthetists opted for the jet ventilator, but 15 of these 36 (41.7%) could not locate the appropriate oxygen outlet on the anaesthetic machine. The median time [interquartile range (range)] to insufflate the dummy lung for the remaining 21 anaesthetists was 30 [23-32 (5.5-60)] s. CONCLUSION: There were widespread deficits in 'can't intubate, can't ventilate' knowledge and skills. All participants received a demonstration of equipment, were shown the location and given the opportunity to rehearse a 'can't intubate, can't ventilate' drill. PMID- 19445059 TI - Nuclear factor-[kappa]B inhibition provides additional protection against ischaemia/reperfusion injury in delayed sevoflurane preconditioning. AB - BACKGROUND AND OBJECTIVE: Sevoflurane anaesthetic preconditioning (SPC) has been shown to limit nuclear factor-[kappa]B (NF-[kappa]B) activation and the production of inflammatory cytokines during myocardial ischaemia/reperfusion (I/R). Similarly, pharmacological inhibition of NF-[kappa]B using parthenolide is effective in limiting I/R injury. We, therefore, postulated that the protective effect of delayed SPC would be enhanced by pharmacological NF-[kappa]B inhibition during I/R. METHODS: Hearts from 2-month-old male Fisher 344 rats were exposed to 25 min global ischaemia followed by 60 min reperfusion. Rats were divided into four groups prior to I/R: control group; parthenolide group, treated with the I[kappa]B kinase inhibitor parthenolide intraperitoneally 10 min prior to heart isolation; SPC group, treated for 60 min with sevoflurane 48 h prior to heart isolation; and SPC + parthenolide group, treated with SPC for 1 h followed by parthenolide 48 h later. Infarct area, left ventricular function and Ca2+(i) were measured after I/R. RESULTS: Delayed SPC + parthenolide resulted in greater protection than either intervention alone, resulting in a significant reduction in infarct area and left ventricular developed pressure (mmHg; 84 +/- 19 compared with 15 +/- 14 in control hearts; P = 0.007). Left ventricular end-diastolic pressure also remained close to baseline values (9 +/- 2 mmHg, P = 0.02) during I/R, and the increase in Ca2+(i) seen with I/R was significantly blunted (P = 0.005). CONCLUSION: SPC followed by parthenolide provides a significant protection from I/R injury in this model. As each intervention alone limits NF [kappa]B activation with I/R, these data are consistent with additive effects of these dual modalities in limiting I/R injury due to NF-[kappa]B activation. PMID- 19445060 TI - Breath pentane: an indicator for early and continuous monitoring of lipid peroxidation in hepatic ischaemia-reperfusion injury. AB - BACKGROUND AND OBJECTIVE: Lipid peroxidation plays an important role during liver ischaemia-reperfusion injury. Pentane in breath is often used as an index of lipid peroxidation. We observed the changes in levels of breath pentane during the lipid peroxidation process caused by liver ischaemia-reperfusion injury. METHODS: Ten male swine were anaesthetized with chloral hydrate 0.3-0.5 g kg(-1) min(-1). Total hepatic ischaemia was induced by occluding the portal inflow vessels. Ischaemia lasted 30 min followed by reperfusion for 180 min. Breath samples were sampled from the anaesthesia circuit and blood samples were collected from the inferior vena cava. Pentane concentrations in breath and blood were quantified by means of solid phase microextraction and gas chromatography mass spectrography technique. RESULTS: Exhaled pentane concentrations (means +/- SE) increased markedly after reperfusion for 1 min (244.13 +/- 33.3 pmol l(-1)) and decreased gradually to initial levels after reperfusion for 60 min. Blood pentane concentrations (means +/- SE) increased significantly after reperfusion for 1 min (333.46 +/- 63.05 pmol l(-1)) and then decreased to basal level. Breath pentane concentrations showed a correlation with blood (r = 0.709, P < 0.05). CONCLUSION: Breath pentane analysis could provide early, rapid, noninvasive and continuous assessment of lipid peroxidation during hepatic ischaemia-reperfusion injury. PMID- 19445061 TI - Comparison between central venous oxygen saturation and tissue oxygenation and perfusion: a case report. PMID- 19445062 TI - Somatosensory evoked potentials in detecting cerebral hypoperfusion. PMID- 19445063 TI - Postoperative nausea and vomiting in cardiac surgery. PMID- 19445064 TI - Evidence-based practice-focused interactive teaching strategy: a controlled study. AB - AIM: This paper is a report of a study to evaluate the effectiveness of the evidence-based practice (EBP)-focused interactive teaching (E-FIT) strategy. BACKGROUND: Although EBP is a mandatory competency for all healthcare professionals, little is known about the effectiveness of E-FIT in nursing. METHODS: Aquasi-experimental, controlled, pre- and post-test study involving senior, 4th-year nursing students (N = 208) at two nursing schools in the USA was carried out from August 2007 to May 2008. The experimental group (n = 88) received the E-FIT strategy intervention and the control group (n = 120) received standard teaching. A Knowledge, Attitudes and Behaviors Questionnaire for Evidence-Based Practice was used to assess the effectiveness of the E-FIT strategy. RESULTS: Independent t-tests showed that the experimental group had statistically significant higher post-test Evidence-Based Practice Knowledge (mean difference = 0.25; P = 0.001) and Evidence-Based Practice Use (mean difference = 0.26; P = 0.015) subscale scores compared to the control group, but showed no statistically significant differences in Attitudes toward Evidence Based Practice and Future Use of Evidence-Based Practice (mean difference = 0.12; P = 0.398 and mean difference = 0.13; P = 0.255 respectively). Hierarchical multiple regression analyses of the post-test data indicated that the intervention explained 7.6% and 5.1% of variance in Evidence-Based Practice Knowledge and Evidence-Based Practice Use respectively. CONCLUSION: The EBP focused interactive teaching strategy was effective in improving the knowledge and use of EBP among nursing students but not attitudes toward or future use of EBP. PMID- 19445065 TI - Counting carbohydrates like a pro. Practical tips for accurate counts. PMID- 19445066 TI - Fast-food cooking at home. Diner food. PMID- 19445067 TI - The secret to solving relationship problems. PMID- 19445068 TI - Lifestyle habits for lipid management. PMID- 19445069 TI - Diabetes quiz. How much do you know about nuts? PMID- 19445070 TI - Diabetes basics. After your hospital stay. Getting back on track. PMID- 19445071 TI - Supermarket smarts. 100-calorie snack packs. PMID- 19445072 TI - Weight loss information and support. PMID- 19445073 TI - Checking your blood glucose. Why using that meter can be a key part of your plan for long-term health. PMID- 19445074 TI - When you go too low. Preventing, recognizing, and treating hypoglycemia. PMID- 19445075 TI - A prescription for wellness. Diabetes medications cna help you take control of your health. PMID- 19445076 TI - So, what can I eat? Meal planning is central to managing your diabetes. Here's how to get started. PMID- 19445077 TI - What's covered? Don't wait to ask your health insurance provider. PMID- 19445078 TI - Dealing with diabetes. Reaching out can help you cope--and thrive. PMID- 19445079 TI - Tender mercies. PMID- 19445080 TI - A good test run. Motivating older adults to exercise. PMID- 19445081 TI - Too much of a good thing. Your body needs cholesterol to function, but it can also make serious trouble. PMID- 19445082 TI - A winter's retreat. PMID- 19445083 TI - 2009 resource guide. New products. This year, the name of the game is convenience. PMID- 19445084 TI - 2009 resource guide. Medications for type 2. If you have type 2 diabetes, you may be managing your condition with diet and exercise alone, or combined with one or more oral medications or injected drugs. PMID- 19445085 TI - 2009 resource guide. Insulin (and other injected drugs). PMID- 19445086 TI - 2009 resource guide. Insulin pumps. Some people with diabetes use wearable pumps to provide their insulin. PMID- 19445087 TI - 2009 resource guide. Home glucose monitoring. At the center of your diabetes care plan is a small, lightweight device that provides lifesaving knowledge at your fingertips--literally. PMID- 19445088 TI - 2009 resource guide. Products for treating low blood glucose. If you have diabetes, at some time or another you will probably have low blood glucose. Here's how to make sure you're prepared. PMID- 19445089 TI - 2009 resource guide. Ketone testing. When the body has no insulin, it's forced to burn fat for fuel. This produces ketones, and when they build up, the result can be a dangerous condition called diabetic ketoacidosis. PMID- 19445090 TI - New influenza A(H1N1) virus infections: global surveillance summary, May 2009. PMID- 19445091 TI - The Paediatric Bacterial Meningitis Surveillance Network in WHO's African Region, 2001-2008. PMID- 19445092 TI - The role of bacteria in blepharitis. PMID- 19445093 TI - [The apogee and decline of indigo and demographic evolution in Maracay, 18th-19th centuries]. PMID- 19445094 TI - [Masonic influences on the establishment of civil marriage and the civil registers of births, marriages, and deaths: Venezuela, 1867-73]. PMID- 19445097 TI - Prevalence of anaemia among HIV-infected patients in Benin City, Nigeria. AB - The aim of this study was to use the World Health Organization (WHO) definition of anaemia to determine prevalence of anaemia among human immunodeficiency virus (HIV)-infected patients on the highly active antiretroviral therapy (HAART) and those that are HAART naive. Haemoglobin concentration was measured in 457 HIV patients consisting of 217 patients on HAART (86 males and 131 females) and 240 HAART naive patients (106 males and 134 females). According to WHO criteria, anaemia was defined as a haemoglobin concentration below 12g/dl in women and below 13g/dl in men. The anaemic HIV patients were further categorized according to WHO/ACTG anaemia toxicity grades. An overall anaemia prevalence of 60.61% was observed. The prevalence of anaemia was significantly higher among HAART naive patients (69.17%) than in HIV patients on HAART (51.15%) (P < 0.001). The prevalence of anaemia differ significantly (P < 0.05) between males and females of HAART naive patients with males (76.42%) having higher prevalence than females (63.43%). The WHO/ACTG categorization showed the same pattern between HIV patients on HAART and those that were HAART naive. Conclusively, the overall prevalence of anaemia was 60.61% among HIV patients. HAART naive patients have higher prevalence as well as males in this group. The WHO definition of anaemia is recommended as this will give the true prevalence of anaemia and allow for policy and interventions to address it. PMID- 19445098 TI - HIV patients presenting common adverse drug events caused by highly active antiretroviral therapy in Tanzania. AB - Antiretroviral (ARV) drug toxicities pose treatment challenges and contribute to poor adherence. This study was carried out to document the commonly reported adverse reactions caused by ARV drugs in HIV patients in Tanzania. Information on drug induced adverse reactions (ADRs) in patients using ARV drugs was collected from the databases maintained in HIV clinics of Dar es Salaam and Mbeya. A total of 7502 and 1234 records of patients under ARV therapy by December 2006 were analysed in Dar es Salaam and Mbeya, respectively. In May, 2008 a cross-sectional study was conducted in which, the association between nevirapine (NVP) plasma concentrations and skin rashes problems was determined in 50 patients put on NVP based HAART for less than 2 weeks. Determination of NVP plasma concentration was carried out using a validated HPLC method in which patients from Dar es Salaam were involved. The study revealed that, anaemia, liver toxicity, skin rash and peripheral neuropathy were the most reported ADRs. The NVP plasma level determination revealed that there was no difference between those who had experienced skin rashes and those who did not (mean of 6.05 and 5.5 microg/ml respectively). There was a slight increase in reported ADRs between 2005 and 2006. A total of 932 (12.4%) patients changed their regimen in Dar es Salaam between January 2005 and December, 2006. Similarly, a total of 542 (44%) patients in Mbeya changed their regimen during that period. It can be concluded that, in both Dar es Salaam and Mbeya patients developed ARV related ADRs which are similar to those reported elsewhere. PMID- 19445099 TI - Alcohol use among school-going adolescents in Harare, Zimbabwe: results from the 2003 Global School-Based Health Survey. AB - Data from the Global School-Based Health Survey (2003) were analysed to estimate the proportions of relevant socio-demographic and behavioural characteristics. Of the 1997 students who participated in the survey, 15.6% (17.1% males and 14.0% females) reported alcohol consumption. Factors associated with consumption of alcohol use were being worried, bullied, smoking cigarettes, truant, and lack of parental supervision. Students who were never worried were 49% (AOR=0.51 [95% CI (0.36, 0.72)]) less likely to consume alcohol compared to students who were most of the time or always worried. Similarly, students who were never bullied were 42% (AOR=0.57 [95% CI (0.42, 0.77)]) less likely to take alcohol compared to students who were bullied at least six times in the previous one month to the survey. Compared to students who smoked cigarettes, non-smokers were 71% (AOR=0.29 [95% CI (0.21, 0.41)]) less likely to consume alcohol. Compared to students who always received parental supervision, students who rarely received parental supervision were more likely (AOR=1.85 [95% CI (1.19, 2.90)] to consume alcohol, and those students who sometimes received parental supervision were less likely (AOR=0.70 [95% CI (0.50, 0.98)] to consume alcohol. There is a need to implement public health interventions with special attention to the determinants of alcohol consumption in this age group. PMID- 19445100 TI - Mosquito larval productivity in rice-fields infested with Azolla in Mvomero District, Tanzania. AB - Azolla (Salviniales: Azollaceae) is known to reduce oviposition and adult emergence of a number of mosquito species. Several species of Azolla are reportedly indigenous to Tanzania. However, the potential of Azolla as a biocontrol agent against malaria mosquitoes has not been evaluated in the country. This cross-sectional study was carried out to assess mosquito larval productivity in irrigated rice-fields infested with Azolla in Mvomero District, Tanzania. A systematic larval sampling covering all open water bodies along designed transect was carried in rice-fields. Larval density was estimated by dipping water bodies with or without Azolla. The degree of Azolla coverage was categorized as 0%, <50%, 50%, and >80%. Larvae densities were categorised as low (<50/m2), medium (50-500/m2) and high (> or = 500/m2) productivity. A total of 120 water bodies were surveyed and 105 (87.5%) had Azolla microphyla and A. pinnata at varying degrees of coverage. Of the total 105 water bodies with Azolla, 80 (76.2%) had a green Azolla mat, and 25 (23.8%) a brown Azolla mat. Eighty-eight (73.3%) of the sites were infested with anophelines and 109 (90.8%) with culicine larvae. Seventy percent of all water bodies contained anophelines and culicines in sympatric breeding, while 20.8% and 3.3% had only culicines and anophelines, respectively. The majority (82%) of mosquito breeding sites were found in area with Azolla substrate. Mosquito larva productivity was low in sites with highest (>80%) Azolla coverage. Seventy-two (81.8%) of the anopheline and 90 (82.6%) culicine breeding sites were infested with Azolla. Water bodies infested with green Azolla were more productive than those covered by brown coloured Azolla substrates for both culicines (13%) and anophelines (8%). Of the 1537 field collected larvae that hatched to adult stage, 646 (42.03%) were Anopheles gambiae s.l., 42 (2.73%) were An. funestus and 769 (50.03%) were Culex quinquefasciatus. These findings suggest that the mosquito productivity is low when the Azolla coverage is high (>80%). The promotion of Azolla in mosquito control should take into consideration the degree of Azolla coverage. PMID- 19445101 TI - Antimicrobial and brine shrimp toxicity of some plants used in traditional medicine in Bukoba District, north-western Tanzania. AB - Herbal medicines constitute a potentially important resource for new and safe drugs for the management of microbial infections and other diseases. In this study, dichloromethane, ethylacetate and ethanol extracts of Canarium schweinfurthii Engl., Dissotis brazzae Cong., Iboza urticifolia (Bak) E.A.Bruce, Isoglosa lacteal Lindau, Strombosia Scheffleri Engl., and Whitfieldia elongate T. Anders were tested for antimicrobial activity and brine shrimp toxicity. The objective was to validate claims that they are used to treat bacterial infections, diarrhoea and heal wounds among the Haya tribe of north-western Tanzania. At least one extract of each plant showed antibacterial activity. Dichloromethane extracts were the most active while ethanol extracts were the least active. Extracts of Whitfieldia elongate and Isoglossa lacteal were the most and least active with MICs in the range 0.08-0.62 mg/ml and 15.6-62.5 mg/ml, respectively. The dichloromethane extract of Whitfieldia elongate exhibited strong antifungal activity against Cryptococcus neoformans. Against brine shrimp larvae, the extracts from the six plants exhibited a low to very low toxicity with LC50 values ranging from 15.35-374.0 microg/ml. However, ethanol extracts of Dissotis brazzae and Strombosia scheffleri had LC50 values of >1000 microg/ml. The seemingly innocuous nature and relatively good antibacterial activity against skin infections and gastrointestinal pathogenic bacteria support the traditional uses of the plants and deserve more detailed studies. PMID- 19445102 TI - Food cravings, aversions and pica among pregnant women in Dar es Salaam, Tanzania. AB - Food cravings, aversions and pica are common during pregnancy and may have a significant input on pregnancy progress and outcome. A study was carried out to determine the frequency and duration of pronounced dietary cravings, aversions and pica during pregnancy among 204 pregnant and lactating women attending two health facilities in Dar es Salaam City, Tanzania. Nausea and vomiting were reported by 82.8% of all women of which 43.2% experienced severe nausea alone, 9.5% severe vomiting alone and 35.5% experienced severe vomiting and nausea. Mild cases of each of the symptoms either occurring alone or both of them occurring together were also reported. Both behaviours were observed more in <3 months of pregnancy. The proportions of women with dietary cravings, aversions, and pica were 73.5%, 70.1% and 63.7% of all women respectively. More women (70.1%) experienced both food cravings and aversions than either symptom alone. Foods craved most were meat (23.3%), mangoes (22.7%), yoghurt (20.0%) oranges (20.0%), plantain (15.3%) and soft drinks (13.3%). Foods avoided most were rice (36.4%), meat (36.4%) and fish (30.8%). Eggs, beans, tea and stiff porridge were also avoided. Reasons given for avoiding foods were unpleasant smell/taste (10.3%), to reduce nausea (11.8%), no particular reason (58.3%) and dislike by foetus (belief) (3.9%). Pica was experienced by 63.7%% of the women and soil, ice and ash were the most commonly non-food substances eaten. The frequency of nausea and vomiting was highest in the early months of pregnancy and most women experienced the symptoms during morning hours. Craving in most women was more intense in the first trimesters. Most women craved for meat and sour and savoury foods, and avoided rice, meat and fish. Soil consumption was the pica observed in most women. Since aversions and cravings are closely linked to dietary intake of pregnant woman understanding these behaviours is important in addressing maternal nutrition. PMID- 19445103 TI - The nutritional intake of undergraduates at the University of Zimbabwe College of Health Sciences. AB - In developing countries the cost of treating disease is much more than prevention and so there is now a lot of interest in understanding nutrition. In this pilot study we selected a cohort of pre-clinical students studying at the College of Health Sciences in the University of Zimbabwe. This study was carried to investigate the gender-based weekly consumption of different food categories amongst University of Zimbabwe students. Semi-structured questionnaires distributed to 100 undergraduate students (male= 47; female= 52). The proportion of male and female respondents, age and body weight did not differ significantly. Principal foods consumed by males included sadza and cerevita; naartjies, bananas and avocado pears; tomatoes, onions, covo and spinach; beef; and condensed milk and powdered milk occupied the larger proportions. Females frequently ate a lot of bread, cerevita, sadza and cereal; lemons and avocado pears; onions, tomatoes, rape and covo; beef and soya meat; creamer, powdered milk and milk. This study suggests that females consumed a greater variety of food, including the infrequent types by comparison with men. PMID- 19445104 TI - Perception and knowledge of mothers on causes and treatment of rickets associated knee deformity in Ile-Ife, Osun State, Nigeria. AB - This descriptive cross-sectional community-based study was carried out in Ile Ife, Nigeria to assess the knowledge of mother's on the aetiology of rickets associated knee deformities and the cultural perception of its treatment. Data collection was done using interviewer based semi structured questionnaires. A total of 464 questionnaires were administered with a response rate of 86.9%. Over half (59.8%; N=241) and 36.5% (147) of the mothers were aware of children with knee deformity and rickets, respectively. Ninety-one (22.6%) mothers had the correct knowledge and perception of the true meaning of rickets. Rickets associated knee deformity aetiology was wrongly perceived to be mainly hereditary (53.8%), cancer (50.9%) and bone infection (48.1%). Very low proportions of mothers had correct knowledge on the causes of rickets such as inadequate exposure to sunshine (21.3%) or inadequate intake of calcium (21.1%). The knowledge of aetiology of rickets was influenced by education (P<0.02), skilled occupation (P<0.0001) and the previous birth of a child with knee deformity from rickets (P<0.001). The mother's cultural perceptions of treatment for childhood rickets associated knee deformities was significantly affected by age (P<0.001), education, (P<0.001), skilled occupation (P<0.000), history of knee deformity (P<0.04) and mothers with children diagnosed to have knee deformity (P<0.004). Lack of finance, poor compliance to treatment, too long treatment periods, lack of information on where to seek for treatment and unaffordable treatment were among the important factors affecting completeness of treatment of knee deformity due to rickets. In conclusion, the awareness of mothers about rickets in Nigeria is still very low. It is a major reason for late presentation or complete failure to seek for adequate treatment of the knee deformity due to rickets. Increase and sustain public health enlightenment programmes are necessary for prevention. Health policy should incorporate free surgical fees for the established knee deformity to encourage community participation in the management of the condition. PMID- 19445105 TI - Towards a sustainable community database: taking advantage of the Road-to-Health cards to monitor and evaluate health interventions targeting under fives. AB - The Road-to-Health (RTH) card has served as a tool for monitoring nutrition and vaccination status individual child for several decades. The card has the potential to serve as a community database for research if kept by the caretaker for a considerable period. This study aimed to assess whether the magnitude of possession and retention of RTH cards is adequate to serve as a community database for monitoring and evaluating health interventions targeting under fives. This cross-sectional study was conducted among under fives in Korogwe town and its suburbs in Tanzania. Six wards and four villages were randomly selected and all under fives found were included. Using a structured questionnaire, demographic information was obtained from the parent/guardian of the child. Information was collected on the presence of RTH card from which the date of birth was recorded. A total of 4899 households were involved and information obtained for 6364 under fives. The overall card possession rate was 74.3%. Possession of RTH cards was found to be highest among the last born under fives (78.3%) than the third-from-last born under fives (45.1%). Caretakers who were married and educated had higher card possession rate. In conclusion the possession of RTH cards was adequate to serve as a community database for monitoring health status and evaluating health interventions targeting the under fives. However, the low retention rate poses a limitation for the cards to serve as a permanent community database. This paper discusses some of the strategies to increase retention of the cards by caretakers. PMID- 19445106 TI - Strengthening capacity, collaboration and quality of clinical research in Africa: EDCTP Networks of Excellence. AB - Developing countries bear 90% of the global disease burden, but only access about 10% of globally available health research funding. Weak south-south networking hampers effective use of limited resources, production of critical mass of quality scientists, career opportunities and incentives to retain the few available scientists. The south must urgently act strategically to accelerate generation of talented scientists, create enabling environment and incentives to retain scientists and attract back those in diaspora. The creation of strong networks of excellence for clinical research among southern academic and research institutions is a novel strategic approach championed by European and Developing Countries Clinical Trials Partnership to achieve the aforementioned goals and mitigate the high disease burden. It will promote strong collaboration, resource sharing and cross-mentorship allowing each partner to grow with complementary capacities that support each other rather than compete negatively. It will enable the south and Africa in particular to participate actively and own the means for solving its own health problems and raise the professional quality and capacity of southern institutions to forge better and equal partnership with northern institutions. PMID- 19445107 TI - Regulation of human immunodeficiency virus-1 latency and its reactivation. AB - Treatment of human immunodeficiency virus (HIV) infection with highly active antiretroviral therapy (HAART) has become highly effective. However the persistence of a small population of infected cells containing transcriptionally silent but re-activatable HIV proviruses prevents complete elimination of the infection. Here, we review recent progress in our understanding of the molecular mechanisms underlying HIV proviral latency and highlight experimental therapies designed to eliminate the latent population. PMID- 19445108 TI - Revelations from the unconscious: studying residual brain function in coma and related states. AB - The purpose of our research is to contribute to a better understanding of the residual brain function of patients who survive an acute brain damage but remain in a coma, vegetative state, minimally conscious state or locked-in syndrome. The diagnosis, prognosis, therapy and medical management of these patients remain difficult. These studies are also of interest scientifically, as they help to elucidate the neural correlates of human consciousness. We here review our studies on bedside behavioral evaluation scales, electrophysiology and functional neuroimaging in these disorders of consciousness and conclude by discussing methodological and ethical issues and current concepts of the standards for care and quality of life in these challenging conditions. PMID- 19445109 TI - [Regeneration of hair cells and auditory neurons in the ear]. AB - Most of deafness have a neuro-sensory origin and are characterized by a loss of hair cells and auditory neurons in the spiral ganglion. At the moment, hearing aids are the only treatment available. To restore hearing in a patient suffering from deafness, it is necessary to study the mechanisms that might lead to the regeneration of neurosensory structures of the inner ear. HAIR CELL REGENERATION: The production of hair cells and supporting cells is terminated during embryonic development of the cochlea in mammals. However, several recent arguments suggest that new hair cells can be produced by the sensory epithelium of mammals. We first identified the presence of progenitor cells in the organ of Corti. In a second approach, the molecular mechanisms underlying the production of new hair cells have been studied. NEURONAL REGENERATION: The study of the development of the ear, cultures of neurons and analysis of animals invalidated for specific genes reveal that a number of growth factors are important for the maintenance and repair of neurons in the inner ear. These molecules induce the survival of auditory neurons in vitro and in vivo. The signaling pathways intra-cellular are analyzed with a better understanding of the mechanisms that lead to survival or death of neurons hearing and with the identification of new pharmacological agents that promote survival of neurons hearing in diseases of the inner ear. These molecules can be administered locally in the inner ear. IN CONCLUSION: Recent studies on the regeneration of neurosensory structures of the inner ear suggest that eventually it will be possible to replace the hair cells in the cochlea of mammals and to reinnervate them by auditory neurons in order to restore hearing in patients suffering from deafness. PMID- 19445110 TI - [End of the word and relegation of bodies in medicine: university formation of physicians]. AB - Medicine is based on a growing demand for science. Yet, the patient's speech is ill adapted to the current desire of rationality. Inaccuracy and errancy have become the features of clinical examination. Self censorship of the speech gradually appears. Presenting the body becomes useless, if not suspicious. Medical technology replaces perceived subjectivity. What medicine says prevails over what the body knows. In a strange paradox, the "echo" precedes the speech. The risk of having an autistic medicine is looming. University teaching must be aware of this. The obvious gap between the speech and the body not only evades the ethical issue but also paradoxically deprives the medicine from its scientific acumen. PMID- 19445111 TI - [General medicine in the 21st century]. AB - General medicine is the main pivot of our healthcare system. General practitioners' tasks are numerous: front line responsibility, networking coordination, long-term patient care, community medicine and also primary care research. In the framework of general medicine that has been undergoing profound change for many years, we have chosen to develop three of these facets: general practitioners' knowledge of family, psychological, social or environmental factors and their capacity to coordinate with other health workers will help them in their primary and secondary prevention and also quaternary work by sparing patients unnecessary treatment and examinations. General medicine will increasingly become a discipline, one of which specific expertise will be to manage bio-psycho-societal complexity. Multidisciplinary action will be the rule: general practitioners will no longer be able to claim they can deal with all the curative, preventive and health education tasks. And the research in general medicine is essential because general practitioners can deal with over 80% of the health problems identified by patients and because the symptoms leading to the treatment cannot only be studied by laboratory or hospital research. PMID- 19445112 TI - [Analysis of growth dynamics of Curcuma wenyujin]. AB - OBJECTIVE: To study the accumulation of matter and dynamic of chemical compositions in rhizoma of Curcuma wenyujin for its cultivation. METHODS: The weight of various parts and chemical composition content of rhizoma were determined at regular time. RESULTS: The growth of Curcuma wenyujin could be divided into the seedling period, the rhizoma growing period and dry matter accumulating period. In seedling period, the aerial parts were the center of organism, the matter accumulated mainly in leaves; In rhizoma growing period, the organic center were gradually transformed from the aerial parts to the underground parts. The tendency of total chemical composition quantity in rhizome presented rises at first but gradually dropped at last. CONCLUSIONS: The growth of Curcuma wenyujin has two organic centers, the seedling period and the rhizoma vegetal and weighted period. The total chemical composition quantity in Curcuma wenyujin rhizome reaches the maximum value from the last third part of October to mid-November. PMID- 19445113 TI - [Experiment on the hibernation of Poecilobdella manillensis]. AB - Poecilobdetla manillensis were divided into different groups with dissimilar number in the wet rice field soil and kept hibernating at room temperature. The results showed that the survival rates decreased along with the increase of the number in different groups. When the number of P. manillensis over 1 800 leech per square meter, the survival rate decreased significantly. However, it wasn't different from the rate of the group which number was below 1500 leech per square meter (P > 0.05). The net weight of various groups decreased about 10.4%-15.6% respectively after hibernation and there was no significant difference among groups (P > 0.05). It is concluded that rice field soil is suitable for the hibernation of P. manillensis. PMID- 19445114 TI - [Construction on ISSR fingerprint of Magnolia officinalis from Enshi in Hubei province]. AB - OBJECTIVE: To establish the ISSR fingerprint of the cortex of Magnolia officinalis produced from Enshi. METHODS: Cultivar and habit identification was based on Inter-simple sequence repeats (ISSR). RESULTS: Two ISSR primes could be used to construct the ISSR fingerprint of M. officinalis from Enshi. CONCLUSION: The ISSR marker is an effective method for the cultivar and habit identification of the cortex of M. officinralis. PMID- 19445115 TI - [Analysis on the volatile oil of Xinhui Pericarpium Citri Reticulatae in different years by GC/MS]. AB - OBJECTIVE: To analyze the difference of the volatile oil of Xinhui Pericarpium Citri Reticulatae in different years. METHODS: The components and contents of the volatile oil of Xinhui Pericarpium Citri Reticulatae were analyzed in different years by GC/MS. RESULTS: The components and contents of the volatile oil of Xinhui Pericarpium Citri Reticulatae changed along with the years. CONCLUSION: With the years' extension, the components of the volatile oil changed slowly during 3 years but quickly after 3 years, a few new components appeared evenly, So there's relevance between using old Xinhui Pericarpium Citri Reticulatae and its component changing. PMID- 19445116 TI - [Study on water processing conditions of Realgar]. AB - OBJECTIVE: To optimize the water processing (shui-fei) condition of Realgar. METHODS: The processing conditions were optimized by L9 (3)4 orthogonal design with three factors as water dose, process times and dryness temperature. The content of dissolved arsenic As(III) in Realgar was tested by High Performance Liquid Chromatography-hydride generation on-line coupled with atomic fluorescence spectrometry (HPLC-HG-AFS). RESULTS: The optimized conditions were 15 times quantity of water, 8 times for processing and dryness temperature of 40 degrees C. CONCLUSION: The method is accurate and effective,which can be used to evaluate the quality of processed products of Realgar. PMID- 19445117 TI - [Study on quality changes of Radix Aconiti Lateralis Praeparata under different storage conditions]. AB - OBJECTIVE: To analyze the changes of the content of water, soluble protein, total alkaloids, polysaccharides of Radix Aconiti Lateralis Praeparata under different storage treatments. METHODS: The experiment was conducted in 4 kinds of storage methods, such as sack storage, sand storage, cold storage, and the natural heap as the control. RESULTS: During storage, the content of water, total alkaloids and polysaccharides tended to decline, while the content of soluble protein increased. CONCLUSION: Compared with the others, the cold storage is most suitable for keeping good quality of Radix Aconiti Lateralis Praeparata. PMID- 19445118 TI - [Study on the fingerprint of processed Rhizoma Atractylodis Macrocephalae by HPLC]. AB - OBJECTIVE: To establish HPLC fingerprint for the quality control of processed Rhizoma Atractylodis Macrocephalae (PRAM). METHODS: 14 batches of PRAM were collected from different places and were analyzed with the developed HPLC fingerprints method. The HPLC separation was performed on a Kromasil C18 analytical column (250 mm x 4.6 mm, 5 microm), and gradient elution was performed by mobile phase containing acetonitrile and water. The flow rate was 1.0 mL/min and the detection wavelength was at 242 nm. The temperature of column was 25 degrees C. RESULTS: Sixteen mutual peaks were selected in chromatography. Among the obtained fingerprints, the most of the detected peaks were separated effectively. The methodological evaluation showed that the method had a good repeatability. CONCLUSION: The RSD of relative retention time of mutual peaks which existed in all samples was less than 1.1%. The results of peak areas were in accordance with the request of fingerprint. The established fingerprint can be used for the quality control and species identifying of PRAM. PMID- 19445119 TI - [Study on microscopic observation and TLC identification of Dai medicine "Guomaguo" (Spondias pinnata)]. AB - OBJECTIVE: To study identification methods of Dai medicine" Guomaguo", the fruit of Spondias pinnata. METHODS: Characteristic, microscopic observation and TLC idertification were used to authenticate this crude drug. RESULTS: The characters of the cross section, powder and TLC of the drug were reported, and the relevant drawings of the tissue, powder and TLC of this ethnomedicine were drawn. CONCLUSION: These results can supply evidences for the identification of the ethnomedicine in its exploitation and utilization. PMID- 19445120 TI - [Studies on chemical constituents of Dendranthema indicum var. aromaticum]. AB - OBJECTIVE: To study chemical constituents of Dendranthema indicum var. aromaticum. METHODS: The constituents were separated and purified by column chromatography with silica gel and Semi-preparative HPLC. Their structures were identified on the basis of physical-chemical properties and spectral data. RESULTS: Seven compounds were isolated and identified as acacetin, apignein, acacetin-7-O-beta-D-glucopy ranoside, apignein-7-O-beta-D-glucopy ranosids, luteolin, beta-sitosterol and daucosterol. CONCLUSION: Apigenin, acacetin-7-O beta-D-glucopy ranoside and apignein-7-O-beta-D-glucopy ranoside are obtained from the plant for the first time. PMID- 19445121 TI - [Studies on chemical constituents of Eleutherine americana]. AB - OBJECTIVE: To research the chemical constituents from Eleutherine americana. METHODS: Column chromatography with silica gel was employed to isolate and purify the constituents. Their structures were elucidated by means of MS and NMR. RESULTS: Eight constituents were obtained and identified as Isoeleutherol (1), eleutherin (2), isoeleutherin (3), beta-sitosterol(4), 8-hydroxy-3, 4-Dimethoxy-1 methyl-anthra-9, l0-quinone-2-carboxylic acid methyl ester (5), Hongconin (6), 4,8-Dihydroxy-3-Methoxy-1-methyl-anthra-9,10-quinone-2-carboxylic acid methyl ester (7), Eleutherinone (8), Kadsuric acid (9). CONCLUSION: Compound 9 is isolated from the plant for the first time. PMID- 19445122 TI - [Study on chemical constituents of Herba Cirsii]. AB - OBJECTIVE: To study the chemical constituents from the aerial part of Herba Cirsii. METHODS: Compounds were isolated by various chromatographic techniques and identified by spectral data. RESULTS: Eight compounds were obtained. Their structures were characterized as (7R,8S)-dehydroconiferyl alcohol-8,5' dehydroconiferyl aldehyde-9-O-beta-D-glucopyranoside(I),(7S,8R)-dihydro dehydrodiconiferyl alcohol-9-O-beta-D-glucopyranoside(II), Isokaempferide-7-O beta-D-glucopyranoside(III), Quercetin-3-O-beta-D-gluco-pyranoside (IV), Pectolinarin (V), Rutin(VI), Sucrose(VII), beta-sitosterol(VIII). CONCLUSION: Among these compounds, compounds I-IV are isolated from Herba Cirsii for the first time, Compounds first time. I and II as lignan compounds from this genus, are reported for the first time. PMID- 19445123 TI - [Analysis of essential oil from different organs of Caryopteris tangutica]. AB - OBJECTIVE: To study the main chemical components of essential oils from Caryopteris tangutica. METHODS: The chemical compositions of essential oils obtained by hydrodistillation from different organs of Caryopteris tangutica were separately analyzed and identified by GC-MS and Kovats retention index. The relative contents of the components by the peak-area normalization method adopted in gas chromatography. RESULTS: 13.48 and 42 components were separately identified from stems, leaves and flowers. The components and relative contents of the leaves were similar with the flowers, and the main constituents were Myrtenal (2.73%, 1.69%), trans-Pinocarvyl acetate (46.69%, 55.48%), Myrtenyl acetate (1.17%, 1.42%), beta-Cedrene (1.62%, 3.21%), Caryophyllene oxide (1.67%, 2.73%) and so on. The components of the stems were different from others, and the main constituents were hexadecanoic acid (47.32%), trans-Pinocarvyl acetate (24.19%), phytol (0.77%). CONCLUSION: The components and relative contents of the essential oils among stems, leaves and flowers were distinctly different, and each of them had a great range of potential utilities and a prospect of development. PMID- 19445124 TI - [Analysis of chemical constituents of the volatile oil from flowers of Oyster Rhoeo by GC/MS]. AB - OBJECTIVE: To analyze the chemical constituents of the volatile oil from the flowers of Oyster Rhoeo. METHODS: The volatile oil from the flower of Oyster Rhoeo was extracted by steam distillation and its chemical constituents were analyzed by GC/MS technique. RESULTS: All 20 compounds which relative content was greater than 0.3% were identified, accounting for 90.24% of the volatile oil. CONCLUSION: The major constituent of the volatile oil is nonaldehyde (25.72%), the other main constituents are hexadecanoid acid (22.79%), nonanoic acid (18.94%), dodecanoic acid (7.72%), isovanillin (2.84%), heptanoic acid (2.20%), octanoic acid (1.89%) and linoleic acid (1.71%), respectively. PMID- 19445125 TI - [Study on chemical constituents and antimicrobial activity of the essential oil from Acanthopanax brachypus]. AB - OBJECTIVE: The chemical constituents and antimicrobial activity of the essential oil from Acanthopanax brachypus were studied. METHODS: The essential oil was extracted from the stem of A. brachypus by steam distillation, and its antimicrobial activity was tested in vitro. The chemical constituents were separated and identified by GC-MS, and the relative contents of each constituent was determined by area normalization. RESULTS: The essential oil showed some certain antibacterial activities against the tested strains escherichia coli, bacillus subtilis, staphylococcus aureus, pseudomonas aeruginosa and candida albicans except aspergillus niger. Forty-seven constituents were separated and identified, accounting for 91.37% of the total oil. The main constituent were Heptanoic acid (7.05%), Vanillin (6.09%), trans-Linalool oxide (6.07%), 1-methyl 2-(-methylethyl)-Benaene (5.83%), alpha-Phellandrene (5.14%), n-Hexadecanoic acid (5.15%) and beta-Myrcene (5.07%). CONCLUSION: The essential oil of A. brachypus contained varied active constituent, has a certain antimicrobial activity, this result will provide some scientific references for the pharmacological further research of A. brachypus. PMID- 19445126 TI - [Effects of Realgar and prescription containing Realgar on stress response proteins, inflammatory mediators and complements in fever rat models]. AB - OBJECTIVE: To explore the pharmacological mechanism of Realgar by the way of studying the effects of Realgar and the prescription containing Realgar named Niuhuang Jiedu Tablet on stress response proteins (heat shock protein 70, HSP70 and heme oxygenase-1, HO-1), inflammatory cytokines (IL-1beta, IL-6 and TNF alpha), activities of nitric oxide synthetase (NOS) and its isoenzyme (inducible nitric oxide synthetase, iNOS), and complements C3, CA under pathologic status (fever model). METHODS: SD rats were randomly divided into four groups, 15 rats in each: untreated normal group, fever model group, Realgar (90 mg/kg) group and Niuhuang Jiedu Tablet (NJT, 1.404 g/kg) group. Each group was divided into three subgroups (5 rats/subgroup). Blood samples of the rats in subgroups were collected at 1 h, 2 h and 4 h after administration, respectively. ELISA method was used to determine HSP70, IL-1beta, IL-6, and TNF-alpha levels in serum. Dual wavelength spectrophotometry was used to determine activity of HO-1 in serum. Spectrophotometry was used to test activities of nitric oxide synthetase (NOS) and its isoenzyme (inducible nitric oxide synthetase, iNOS) in serum. Immunonephelometery method was used to test complements C3, C4 in serum. RESULTS: Realgar and NJT significantly increased the level of HSP70 in rat serum as compared with the fever model group. Realgar and NJT significantly enhanced the activity of HO-1 in rat serum as compared with the fever model group. The increase ranges of HO-1 activities at different time post administration changed with the arsenic concentration in rat serum. Realgar and NJT significantly decreased the level of IL-1beta in rat serum as compared with fever model group, and the level of IL-lbeta recovered normaly at 4 h after administration. NJT significantly inhibited activities of NOS and iNOS in rat serum as compared with the fever model group at 2 h after administration. CONCLUSION: Realgar as contained in certain prescriptions, at certain specific levels, assists in removal of internal toxins by inducing stress protein (HSP70, HO-1) to improve the positive stress level in the body and inhibiting some over-releasing inflammatory mediators (IL-1beta) to reduce the inflammatory reactions under pathologic status. PMID- 19445127 TI - [Effects of PUVA on expression of Fas and FasL in inducing apoptosis of NB4 and K562 cells]. AB - OBJECTIVE: To explore the effects of psoralen (PSO) and long wave ultraviolet A (PUVA) on expression of Fas and FasL in apoptosis of NB4 and K562 leukemia cells. METHODS: The NB4 and K562 cells were taken as the study objects and their apoptosis ratios, ultrastructure changes and the expression of Fas and FasL were detected in order to observe the effects of PSO and UVA of wave length 360 nm on human leukemia cells. The factorial design and analysis of variance were used to analyze the interaction among the factors. RESULTS: All of PSO, UVA and PUVA could induce the apoptosis of NB4 and K562 cells, and the effects of PUVA were stronger than the other two. After treated with PUVA, the NB4 and K562 cells all showed obvious ultrastruture changes about apoptsis under the electron microscope. All of PSO, UVA and PUVA could increase the expression of Fas gene and protein, and decrease the expression of FasL gene and protein. Moreover, the effects of PUVA were stronger than the other two. CONCLUSION: PUVA can induce the apoptosis of NB4 and K562 cells and the effects are the strongest, one of the pathway of PUVA to induce apoptosis is to upregulate the expression of Fas gene and downregulate the expression of FasL gene. PMID- 19445128 TI - [Inhibitive effects of Panax notoginseng saponins on expression of Abeta(1-40), Abeta(1-42) protein in SAMP8's brain]. AB - OBJECTIVE: To observe inhibitive effects of Panax notoginseng saponins on expression of Abeta(1-40), Abeta(1-42) protein in SAMP8's brain. METHODS: Amount of Abeta(1-40), Abeta(1-42 immuno-positive neurons was detected in parietal cortex and hippocamp in their brains under high power lens (40 x) by immunohistochemistry analysis. RESULTS: PNS could reduce the amount of Abeta(1 40), Abeta(1-42) protein in parietal cortex and hippocamp. CONCLUSION: PNS can reduce the amount of Abeta(1-40), Abeta(1-42) protein in SAMP8's brain. PMID- 19445129 TI - [Effects of Astragalus membranaccus on cardiac function and SERCA2a gene expression in myocardial tissues of rats with chronic heart failure]. AB - OBJECTIVE: To investigate the effects of Astragalus membranaccus (As) on cardiac function and SERCA2a gene expression in left ventricular tissues of rats with chronic heart failure. METHODS: Heart failure was induced by clipping the abdominal aorta 60 male SD rats were divided into four groups: sham-operated (Sham), aortic stenosis (Model), Model + As (20 g/kg) and Model + Captopril (0.05 g/kg). The drugs were administered orally from the 13th week after surgery. Rats were examined after 12 weeks' treatment with drugs. The parameters of hemodynamics including LVSP, LVEDP, and +/- LVdp/dt(max) were measured. SERCA2a mRNA and protein expressions in left ventricular tissues were determined by half quantitative RT-PCR and Western blot normalized to abundance of GAPDH mRNA and portein, respectively. RESULTS: LVSP and LVEDP were obviously enhanced (P < 0.01 or P < 0.001) in model rats in vivo. Both Captopril and As prevented the increase of LVSP (P < 0.05 or P < 0.01) and LVEDP (P < 0.05 or P < 0.01). RT-PCR and Western blot results demonstrated that SERCA2a gene expression was downregulated (P < 0.05) significantly in model group compared with sham group. As upregulated SERCA2a gene expression (P < 0.05), whereas Captopril had no effect on that. CONCLUSION: As can ameliorate abnormity of cardiac function, especially diastoilc function in rats with pressure overload-induced heart failure, and that may be partly related to its up-regulation of SERCA2a gene expressions in left ventricular tissues. PMID- 19445130 TI - [Study on inhibitive effect of extracts from Scindapsus aureus on alpha glucosidase and its antioxidant activity]. AB - OBJECTIVE: To study the inhibitive effect of extracts from Scindapsus aureus on alpha-glucosidase and its antioxidant activity. METHODS: The 70% ethanol extracts was extracted by petroleum, ethyl acetate and n-butanol, and the inhibitory activity against alpha-glucosidases and antioxidative effects of each fraction were determined in vitro, and the inhibitory kinetics of ethyl acetate fraction was investigated. RESULTS: The inhibitory activity of ethly acetate fraction against alpha-glucosidase was higher as its IC50 was 43.63 microg/mL. The inhibition kinetics analyzed by Hnewaver-Burk plots showed that ethyl acetate fraction was a competitive type inhibitor, and the inhibition constants for free ennzyme (Ki) was determined to be 21.49 microg/mL. The antioxidative effects of ethly acetate and n-butanol fractions exhibited stronger than that of other fractions, the scavenging ability on DPPH at the concentration of 0.42 mg/mL were 88.5% and 93.6%. Ethly acetate fraction showed scavenging ability on autioxidantor, and the IC50 values was 0.27 mg/mL. CONCLUSION: Ethyld acetate fraction of extract from Scindapsus aureus has potential inhibitroy activity against alpha-glucosidase and antioxidant effects, and n-butanol fraction has great antioxidative effects. PMID- 19445131 TI - [Ginkgo biloba extracts (EGb761) inhibits aflatoxin B1-induced hepatocarcinogenesis in Wistar rats]. AB - OBJECTIVE: To investigate the effect of Ginkgo biloba extracts (EGb761) on aflatoxin B1 (AFB1)-induced hepatocarcinogenesis and its antioxidant activity in Wistar rats. METHODS: 71 Wistar rats were randomly divided into three groups: AFB1 (group A); AFB1 +EGb761 (group B), Control (group C). Rats in gurop A and B were injected with AFB, through abdomen and the doses were 100-200 microg/kg, one to three times a week. Liver biopsy were performed in all rats during 14th w, 28th w, 42th w and 55th w, and were executed at 64th w. Gammaglutamyl transpeptidase-positive hyperplastic cell foci (gamma-GT foci) and histopathology of the liver tissue were observed. The levels of malondialdehyde (MDA), as well as the activity of Glutathione peroxidase (GSH-Px) was examined. RESULTS: At 42th w and 55th w, the gamma-GT focus area (mm2/focus) and general area of foci (mm2/cm2) of group B were significantly smaller than that in group A (P = 0.000). The incidence of hepatocelluiar carcinoma (HCC) in group B (26.92%) was significantly lower than that in group A(76%) (P = 0.000). Group C didnt have HCC development. EGb 761 markedly increased GSH-Px activity, reduced MDA levels (P < 0.05). CONCLUSION: EGB761 shows effective inhibition to hepatocarcinogenesis induced by AFB1 in rats, which may be related to its antioxidant activity. PMID- 19445132 TI - [Effects of Geranium sibirum extracts on liver metastases in nude mice with colonic cancer]. AB - OBJECTIVE: To establish nude mice models with the liver metastases of colonic adenocarcinoma and study the effects of Geranium sibirum extracts on them. METHODS: Nude mice liver metastases model of colonic cancer was established with human colonic cancer cells line( Ls 174t) inoculated into mice spleen. 36 nude mice were randomly divided into 3 groups, containing control group, Geranium sibirum extracts group and hydroxycamptothecine group. The weight and size of the mice and growth of the carcinoma were recorded. All specimens were examined histologically. pS2 in blood in nude mice with liver metastasis of colonic carcinoma was detected with nested RT-PCR. RESULTS: The incidence of liver metastasis was 100% in this intrasplenic injection model. The pathological results showed that tumour cells of liver metastases were poorly differentiated human colonic adenocarcinoma. In Geranium sibirum extracts group, the tumor number and the weight of liver metastases were significantly lower than those in hydroxycamptothecine group (P < 0.05). Using semiquantitative examination,in Geranium sibirum extracts group,the relative value of pS2 expression in blood was significantly higher than that in hydroxycamptothecine group (P < 0.05). CONCLUSION: Geranium sibirum extracts can effectively inhibit the occurrence of liver metastases carcinoma and decrease the positive expression of pS2, it also has better effect than hydroxycamptothecine so that Geranium sibirum extracts may become the potential therapeutic strategy for liver metatstases of colonic cancer. PMID- 19445134 TI - [Effect of gensenoside Rg3 on apoptosis of Hep-2 and expression of HIF-1alha in human laryngeal cancer cell line under anoxic conditions]. AB - OBJECTIVE: To study the mechanism and effect of gensenoside Rg3 on Hep-2 Cell Line during the normoxia and hypoxia. METHODS: Hep-2 Human Laryngeal Cancer Cell Line was cultured under anoxic conditions, and set the normal control group and positive control group (DDP). MTT was used to observe the growth inhibition rates of Hep-2 Human Laryngeal Cancer Cell by Rg3; The cell cycle and cell apoptosis analysis were detected by FCM. Then the expression of HIF-1alpha and VEGF protein was detected by immunohistochemistry and FCM; The expression of HIF-1alpha and VEGF mRNA were detected by transcription-polymerase chain reaction (RT-PCR). RESULTS: Rg3 could significantly inhibit the growth of Hep-2 cells and arrest the cells in G0/G1 phase during normoxia and hypoxia The mRNA and protein expression of HIF-1alpha were dolon-regulated. CONCLUSION: Rg3 can inhibit Hep-2 cells growth by delaying the progress of cell cycle and inhibit the expression of HIF 1alpha during hypoxia, this may be the mechanism of its anti-tumor effect. PMID- 19445133 TI - [Experimental study on effect of total flavone of Ginkgo biloba on delaying cell senescence]. AB - OBJECTIVE: To investigate the mechanism of delaying the senescence of human diploid fibroblast (2BS) by total flavone of Ginkgo biloba (FG). METHODS: The drug sera of FG was used to treat the 2BS. The population doublings of 2BS cells were observed, the mRNA expression of P16 gene was determined by fluorescence real-time quantitative PCR. RESULTS: FG significantly extended the population doublings of 2BS cells, and decreased the expression of P16 mRNA. CONCLUSION: FG can delay the senescence of cells by inhibiting the P16 gene expression. PMID- 19445135 TI - [Study on the preparation process of inclusion complex of volatile oil of Dalbergia odorifera-beta-cyclodextrin]. AB - OBJECTIVE: To study the optimum preparation process of the volatile oil of Dalbergia odorifera-beta-cyclodextrin. METHODS: The saturated water solution mixing method was compared with microwave method and ultrasonic method by determining the ultilization ratio of the volatile oil in Dalbergia odorifera. The optimum preparation conditions were investigated by the orthogonal design. The quality of the volatile oil before and after included were analyzed by TLC. RESULTS: The optimum preparation conditions for inclusion were as follows: m(volatile oil of Dalbergia odorifera): m (beta-CD) = 1:10 (g/g), ultrasonic time was 1h, the temperature was 70 degrees C. The ultilization ratio of the volatile oil was 82.02%. CONCLUSION: Ultrasonic method is the best method. PMID- 19445136 TI - [AOTF-near infrared spectroscopy for determining tanshinone II A in returning extraction process of Salvia miltiorrhiza]. AB - OBJECTIVE: To explore a method on-line determining the contents of tanshinone II A in returning extraction process of Salvia miltiorrhiza by AOTF-Near infrared spectroscopy. METHODS: Firstly, the sample was collected in the extraction process of Salvia miltiorrhiza. Then HPLC was used as a reference method to determine the contents of tanshinone II A in the sample. Multivariate calibration models based on PLS1 algorithm were developed to correlate the spectra and the corresponding values determined by the reference methods. RESULTS: RMSECV of the models for tanshinone II A was 0.0092. The correlation coefficients of the calibration models was 0.9918. External validation with external validation samples proved that the relative deviation was 5.74%. CONCLUSIONS: AOTF-NIRS can be used in the determination of tanshinone II A in returning extraction process of Salvia miltiorrhiza. The method is rapid, accurate and non-destructive, and can be applied for process analysis and quality control of Chinese medicine manufacturing process. PMID- 19445137 TI - [Extraction of polysaccharide from Penthorum chinense]. AB - OBJECTIVE: To study the extraction technology of polysaccharide from Penthorum chinense. METHODS: Single factor test and orthogonal experiment design methods L9 (3(3)) were applied to analyze the influence of solid-liquid rate, extraction temperature and time on the extraction percent of polysaccharide from Penthorum chinense. RESULTS: The temperature significantly affected the extraction percent of the soluble polysaccharide, and the optimum conditions for the extraction technology were as follows: solid-liquid rate at 1:15, temperature at 95 degrees C, time for 3h. Under this condition, the extraction percent of polysaccharide from Penthorum chinense was 1.12%, RSD = 1.21%. CONCLUSION: The research can provide a theoretical foundation for further development and utilization of polysaccharide from Penthorum chinense. PMID- 19445138 TI - [Extraction process and content determination of total organic acids from Pothos chinensis]. AB - OBJECTIVE: To study the optimum extracting process of total organic acids from Pothos chinensis and establish a determination method for total organic acids. METHODS: By orthogonal design, we investigated the effects of 4 factors containing concentration of ethanol, ratio of solid to liquid, frequency of extraction and time of extraction. After the extraction, the determination was done with potential titration. RESULTS: The best extraction conditions were using 75% (V/V) ethanol as extractor with the radio of 1:10, and extracting for 2.5 h and 3 times. The determination method was simple, reproducible and suitable. CONCLUSION: These results provide certain scientific basis for further efficacy of research and development of Pothos chinensis. PMID- 19445139 TI - [Purification of Ganoderma lucidum polysaccharide by ultrafiltration technology]. AB - OBJECTIVE: To investigate the feasibility and technology for purifying Ganodermna lucidum polysaccharide (GLP) by ultrafiltration. METHODS: A spire roll ultrafiltration unit was selected to purify GLP. RESULTS: Purity of 73.5% and recovery ratio of 69.4% for GLP were obtained by using a membrane with cut-off molecular mass of 6000, while operating temperature, pressure and time were 45-50 degrees C, 0.6 MPa and 45 min, respectively. CONCLUSION: Ultrafiltration is one of the new feasible methods for the purification of GLP. PMID- 19445140 TI - [Review on application of microdialysis in medicine study]. AB - Recent publications are quoted to summarize multiple use of microdialysis in medical fields, especially in pharmacology and pharmacokinetics. Microdialysis was coupled with HPLC-ECD, HPLC-MS and other detectors to study endogenous substances and medicines, including neurotransmitters, amino acid, other endogenous metabolites and drugs as well as Chinese medicines. Microdialysis is a relatively new sampling technique and its advantages as well as disadvantages are briefly assessed. At the end of this review, an outlook to apply this technique in traditional Chinese medicine study is given forward. PMID- 19445141 TI - [Create mathematical model and analysis of correlation between traditional Chinese medicinal characteristics and neurobehavioral effects]. AB - In the guidance of system theory, using Multidisciplinary technology to study on the combination of Chinese traditional and western medicine, helps to promote fingding the common points between the Chinese traditional and western medicine. In this article, it intends to create mathematical model and analysis of correlation between Chinese medicinal characteristics and neurobehavioral effects based on literature informatics. The numbers of the Chinese medicines with neurobehavioral effects were worked out within the frame work of 'The China Pharmacopeia' of 2005 edition, from the literature publicized since 1980. The correlation and mathematical model were figured outbetween Chinese medicinal characteristics including traditional functional classification, different tastes as well as channel tropism and immunoregulatory activity based on the statistical software SPSS. The results showed that the neurobehavioral effects was related to the qi-invigorating drugs, yang-invigorating herbs, blood-invigorating herbs, resuscitative drugs and kidney meridian herbs, tastes mild of Chinese medicines (P<0.05). It also accords with the theory of 'Kidney produce marrow' of TCM, The coincidencewas 82.8% between mathematical computing and original classification. There are correlations between Chinese medicinal characteristics and neurobehavioral effects. The mathematical model based on these results can be used for studing of neurobehavioral effects and clinical treatment. PMID- 19445142 TI - [Study on genetic diversity of Codonopsis tangshen by SRAP and ISSR markers]. AB - OBJECTIVE: To study the genetic diversity of Codonopsis tangshen. METHOD: Eighteen germplasmic resources of C. tangshen were analyzed by SRAP and ISSR molecular markers. The systematic diagram of genetic relationship was made by TREECONW software and clustered by UPGMA method. RESULT: Twenty-nine SRAP primer combination amplified 329 bands with 266 (80.85%) polymorphic and 21 ISSR primers amplified 223 bands with 166 (74.44%) polymorphic. The average genetic similarity coefficient was 0.7121 (by SRAPs) and 0.7781 (by ISSRs). Both SRAP and ISSR analyses revealed a high level of genetic diversity in C. tangshen. By cluster analysis, the geographical distribution was not distinctive. The significant positive correlation between SRAPs and ISSRs was observed (r=0.802, P<0.01), although the dendrograms based on SRAP and ISSR markers were not all the same. CONCLUSION: Different germplasms diversity of C. tangshen is high and SRAP and ISSR can be used in genetic diversity study of C. tangshen. PMID- 19445143 TI - [AFLP analysis of genetic diversity of Prunella]. AB - OBJECTIVE: To explore the variety of the genetic polymorphism of eight Prunella germplasm resources by AFLP analysis. METHOD: The amplified fragment length polymorphism (AFLP) tags were applied to screen out 32 selective amplification primer pairs, the amplified bands as original matrix were analyzed with NTSYS-PC software for the similarity between the Prunella germplasm and the construction of genetic phylogenetic tree. RESULT: SDS extraction of genomic Prunella DNA showed a good quality, could meet the requirements of AFLP analysis. From 32 selective amplification primer pairs, 10 pairs with strong polymorphism, better band and higher resolution were used for the construction of the AFLP Prunella fingerprint, all eight Prunella germplasms were separated, they were divided into 3 categories. CONCLUSION: Prunella germplasm resources are rich in genetic diversity, certain morphological characteristics and differences are associate with genotype. PMID- 19445144 TI - [Analysis on Cistanche tubulosa that parasites on different Tamarixs by RAPD]. AB - OBJECTIVE: To study genetic difference of Cistanche tubulosa that parasites on different Tamarixs and give a reference to select host of C. tubulosa. METHOD: Sixteen selected primers by random amplified polymorphic DNA (RAPD) markers were used to analyze genetic distance of C. tubulosa that parasites on eight different hosts. RESULT: Sixty-six point seven percent of the total bands were polymorphic, that proved the genetic diversity level in different C. tubulosa types was relatively high, especially the two that parasites on Tamarix hispida and T. chinensis. Cultural areas had more remarkable influence on genetic distance of Cistanche tubulosa than the hosts, and introduction was helpful to maintain the more genetic diversity in different C. tubulosa types. Genetic difference in different C. tubulosa types was far less than that between different species in Cistanche. CONCLUSION: C. tubulosa types which parasite on different Tamarixs have high genetic diversity. PMID- 19445145 TI - [Inspection on result of artemisinin content rank distribution in Guangxi]. AB - OBJECTIVE: In order to enhance the yield of artemisinin, makes out the Artemisia annua adaptive area regional assignment in Guangxi. To ensure the nicety in study, on the base of literature study and experience on the spot, the article inspect the division result. METHOD: By document analysis and colleted data of A. annua, make out sample collect proceed and inspect the result of artemisinin content rank distribution in Guangxi. RESULT AND CONCLUSION: Result of A. annua regional assignment is checked out in the article, the result passes the check by AQL (32, 4). The conclusions insure subsequence study and the A. annua sample collect. The result of artemisinin content rank distribution in Guangxi can be used in artemisinin production. PMID- 19445146 TI - [Study on factors affecting mucosal permeability of gardenia extract]. AB - OBJECTIVE: To study the factors that affect mucosal absorption of gardenia extract. METHOD: Take vitro frog skin as a model to study the vitro mucosal permeation. The impacts of the osmotic pressure and the pH value of permeation medium on the Papp of the Jasminoidin were studied, and the effect of frog skin on the stability of Jasminoidin was investigated also. RESULT: The Papp of Jasminoidin were (0.53 +/- 0.01), (0.21 +/- 0.05), (0.44 +/- 0.12), (0.42 +/- 0.13), (0.26 +/- 0.03) cm x min(-1) by using the normal saline (pH 6.88), pure water, 1.8 % NaCl solution, normal saline (pH 4.05) and normal saline (pH 10.05) as permeation medium for each. The accumulated permeation rate was (55.69 +/- 9.81)% by 12 h, using normal saline as permeation medium respectively, and there was no obvious time lag. Jasminoidin began to degrade around 8 h by affectedof frog skin, the constant of degradation rate (K) was 1.999, and the t1/2 was 0.347 h. CONCLUSION: The mucosal permeability of gardenia extract by using the vitro model of frog skin is good, and consistent with zero level absorption process. The osmotic pressure and pH value significantly affected the permeation and the isotonic and partial neutral permeation medium are more conducive to the permeation and absorption of Jasminoidin. The degradation effect of frog skin to the Jasminoidin will not affect mucosal permeation research. In vitro model of frog skin is a suitable way to simulate mucosal permeation process of the gardenia extract. PMID- 19445147 TI - [Study on optimization of formulation and preparation process of sinomenine liposomes]. AB - OBJECTIVE: To optimize the formulation and preparation process of sinomenine liposomes. METHOD: Method of aether injection and mixture uniform design were adopted to determine the formulation of sinomenine liposomes is the proportion of phospholipids, cholesterol and Vitamin E with the index of entrapment efficiency. And the single-factor test was used to study the preparation process of the liposomes, including the volume of buffer solution, the preparation temperature and the ultrasonic time. RESULT: The optimized formulation was that the ratio of sinomenine : phospholipids : cholesterol : vitamin E mass ratio was 8.92 : 60.35 : 28.81 : 1.91. The volume of buffer solution was 50 mL x g(-1) membrane, the preparation temperature was 50 degrees C, and the ultrasonic time was 20 min. CONCLUSION: Satisfactory shape and entrapment efficiency of the liposomes can be obtained by the optimized formulation and preparation process. PMID- 19445148 TI - [Studies relationship between powder characteristic of kinds of granules and their hygroscopicity]. AB - OBJECTIVE: To choose the granuling way for preparing granules that had low moisture-absorption characteristics. METHOD: Granules were prepared by five ways, for studying the relationship between characteristics of powder and hygroscopicity were determined. RESULT: The prepared ways of granuling that had low hygroscopicity were dry granuling and secondary swinging granuling. CONCLUSION: The hygroscopicity of granules can be explained by characteristics of powder, which are made in different granuling ways. The prepared ways of granuling that have low hygroscopicity are dry granuling and secondary swinging granuling. PMID- 19445149 TI - [Chemical constituents of flavonoids from rhizome of Sophora tonkinensis]. AB - OBJECTIVE: To study the chemical constituents of the flavonoids from Sophora tonkinensis. METHOD: The compounds were isolated by chromatography on silica gel, Sephadex LH-20 column and identified by spectroscopic analysis. RESULT: Eight compounds were isolated and their structures were identified as tonkinochromane I (1), glabrol (3), lupinifolin (2), tonkinensisol (4), 8-C-prenylkaempferol (5), 7,2'-dihydroxy-4'-methoxy-isoflavanol (6), formononetin (7), and genistein (8), respectively. CONCLUSION: Compound 1 was a new compound. And compound 6 was firstly isolated from the genus Sophora. Compounds 2, 3 and 5 were isolated from S. tonkinensis for the first time. PMID- 19445150 TI - [Study on Diels-Alder type adducts from stem barks of Morus yunanensis]. AB - OBJECTIVE: To isolate and identify the Diels-Alder type adducts from stem barks of Morus yunanensis. METHOD: The compounds were isolated and purified by silicagel, Sephadex LH-20 and RP-18 colum chromatography. Their chemical structures were elucidated on the basis ofphysicochemical properties and spectral data. RESULT: Nine compounds were isolated and identified as: kuwanon G (1), sanggenol M (2), mulberrofuran J (3), guangsangon B (4), resveratrol (5), kuwanon X (6), kuwanon P (7), mulberrofuran O (8), mulberrofuran Q (9). CONCLUSION: All the compounds are isolated from the plant for the first time, and compounds 4, 5 have anti-inflammation activities with inhibitory ratios of 57.3%, 50.5% respectively at a concentration of 10 microg mL(-1). PMID- 19445151 TI - [Studies on triterpenoid saponins in Hemsleya chensnsis]. AB - OBJECTIVE: To study the triterpenoid saponins in Hemsleya chensnsis. METHOD: The chemical constituents were isolated and purified by various chromatographic methods and their structures were elucidated on the basis of spectral analysis. RESULT: Seven known triterpenoid saponins were isolated from the root of H. chensnsis and were identified as 3-O-beta-D-glucuropyranosyl-oleanol-icacid (1), 3-O-beta-D-glucopyra-noside-oleanolicacid-28-O-beta-D-glucopyranoside (2), 3-O (6'-methylester)-beta-D-glucuropyranosyl olea- nolic acid-28-O-alpha-L arabinopyranoside (3), 3-O-(6'-methylester)-beta-D- glucuropyranosyl- oleanolic acid-28-O-beta-D-mannupyranoside (4), 3-O-(6'-ethyl ester)-beta-D glucuropyranosyl oleanolic acid-28-O-beta-D- glucopyranoside (5), 3-O-alpha-L arabinopyranoside-(1-->3) -beta-D-glucuropyranosyl- oleanolic acid-28-O-beta-D glucopyranoside (6), 3-O-beta-D-glucu-ropyranosyl-oleanolic acid-28-O-beta-D glucopyra-noside-(1-->6)-beta-D-glucopyranoside (7). CONCLUSION: Compounds 1-7 were isolated from this plant for the first time. PMID- 19445152 TI - [Studies on chemical components of Lobelia chinensis]. AB - OBJECTIVE: To study on the chemical constituents of Lobelia chinensis. METHOD: The coloumn chromatographic techniques were applied to isolate constituents, and their structures were elucidated by means of spectral data analysis. RESULT: Sixteen compounds were isolated and identified as daucosterol (1), diosmetin (2), apigenin (3), chrysoeriol (4), loteolin (5), hesperidin (6), loteolin-7-O-beta-D glucoside (7), apigenin-7-O-beta-D-glucoside (8), linarin (9), diosmin(10), 5,7 dimethoxy-8- hydroxycoumarin (11), palmitinic acid (12), lacceroic acid (13), stearic acid (14), beta-sitosterol (15), daucosterol (16). CONCLUSION: All of these compouds were obtained from L. chinensis for the first time. PMID- 19445153 TI - [Determination of 5-hydroxymethyl-furfural in root of Achyranthes bidentata expressing different degree of floating sugar]. AB - OBJECTIVE: To study the relation between the content of 5-hydroxymethyl-furfural (5-HMF) and the degree of floating sugar in root of Achyranthes bidentata. METHOD: An HPLC method was applied with a Waters Symmetry C18 3.9 mm x 150 mm (5 microm) column by using methanol-water (12:88) as the mobile phase at a flow rate of 1.0 mL x min(-1) and a UV detection of 280 nm. RESULT: Along with the degree's deepening of floating sugar, the content of 5-HMF varied with the different shades of the sample. The content was 10 times higher in the black sample (highest degree of flowing suger) than that in the yellowish sample (normal). The concentrations of 5-HMT in five yellowish samples of roots of A. bidentata were 0.162 mg x g(-1) to 0.332 mg x g(-1). CONCLUSION: The content increasing of 5-HMF in the root of A. bidentata was related to the degree of flowing sugar. PMID- 19445154 TI - [RP-HPLC determination of tiliroside in Daphne genkwa]. AB - OBJECTIVE: To determine the contents of tiliroside [kaempferol 3-O-beta-D-(6 " -p coumaroyl) glucopyranoside] in the Daphne genkwa. METHOD: The separation was performed on ZORBAX XDB C18 column (4.6 mm x 250 mm, 5 microm), using acetonitrile and water/acetic acid mixture (1,000/1) (gradient elution: 0-18 min, 26 : 74; 18-33 min, 80 : 20) as mobile phase with the rate of 1.0 mL x min(-1) at 25 degrees C, the wavelength for measurement was 310 nm. RESULT: The linearity was in the range of 0.1-5.0 microg (n=6), and the correlation coefficient was 0.9999. The average recovery for compound tiliroside was 101.50% (RSD 0.90%) (n=6). CONCLUSION: This method is accurate, reliable and reproducible to determine tiliroside in the D. genkwa. PMID- 19445155 TI - [Determination of oleuropein in stem of Syringa oblata from different districts by HPLC]. AB - OBJECTIVE: To develop an HPLC method for the determination of oleuropein in Syringa oblata. METHOD: An Aigilent ZORBAX SB- C18 column (4.6 mm x 250 mm, 5 microm) was used. The mobile phase was acetonitrile-water (21 : 79). The flow rate was 1.0 mL x min(-1). The detection wavelenghth was set at 232 nm and the column temperature was 30 degrees C. RESULT: The linear range of oleuropein were from 0.011 62 g x L(-1) to 1.162 g x L(-1). The average recovery was 98.7% with RSD 2.5% (n=9). CONCLUSION: The method is reliable, accurate and specific. It can be used for quality control of the stem of Syringa oblata. PMID- 19445156 TI - [Effects of 18beta-glycyrrhizic acid and 18alpha-glycyrrhizic acid on mRNA and protein expression of cytochrome P450 3A in cultured rat primary hepatocyte]. AB - OBJECTIVE: To study the effects of 18beta-glycyrrhizic acid and 18alpha glycyrrhizic acid on mRNA and protein expression of cytochrome P450 3A in cultured rat primary hepatocyte. METHOD: Rat heaptocyte were isolated by two-step in situ collagenase perfusion method; the hepatocytes were seeded in dishes coated with type I rat tail collagen, culture medium was added and changed daily after gelation, the effect of 18beta-glycyrrhizic acid and 18alpha-glycyrrhizic acid on the expression of CYP3A was determined by reverse transcriptase polymerase chain reaction (RT-PCR) and western blot respectively. RESULT: Treatment with 18beta-glycyrrhizic acid of primary rat hepatocytes resulted in marked up-regulation of CYP3A1 expression at both mRNA and protein levels in a concentration dependent manner, while exposure to 18alpha-glycyrrhizic acid of primary rat hepatocytes resulted in marked down-regulation of CYP3A1 expression at both mRNA and protein levels in a concentration dependent manmer. CONCLUSION: 18beta-glycyrrhizic acid and 18alpha-glycyrrhizic acid up-regulate and down regulate CYP3A1 expression at the transcriptive levels. PMID- 19445157 TI - [Study on hepatoxicity and nephrotoxicity of cinnabar in rats]. AB - OBJECTIVE: To investigate hepatoxicity and nephrotoxicity of cinnabar to provide the scientific basis for safe uses in clinic. METHOD: Maximally tolerated dose of cinnabar (MTD) was tested by single oral administration. Chronic toxicity of cinnabar at different dose level (0.025, 0.05, 0.1, 0.4, 0.8 g x kg(-1) x d(-1)) corresponding to 1/2, 1, 2, 8, 16 times of clinic doses of cinnabar was investigated. The rats were treated with the cinnabar through oral administration once a day for successive 90 days. Urinary qualitative test, blood routine examination, serum chemistry measurement and histomorphologic observation were conducted at day 30, 60 and 90. Toxic changes related to the treatment of cinnabar and no-observed adverse effect level (NOAEL) were evaluated. RESULT: For the content of 98.1% total Hg and 21.5 microg x g(-1) absoluble Hg, MTD of cinnabar with oral administration was 24 g x kg(-1) (corresponding to 516 microg x kg(-1) absoluble Hg), equivalent to 3,000 times of clinical daily dose for an adult, and no obvious adverse effect was showed at this dose. Cinnabar can cause kidney and liver pathological changes when it is repeatedly administrated for over 30 days. The kidney was more sensitive to cinnabar than liver. Based on repeated dose toxicity study, NOAELs were 0.1, 0.05 g x kg(-1) x d(-1)) respectively for 30 day and 90 day treatment, and those were approximately accumulative intake of absoluble Hg 64.5 microg x kg(-1) and 96.76 microg x kg( 1). Thus, for safe use of cinnabar, the acceptable daily intake (ADI) of cinnabar was 0.0009-0.0017 g x kg(-1) x d(-1), namely daily dose 0.05-0.1 g for an adult with body weight about 60 kg. Considering the difference of drug sensitivity and lifecircle between human and rats, we suggest that cinnabar which contains absoluble Hg < or = 21 microg x g(-1) should be used for no longer than 2 weeks at daily dose 0.05-0.1 g. CONCLUSION: Long term use of cinnabar can cause kidney and liver pathological change, so the dose and administration duration should be limited. The suggestion is as follows: cinnabar which contains absoluble Hg < or = 21 microg x g(-1) should be used less than 2 weeks at the daily dose below 0.05 0.1 g. PMID- 19445158 TI - [Antioxidative and cytotoxic properties of diarylheptanoids isolated from Zingiber officinale]. AB - OBJECTIVE: To investigate the antioxidant and cytotoxic properties of five diarylheptanoids (1-5) isolated from the rhizomes of Zingiber officinale. METHOD: Various models such as scavenging superoxide anions and 1,1-diphenyl-2- picrylhydrazyl (DPPH) radicals, inhibiting lipid peroxidation, as well as protecting of rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H2O2) were employed to assay the antioxidative effects of the diarylheptanoids. The cytotoxicities of compounds 1-5 were measured with MTT assays. RESULT: The test compounds (1-5) showed promising DPPH inhibitory activities, and compound 5 exhibited the strongest DPPH scavenging activity with an IC50 value of (22.6+/ 2.4) micromol x L(-1). Compounds 1, 3 and 4 showed potential anti-peroxidative effects with inhibitory rates of (66.3+/-15.4)%, (68.7+/-15.8)% and (72.2+/ 10.6)%, respectively, at 100 microg x mL(-1). It could be observed that compounds 1, 3 and 4 demonstrated significant neuroprotective activities in a dose dependent manner. Moreover, compound 3 exhibited certain cytotoxicities against human chronic myelogenous leukemia cells (K562) and its adriamycin-resistant cells (K562/ADR) with IC50 values of (34.9+/-0.6), (50.6+/-23.5) micromol x L( 1), respectively. CONCLUSION: In vitro results demonstrated that five diarylheptanoids (1-5) isolated from the roots of Z. officinale were capable of scavenging radicals, inhibiting lipid peroxidation and protecting PC12 cells against the insult by H2O2. Additionally, compound 3 could inhibit the growth of K562 and K562/ADR cells. PMID- 19445159 TI - [Effects of ginseng total saponins with berberine on plasma brain natriuretic peptide and Ca2+ concentration in experimental rats with chronic congestive heart failure]. AB - OBJECTIVE: To study the effects of total saponins of Panax ginseng combined with berberine on hemodynamics, Plasma brain natriuretic peptide and Ca2+ concentration in cardiac cells of chronic congestive heart failure rats. METHOD: Animal models of heart failure were induced by subcutaneously injecting a large dose of ISO (80 mg x kg(-1)) for 12 days Rat and then were randomly divided into four groups: model group was given distilled water by gavage; total saponins of P. ginseng combined with berberine group was treated with total saponins of P. ginseng and berberine (each 20 mg x kg(-1); once per day) taken orally; captopril group was given captopril (45 mg x kg(-1); once per day) orally; shenmai injection group was injected intraperitoneally with shenmai injection (5 mL x kg( 1), once per day). The normal control group was given distilled water by gavage. After 4 weeks of drug treatment, rat To determine the contents of hemodynamics and plasma brain natriuretic peptide were determined and rat Ca2+ concentration in cardiomyocytes was measured by flow cytometer of each group. RESULT: Compared with normal control group, in model group can decrease the contents of LVSP, +dp/dtmax, and -dp/dtmax were decreased, but increase the contents of LVEDP, plasma brain natriuretic peptide and Ca2+ concentration were increased. The difference between two groups was significant meaning (P<0.01). Compared with model group, in total saponins of P. ginseng combined with berberine group can increase the contents of LVSP, +dp/dtmax, -dp/dtmax were increased, but were increased contents of LVEDP, plasma brain natriuretic peptide and Ca2+ concentration were decreased. The difference between two groups was significant was (P<0.01, P<0.05). Moreover, Total saponins of P. ginseng combined with berberine group had an efficacy similar to that of captopril group but superior to that of shenmai injection group. CONCLUSION: Total saponins of P. ginseng combined with berberine has a good effect on hemodynamics, plasma brain natriuretic peptide concentration and calcium overload in experimental rats with chronic congestive heart failure. PMID- 19445160 TI - [Antagonism for different doses of taurine on calcium overload in myocardial cells of diastole heart failure rat model]. AB - OBJECTIVE: To study the effects of different doses of taurine (Tau) on calcium ion concentration ([Ca2+]i) and ATPase on cardiocyte membrane of diastole heart failure rats. METHOD: Diastole heart failure model was established by the coarctation of abdominal aorta. Four weeks after operation, forty diastole heart failure rats were divided into four groups randomly as follows, model (normal saline 2 mL), taurine (400 mg x kg(-1) x d(-1)), taurine (200 mg x kg(-1) x d( 1)), taurine (100 mgx kg(-1) x d(-1)), with 10 rats for each group (n=10), and 10 sham operation rats was taken as control(normal saline, 2 mL). After 4 weeks administration, Isolate single cardiocyte by enzymatic isolation method which were loaded with Ca2+-sensitive fluorescent indicator Fluo-3/AM. [Ca2+]i was measured by laser scanning confocal microscope [LSCM], and represented it by fluorescent intensity [FI]; ATPase activity of cell membrane was measured by the method of enzymatic reaction chromatometry. RESULT: Compared with the control group, [Ca2+]i in cardiocyte increased markedly and the ATPase activity of cardiocyte membrane decreased significantly in the model group. Compared with the model group, fluorescent value decreased and ATPase activity increased significantly in Tau high-dose group; fluorescence value and ATPase activity decreased significantly in Tau mid-dose group; fluorescent value decreased and ATPase activity increased significantly in Tau low-dose group. CONCLUSION: Large dosage of Tau can increase ATPase activity on cardiocyte membrane, improve [Ca2+]i in cardiocyte and antagonise calcium overload of DHF rats. PMID- 19445161 TI - [Endothelium-independent vasorelaxant effect of Taurine on rat aorta rings]. AB - OBJECTIVE: To investigate the vasorelaxant effect of taurine (Tau) in rat aortic rings and the mechanism. METHOD: The isolated thoracic aortic rings of male Wistar rats were mounted on the organ bath. The effect of Tau 10, 20, 40, 80 mmol x L(-1) on the rings with endothelium intact or endothelium denuded precontracted by the phenylephrine (1 micromol x L(-1)) or KCl (60 mmol x L(-1)), and the effect of Tau on the vessel reaction induced by various drugs were recorded with biological signal analytical system. RESULT: Taurine completely relaxed the contractions induced by KCl and phenylephrine in a concentration-dependent manner in endothelium-intact and endothelium-denuded rat aorta. Taurine attenuated the contraction to PE both in the absence and presence of calcium, but had no significant effect on the contraction induced by caffeine. The relaxant effect of taurine was significantly inhibited by pretreatment of endothelium-denuded aorta with potassium channel antagonists glibenclamide and tetraethylamine but not by BaCl2 or 4-aminopyridine. CONCLUSION: Taurine induces an endothelium-independent relaxation in rat aortic rings. The mechanisms may involve the reduction in Ca2+ influx and Ca2+-release and the participation of the potassium channels (KATP and KCa, but not Kir or KV). PMID- 19445162 TI - [Discovering active components from traditional Chinese medicine by component knockout approach]. AB - OBJECTIVE: A component-knockout approach was established to discover active components from traditional Chinese medicine. METHOD: According to the principle of gene knockout technique, an experiment workflow for component-knockout method was developed, which is distinct from the bio-guided screening method. The differences of therapeutic efficacies between different combinations of individual components were analyzed by some statistical methods including Analysis of Variance (ANOVA), whilst a set of criterias were established to assess active components. By comparing the difference of drug efficacy between the original formulae and the mixture being knockout certain component, the active components can be identified. RESULT: The presented component-knockout method was applied to discover the active components of Shenmai formulae for the synergistic effects on the cyclophosphamide chemotherapy for S180 tumor-bearing mice. The results indicated that panoxadiol, a type of ginsenosides, were the effective components of Shenmai formulae. CONCLUSION: A new method for identifying effective components from Chinese medicinal formulae was developed and successfully applied to discover the active components of Shenmai Formulae, which possesses the synergistic actions towards chemotherapy process. PMID- 19445163 TI - [Metabolism and excretion of total flavonoids of Semen Ziziphi Spinosae in rat urine and feces]. AB - OBJECTIVE: To study the metabolism and excretion of total flavonoids of Semen Ziziphi Spinosae in rat urine and feces. METHOD: The urine and feces of rats were collected at different times after orally administration of total flavonoids from Semen Ziziphi Spinosae, disposed by HP-20 macroporous resin, and then detected by both HPLC and LC-MSn methods. RESULT: Two main proto-drugs, spinosin and 6'" feruloylspinosin, along with a metabolite, swertish (M1), are detected in both urine and feces of rat. CONCLUSION: Flavonoids of Semen Ziziphi Spinosae are excreted in urine and feces mainly in form of proto-drug, while little in form of metabolites, such as swertish. PMID- 19445164 TI - [Effect of additives on absorption of Coptis chinensis total alkaloids and pharmacokinetics in mice]. AB - OBJECTIVE: To evaluate the effect of additives on absorption of Coptis chinensis total alkaloid and their pharmacokinetics in mice. METHOD: The mice were fed with the mixture of C. chinensis total alkaloids and additives (1:1). And then the feces and orbital blood were taken to detect the content of total alkaloids by HPLC and their pharmacokinetics. RESULT: Glutin could make the absorption of jatrorrhizine, coptisine, berberine and total alkaloids increased by 30%. Tween 80 and arabic gum did not affect the absorption of berberine, but inhibit that of other alkaloids. There had no influence of lecithin on the absorption of alkaloids. The peak time of total alkaloids in blood were 2 h (Cmax 1=5.9 mg x L( 1)) and 5.0 h (Cmax 2=3.4 mg x L(-1)), respectively, AUC was 17.6 mg x h x L(-1), the elimination of Half-life t1/2 was 5.2 h. After addition of glutin, the peak time of total alkaloids in blood were 1.5 h (Cmax 1=7.6 mg x L(-1)) and 4.8 h (Cmax 2=8.5 mg x L(-1)), AUC was up to 31.1 mg x h(-1) x L(-1), the elimination of Half-life t1/2 was 6.2 h. CONCLUSION: Glutin could accelerate the mice on the absorption of C. chinensis total alkaloids, to extend the elimination half-life, increase the blood concentration and bioavailability. PMID- 19445165 TI - [Effect of Acorus tatarinowii schott on ultrastructure and permeability of blood brain barrier]. AB - OBJECTIVE: To explore the influence of Acorus tatarinowii schott on ultrastructure and permeability of BBB. METHOD: The ultrastructure and permeability of BBB on rats with A. tatarinowii by electron microscope were observed. The even's blue (EB) and sodium phenytoin in brain was determined by UV and HPLC-MS. RESULT: After give A. tatarinowii, tight junctions of the endothelial cell opened in cotex, and the concentration of EB and sodium phenytoin in brain are significant increased. CONCLUSION: A. tatarinowii can increase the permeability of BBB, and show its 'Kaiqiao' effect. PMID- 19445166 TI - [Interaction between Actinobacillus pleuropneumoniae RTX toxin and host--a review]. AB - Actinobacillus pleuropneumoniae (App) is the etiological agent of porcine pleuropneumonia which causes huge economic losses to the pig industry. RTX (repeat in the structural toxin, RTX) is the main virulence-associated factor of the pathogen and, plays a dual role on the pathogen's infection and immunity. Recently research progress is updated in this paper and the necessity and techniques to initiate the pathogen-host interaction study is also raised and discussed. It is believed that the research on the interaction between host and App RTX may further elucidate the pathogen' s molecular pathogenesis. PMID- 19445167 TI - [Advances in helper-dependent adenoviral vector--a review review]. AB - Helper-dependent adenoviral vector (HDAd) lacking all viral coding sequences with the advantages of minimal immunogenicity, negligible chronic-toxicity, and durable transgene expression over first-generation adenoviral vector (FGAd). HDAd vehicles have demonstrated tremendous potential for gene therapy in animal models for inherited diseases, neurodegenerative diseases and cancer etc. Additionally, the large cloning capacity of HdAd, up to 37 kb, permits the delivery of whole genemic loci, multiple transgenes. In this review we characterize the basic features of HdAd and summarize some of their experimental and potential clinical applications both at present and in future. PMID- 19445168 TI - [Antibacterial activity of Porphyra spp. epiphytic bacteria and polyketide synthase I gene screening]. AB - OBJECTIVE: Based on the antibacterial analysis, we screened Polyketide synthase (PKS I) gene from the epiphytic bacteria of Porphyra spp., in order to obtain the PKS I positive strains and detect the potential connection between the PKS pathway and the antibacterial mechanisms. METHODS: A total of 31 bacteria with broad-spectrum antibacterial activity were screened by agar-screening methods. The 16S rDNA and the Ketosynthase gene were amplified from the genome DNA of these bacteria, which were cloned into pMD19-T vector for sequencing analysis. RESULTS: Porphyra spp. epiphytic bacteria showed broad-spectrum antibacterial activity. Three PKS I positive epiphytic bacteria were obtained from Wenzhou rotten Porphyra spp. samples which had high antibacterial activity. The BLAST results indicated that the Ketosynthase fragments of PKS I from the strains of WPhG3, WPySwl and WPySw2 shared highest similarity (98%, 99%, 98%) to the strains of Bacillus subtilis subsp. Subtilis str. 168 (NP_389602), Bacillus subtilis (ABR19776) and Aspergillus carbonarius (AAZ99721), respectively. Furthermore, the phylogenetic analysis based on 16S rDNA sequences indicated that they belonged to the genus of Bacillus. CONCLUSION: The flora of Porphyra spp. epiphytic bacteria was complex, which regulated the phycosphere in many ways. The PKS I pathway might be a performance of antibacterial function of Bacillus from Wenzhou rotten samples. PMID- 19445169 TI - [Kinase domain analysis of MDV-1 CVI988/Rispens UL13 and preferred codon fragments expression in Escherichia coli]. AB - OBJECTIVE: To find catalytic center of MDV-1 UL13 and express it in vitro to investigate the function of UL13 kinase. METHODS: UL13 gene was amplified by polymerase chain reaction (PCR) from MDV-1 CVI988/Rispens strain. The codon bias and antigenicity of UL13 in Escherichia coli was analyzed by online service GENEART (www.gcua.de)and DNAstar software respectively. Then the UL13 truncated fragments were expressed in Escherichia coli, and mice were immunized with the expressed Glutathione S Transferase fusion protein. The conserved domain was analyzed with protein blast and Cn3D 4.1 online software of National Center for Biotechnology Information. RESULTS: UL13 gene was successfully amplified. The sequence analysis suggests that 259-400 and 431-513 amino acid residues are low abundance for rare codon and strong antigenicity in UL13. Result of conserved domain analysis demonstrated that 152-297 residue iskinase catalytic center of UL13. However, conserved glycin in kinase subdomain VII for most protein kinase was replaced by serine in UL13 and proline in kinase subdomain VIII replaced by cysteine. The serum from mice immunized with truncated fragment, 259-400 amino acids, could react with recombinant UL13 protein expressed in insect cells in immunofluorenscence assay. CONCLUSION: The 152-297 residue is kinase catalytic center of MDV-1 UL13; UL13 protein expressed in vitro induced specific antibodies against UL13. PMID- 19445170 TI - [Isolation, identification and rumen fermentation characteristics of Propionibacterium acnes]. AB - OBJECTIVES: Characteristic of energy metabolism in ruminant is a negative energy balance in perinatal period. Propionic acid from ruminal microbe fermentation is a vital glyconeogenesis substrate for preventing negative energy balance. We isolated and screened a Propionibacterium acnes strain from health cow rumen fluid, and studied its rumen fermentation characteristics. METHODS: A Propionibacterium acnes strain from rumen fluid of health cow with permanent rumen fistula under sterile condition was isolated by segregation procedure of anaerobic bacterium and Sodium Lactate Broth (SLB), and identified by extraction of the genome DNA, cloning of the 16S rRNA gene, and sequencing. We studied the effect of the strain on pH, volatile fatty acid and lactic acid in rumen fluid in vitro and in vivo. RESULTS: A bacterium isolated from health cow rumen fluid was identified as Propionibacterium acnes by morphology, biochemical characteristics and sequence homology. In vitro, pH in rumen fluid decreased to the lowest after rumen fermentation of the strain for 12 h, then increased gradually. However, concentration of volatile fatty acid, such as acetic acid, propionic acid and butyric acid, increased to the highest after rumen fermentation of the strain for 12 h, then decreased gradually in vitro. The concentration of lactic acid and ratio of acetate to propionate decreased overall in vitro. In vivo, pH in rumen fluid decreased overall, concentration, of the volatile fatty acid increased overall. CONCLUSIONS: A strain of Propionibacterium acnes was isolated successfully from health cow rumen fluid. It is an important basis to develop microecological preparation for preventing cows' negative energy balance in perinatal period in future. PMID- 19445171 TI - [Bioconversion kinetics of conjugated linoleic acid by Lactobacillus plantarum ZS2058]. AB - OBJECTIVE: Studying the kinetics of conjugated linoleic acid (CLA) bioconversion by Lactobacillus plantarum ZS2058. METHODS: We studied the effects of the substrate concentration, cell mass, reaction pH and temperature on the reaction rate of producing CLA by L. plantarum ZS2058, and established the equations of reaction rate at the initial response stage under different substrate concentrations by double-reciprocal plot and Hanes-Woolf plot method. RESULTS: A marked substrate inhibition effect existed, and the early reaction rate of producing c9, t11-CLA reached the maximum of 15.99 microg/(mL x h) when linoleic acid concentration was 0.4 mg/mL. The early reaction rate increased with the cell mass increase, and when the cell mass was at 5 x 10(10) cfu/mL, the response reaction rate close to the maximum. The optimum pH and temperature of bioconversion of CLA were 6.5 and 40 degrees C. Michaelis constant was obtained by double-reciprocal plot and Hanes-Woolf plot method, the reaction rate equation followed the classic Michaelis-Mentent equation at the low substrate concentration, while there existed in a marked substrate inhibition effect at the high substrate concentration. CONCLUSION: Rough exploring the various factors of CLA bioconversion by L. plantarum ZS2058, we established the reaction rate equations of the initial response stage under different substrate concentrations, and got the optimal reaction conditions. These results will, contribute to the CLA production and its physiological functions research. PMID- 19445172 TI - [Chitinase B from Bacillus thuringiensis enhancing potential and its antagonism and insecticidal]. AB - OBJECTIVE: We studied the characteristics of chitinase B (ChiB) from Bacillus thuringiensis subsp. colmeri 15A3 (Bt 15A3) and evaluated its antagonism and insecticidal potential. METHODS: ChiB was expressed in Escherichia coli. Expression product was purified by ammonium sulfate precipitation, dialysis and Sephadex G-200 gel filtration chromatography. The molecular mass of ChiB was directly estimated by zymogram after sodium dodecyl sulfate-polyacryamide gel electroresis (SDS-PAGE). The proteins with different molecular weight were identified by mass spectrum (MS) and analyzed through bioinformatics. We studied some metal ions' impacts on chitinase activity; optimal temperature, pH and its stability at different temperature and pH. We also studied the inhibition effects on sporangia germination of fungi and the synergistic effects of ChiB on larvicidal activity. RESULTS: The molecular mass of ChiB was estimated as 70 kDa by zymogram. The protein with 64 kDa was the product of C-terminal degradation of ChiB in E. coli. Chitinase activity was improved by Fe3+ and inhibited by Zn2+ and Ag2+. The optimal temperature for ChiB was 60 C and the optimal pH was 5.0. The enzyme was quite stable at temperature below 60 degrees C and pH between 4.0 and 8.0. ChiB inhibited sporangia germination and the IC50 (50% inhibited concentration) was about 4 microg/mL. Moreover, the bioassays showed that ChiB could reduce the LC50 (50% lethal concentration) of the crystal protein of Bt. against Spodoptera exigua and Helicoverpa armigera larvae by approximately 26% and 30%. CONCLUSION: ChiB was not only stable, but also with good antagonism and insecticidal activity. PMID- 19445173 TI - [Cloning and expression of the novel antimicrobial target enzyme Sortase gene in two prokaryotic vectors]. AB - OBJECTIVE: Sortase is a novel anti-infection target enzyme for its critical action of anchoring surface proteins to the cell wall. METHODS: We amplified the srtA gene from Staphylococcus aureus chromosomal DNA by PCR technique, and then constructed two prokaryotic expression vectors pet22-srtA and pTRX-srtA with regular molecular cloning operation. The pet22-srtA and pTRX-srtA were transformed into Eschericheria coli BL21 (DE3) competent cells and overexpressed under 1 mmol/L IPTG (isopropy-beta-D-thiogalactoside) induction. RESULTS: SDS PAGE and western blot results show that approximately 45 kDa and 39 kDa proteins were expressed by pet22-srtA and pTRX-srtA respectively. CONCLUSION: The molecular chaperone thioredoxin was beneficial to the prokaryotic expression of srtA gene. Moreover, the experiment laid solid foundation to study sortase's enzymatic property and inhibitors screening especially. PMID- 19445174 TI - Glycine-aspartic_ acid-serine-leucine esterase Xcc_ est from Xanthomonas campestris pv. campestris 8004 and its esterase domain: gene expression in Escherichia coli, refolding and characterization. AB - OBJECTIVE: To characterize the GDSL (glycine, aspartic acid, serine and leucine motif in protein sequence) esterase Xcc_ est from Xanthomonas campestris pv. campestris (Xcc) 8004. METHODS: Xcc_ est gene and different domains of Xcc_ est gene were PCR amplified and expressed in Escherichia coli, the HIS-Tagged fusion proteins were purified by Ni-NTA chromatography. RESULTS: The optimum pH and temperature of partly purified Xcc_ est were 8.0 and 52 degrees C when pNPB (4 nitrophenylbutyrate) was used as substrate. The Km and Vmax value of Xcc_ est and the passenger domain (Xcc_ estN1-334) for pNPB were 47.6 +/- 4.6 mol/L, 67.6 +/- 7.8 U/mg and 469.4 +/- 9.8 mol/L, 2.5 +/- 0.9 U/mg respectively. Inclusion bodies of mature domain Xcc_ est (Xcc_ estN26-606) could be refolded but inclusion bodies of the passenger domain (Xcc_ estN26-334) could not be refolded. Refolded mature domain had broad substrate spectrum and showed higher stability than Xcc_ est when stored at 25 degrees C. CONCLUSIONS: Refolded Xcc_ estN26-606 can be a candidate for biotransformation application. PMID- 19445175 TI - [Influence of amino acid and dipeptide composition on protein stability of piezophilic microbes]. AB - OBJECTIVE: To compare the amino acid and dipeptide composition of proteins from piezophilic and non-piezophilic microbes is of great significance for understanding the stability of piezophilic protein and directed mutation of them. METHODS: The amino acids of different secondary structure and the dipeptides of 639 orthologs proteins were counted and the deviation of them were calculated. RESULTS: The amino acid composition based on secondary structure and the dipeptide composition reveals some common trends. The amino acids vary widely in beta sheet and coil. In beta sheet, piezophilic proteins contain more amino acids such as Val, Ile and Leu, whereas less Arg, Lys and Asp; in coil, piezophilic proteins contained more amino acids such as Val and Ile, whereas less Gly and Pro. On the other hand, piezophilic proteins contain more dipeptides such as YM, MN, KD, QC, CI, MW, MM, CY, WQ, HC, RC and QH, whereas less dipeptides such as TW, MS, VD, DH, YE, CT, MW, CF, CK, CM, MY, QI, TH, MQ, QQ and MC. CONCLUSION: Dipeptide contains more structure and sequence information than amino acid, and it will be more helpful for understanding the mechanism of piezophilic adaptation and guiding the engineering of proteins. PMID- 19445176 TI - [Construction of an enzyme-coupled system consisting of (R)- and (S)-specific carbonyl reductases for one-step preparation of (S)-1-phenyl-1,2-ethanediol]. AB - OBJECTIVE: To prepare (S)-1-phenyl-1,2-ethanediol by a one-step method, we constructed an enzyme coupled system consisting of (R)- and (S)-specific carbonyl reductases in Escherichia coli. METHODS: The genes coding (R)- and (S)-specific carbonyl reductases from Candida parapsilosis were inserted into a co-expression vector pETDuet-1. The positive plasmid was transformed into codon optimized E. coli Rosetta and an enzyme-coupled recombinant strain E. coli Rosetta / pETDuet rcr-fdh was constructed. When the OD600 value of the culture reached 0.6-0.8, IPTG with a final concentration of 1 mmol/L was added to induce both target proteins at 30 degrees C for 10 h. RESULTS: SDS-PAGE analysis showed that two target enzymes were expressed simultaneously with the relative molecular weights of 37 kDa and 30 kDa. When 5 mol/L Zn2+ was added into a phosphate buffer (pH7.0), the biotransformation results showed that the product (S)-1-phenyl-1,2 ethanediol was produced with the optical purity of 91.3% enantiomeric excess and a yield of 75.9% by E. coli Rosetta/pETDuet-rcr-scr. CONCLUSION: The functions of two redox enzymes were integrated by molecular recombinant technique and a one step method for preparation of (S)-1-phenyl-1,2-ethanediol was developed through an enzyme-coupled system. The method may supply a new procedure in chiral alcohols preparation. PMID- 19445177 TI - [Screening and identification of probiotic bifidobacterium from Mongolian children]. AB - OBJECTIVE: Bifidobacterium has important physiological activity in gastrointestinal tract of human and animals, and the tolerability of acid, intestinal juice and oxgall bile salt are the key factors that influence the function of living bacteria preparation. In this study, feces of 12 healthy Mongolian children were selected to isolate Bifidobacterium with probiotic properties. METHODS: Bifidobacterium was isolated from feces by selective medium and identified by physiological biochemical test. The tolerability of acid, intestinal juice and oxgall bile salt of 11 Bfidobacteria were studied and B. animalis V9 was identified further by molecular biological approach 16S rDNA. RESULTS: Eleven Bifidobacteria isolated from feces of 12 healthy Mongolian children were identified as B. adolescentis (A1, H3, G4, A8 and V10), B. longum (C6, C7 and D11), B. pseudocatenlatum (B2), B. bifidum (G5), B. animalis (V9). B. animalis V9 had the best acid tolerance with the survival rate 92.4% in artificial gastric juice at pH2.0 for 3h, whereas others had lower than 31.25%. B. animalis V9 also had good survival rate (99.7%) in artificial intestinal juice at pH8.0 for 8h after anaerobic cultured 3h in artificial gastric juice at pH2.0, and tolerated oxgall bile salt at concentration of 0.3%. B. animalis V9 was identified further by molecular biological approach 16S rDNA and result showed the homologies of B. animalis V9 was 99% with Bifidobacterium animalis subsp. lactic BB12. CONCLUSION: B. animalis V9 had good probiotic properties to be potentiallyused in dairy products and health products. PMID- 19445178 TI - [Bacterial diversity of disused thermal vents in Tibetan Yangbajing Region]. AB - OBJECTIVE: To study the bacterial diversity in sediment and water from two disused thermal vents in Yangbajing, Tibet, China. METHODS: We constructed 16S rRNA gene libraries of the total DNA from three samples. Sediment sample A and water sample A were from thermal vent A. Sediment sample B was from thermal vent B. Positive clones from the libraries were analyzed randomly by amplified ribosomal DNA restriction analysis. Positive clones' sequences of every Operational Taxonomic Units from libraries were determined, and sequence data were submitted to GenBank and contrasted to those known sequences. Phylogenetic trees were built up by using MEGA4.0 program. RESULTS: Most of bacteria communities of the two thermal vents were typical thermophilc inhabitants, the predominant proteobacteria communities were found in thermal vent A and thermal vent B (ratios in sediment A, water sample A and sediment B were 41.08%, 38.00% and 42.57%) One of the sub-predominant bacteria communities, Deinococcus-Thermus, was found in thermal vent A and thermal vent B (ratios in sediment A, water sample A and sediment B were 10.71%, 20.00% and 21.30%). Moreover, one of the sub predominant bacteria communities, Acidobacteria that was rarely found in hot springs or thermal vents, was present both in sediments of thermal vent A and B (16.07%, 19.15%). The third sub-predominant community in sediment of thermal vent A was Eubacterium sp. (14.28%), belonging to phylum Firmicutes whereas no Acidobacteria was found in water sample A. Instead, Hydrogenobacter, belonging to phylum Aquificae, was another sub-predominant community (16.00%) in water sample A. In addition, Chloroflexi, Cyanobacteria and CFB group ( Cytophaga-Flexibacter Bacteroides) were detected in both thermal vents. CONCLUSION: Compared with and contrasted to the references, we found that bacteria communities in Yangbajing thermal field were similar to that in some hot springs and thermal vents around the world but slightly abnormal. Some bacteria communities in thermal vent A and thermal vent B were not very popular, such as Vibrio sp., Bacteriovorax sp., HolophagalAcidobacterium, Verrucomicrobium. PMID- 19445179 TI - [Bacterial communities in the phase II of Agaricus bisporus compost by denaturing gradient gel electrophoresis]. AB - OBJECTIVE: We studied the bacterial community during Agaricus bisporus composting phase II, to develop a quick and accurate method by modern molecular ecology technique for dynamic inspection on bacterial community during A. bisporus composting. METHODS: We selected seven A. bisporus compost samples from different stages of phase II. We used PCR to amplify the V3 regions of the 16S ribosomal DNA from those samples. We analyzed PCR products by denaturing gradient gel electrophoresis. RESULTS: The denaturing gradient gel electrophoresis profile showed a dramatic change of bacterial communities which related to the process of phase II of A. bisporus compost. DNA sequencing of the dominant bands of denaturing gradient gel electrophoresis profile indicated that the bacterial diversity in the phase II of A. bisporus compost was much higher than that studied by traditional method cultured-based approach. We found not only the genus of Bacillus, commonly believed to dominate high temperature compost, but also some new groups belonged to the class of Bacilli such as Trichococcus, Planococcus, Caryophanon and even the gamma-subgroup of Proteobacteria. At the same time, some sequences were related to the genus of Thermus thermophilus and alpha-subdivision of Proteobacteria which were only recently reported in the hot compost. Several sequences display extremely low similarity with the cultivated species in the GenBank, indicating high diversity of uncultivated bacteria in the process of A. bisporus composting. CONCLUSION: We found distinctly changes on bacterial communities during A. bisporus composting phase II by denaturing gradient gel electrophoresis profile. Also we found a lot of presently uncultured bacteria species during A. bisporus composting. The results indicted that molecular ecology methods broaden and deepen our knowledge about the environmental microbes, and also shown the potential application for A. bisporus compost evaluation. PMID- 19445180 TI - [Effect of clpE gene deletion on virulence of Streptococcus pneumoniae]. AB - OBJECTIVE: To study the effect of clpE gene deletion on the virulence of Streptococcus pneumoniae. METHODS: The clpE-deficient strain was constructed by LFH-PCR and identified by PCR and sequencing. The impact of clpE mutant on the virulence of S. pneumoniae was evaluated in a mouse model. In addition,we also studied the effect of clpE mutant on adherence and invasion of host cells. Real time RT-PCR was used to measure the mRNA expression levels of autolysin A, pneumococcal surface adhesion A, pneumolysin, pneumococcal surface protein A and neuraminidase. RESULTS: The clpE gene was replaced completely by erm cassette. Mice virulence experiments showed that the median lethal time of the wide-type was 54 h, whereas that of clpE mutant was 21d (P < 0.01). Cell culture infection experiments indicated that adherence and invasion of clpE mutant were strongly reduced (P < 0.05). The expression of virulent factors in clpE mutant was lower than that of the wild-type (P < 0.05). CONCLUSION: ClpE is involved in virulence by modulating the expressions of virulence factors. PMID- 19445181 TI - Upregulation of TLR7 and TLR3 gene expression in the lung of respiratory syncytial virus infected mice. AB - OBJECTIVE: TLR7 and TLR3 (Toll-like receptor, TLR) are important pattern recognition receptors (PRRs) that recognize the single-strand RNA and double strand RNA of virus-origin. Respiratory syncytial virus (RSV) could be recognized by both TLR7 and TLR3. We studied the kinetics and profile of lung TLR7 and TLR3 expression during the early phase of the RSV infection, and explored their expression correlation with pulmonary inflammatory response. METHODS: We intranasally inoculated BALB/c mice with live RSV to induce acute lung inflammation,and detected the lung expression of TLR7 and TLR3 mRNA by semiquantitative RT-PCR analysis at day 1 after RSV infection. We also measured the transcription factor nuclear factor-kappaB (NF-kappaB) protein expression with western blot assay in nuclear extracts. Lung tissue sections were stained with hematoxylin and eosin, and examined under a light microscope for histopathological examination. RESULTS: SV infection could rapidly upregulate the lung expression levels of both TLR7 and TLR3 gene in a time-dependent manner. Furthermore, the response of TLR7 to RSV (1 h) was prior to that of TLR3 (4 h). It resulted in activation of NF-kappaB as soon as 4 h later in lung tissue. Moreover, RSV mediated early transcriptional responses of TLR7 and TLR3 were paralleling with the severe extent of RSV-induced pulmonary inflammation. CONCLUSION: TLR7 and TLR3 were really involved in RSV-induced lung inflammation by detecting the viral RNA. This may allow to detect viral infections and initiate a proinflammatory response via multiple TLRs. This study may be useful in the development of tools to modulate the activities of therapeutic TLR ligands. PMID- 19445182 TI - [Phylogenetic diversity of cultivable bacteria associated with a sea anemone from coast of the Naozhou island in Zhanjiang, China]. AB - OBJECTIVE: To understand the diversity of cultivable bacteria isolated from a sea anemone collected from the coastal water of the Naozbou island in the Leizhou Bay on South China Sea. METHODS: Bacteria were isolated from a sea anemone by using conventional culture-dependent method and investigated by using phylogenetic analysis based on 165 rRNA gene sequence comparisons. RESULTS: We isolated 126 bacteria strains from the sample on marine agar 2216 (Difco), International Streotomyces Project medium 2 agar, nutrient agar, sea water agar and humic acid agar supplemented with 0-2 mol/L NaCl. Based on partial morphological, physiological and biochemical characteristics, we selected 42 strains for molecular systematic study based on 16S rRNA gene sequences. Our results showed that 42 isolates were members of eighteen genera (Alteromonas, Bacillus, Brachybacterium, Brevibacterium, Halobacillus, Halomonas, Nocardiopsis, Oceanobacillus, Piscibacillus, Planococcus, Pontibacillus, Pseudoalteromonas, Pseudonocardia, Salinicoccus, Salinivibrio, Staphylococcus, Vibrio, Virgibacillus) of eleven families (Alteromonadaceae, Bacillaceae, Brevibacteriaceae, Dermabacteraceae, Halomonadaceae, Planococcaceae, Pseudoalteromonadaceae, Pseudonocardiaceae, Nocardiopsaceae, Staphylococcaceae, Vibrionaceae) in three major phylogenetic groups (Actinobacteria, Firmicutes, Gamma-Proteobacteria). The most abundant and diverse isolates were within the phylum Firmicutes (40.5%) and the subphylum Gamma-Proteobacteria (33.3%). The phylogenetic distance matrix results suggested that, out of 42 isolates, 37 were different strains of 19 known species,and that at least 6 strains represented 6 new species within 6 characterized genera. CONCLUSION: The results presented above showed that there were abundant species diversity and phylogenetic diversity of bacteria isolated from the sea anemone. PMID- 19445183 TI - [Bacterial diversity in Guangxi buffalo rumen]. AB - OBJECTIVE: To analyze the diversity of bacterial community in Guangxi buffalo rumen and to identify the possible cellulolytic bacterial group. METHODS: Metagenomic DNAs were isolated directly from a buffalo rumen and its enriched culture, and were used as PCR templates to amplify 16S rRNA genes. Two libraries carrying 16S rRNA genes of bacteria in the two samples were constructed. The bacterial community composition was revealed by the constructed phylogenetic tree of known sequences and the sequences randomly selected from the libraries. RESULTS: We found that both samples contained low G + C Gram-positive bacteria (LGCGPB) and Cytophaga-Flexibacter-Bacteroides (CFB) phyla as the majorities, and Spirochaetes as the minorities. LGCGPB accounts for 56.66% and 73.33% of the bacterial communities in buffalo rumen and its enriched culture. We detected Fibrobacteres in the rumen sample (3.33%) but not in the enriched sample. Furthermore, we found Proteobacteria as a major component in the enrichment (13.33%) but not in the rumen sample. Clone R46 was not clustered into any known phyla and might belong to a novel taxonomic group. CONCLUSION: The LGCGPB and Proteobacteria may play important roles in the hydrolysis of cellulose in buffalo rumen. The bacterial composition in the rumen of buffalo is quite similar to those in the rumen of yak, cattle and sheep. PMID- 19445184 TI - [Resistance of Lactobacillus casei subsp. casei SY13 and Lactobacillus delbrueckii subsp. bulgaricus LJJ to reactive oxygen species]. AB - OBJECTIVE: We evaluated antioxidative effect of two antioxidative strains, isolated from the traditional fermented dairy products. METHODS: Both intact cells and cell-free extract of Lactobacillus casei subsp. casei SY13 and Lactobacillus delbrueckii subsp. bulgaricus LJJ were used to study the inhibited effect of linoleic acid peroxidation, the ability of scavenging 1,1-diphenyl-2 picrylhydrazyl radical, hydroxyl radical, superoxide anion radical,the ability of tolerancing hydrogen peroxide and the chelating capacity of ferrous ion and reducting activity. RESULTS: Lactobacillus casei subsp. casei SY13 and Lactobacillus delbrueckii subsp. bulgaricus LJJ demonstrated highest inhibition on linoleic acid peroxidation by 62.95% and 66.16%, respectively. The cell-free extract showed excellent scavenging superoxide anion and hydroxyl radicals activity. However, the intact cells of Lactobacillus delbrueckii subsp. bulgaricus LJJ scavenging superoxide and hydroxyl radicals capacity were not detected. The intact cells of Lactobacillus casei subsp. casei SY13 and Lactobacillus delbrueckii subsp. bulgaricus LJJ on 1,1-diphenyl-2-picrylhydrazyl radical scavenging ability and chelating ferrous ion capacity were superior to cell-free extract. The highest reduced activety was equivalent to 305 micromol/L and 294 micromol/L L-cysteine. CONCLUSION: Two latobacilli strains had good antioxidant capacity. As potential probiotics, it can be used in future. PMID- 19445185 TI - [Cloning of the gene encoding alpha-glucosidase from aspergillus niger and its expression in Pichia pastoris]. AB - OBJECTIVE: Alpha-glucosidase from Aspergillus niger SG136 was expressed in Pichia pastoris. METHODS: cDNA of mature alpha-glucosidase (aglu) was amplified from the total DNA of A. niger SG136 by PCR and overlap-PCR with primers designed based on the sequence of A. niger CBS 513.88 in NCBI database. The gene was cloned into pMD18-T simple vector. The sequencing result showed that the gene encoded for a protein of 960 amino acids residues, which was 1 amino acid different from that of A. niger CBS 513.88. The expression vector pPIC9K-aglu was constructed by subcloning the gene into plasmid pPIC9K, and then transformed into P. pastoris through electroporation after linearized by Bgl II digestion. The recombinant P. pastoris KM71/pPIC9K-aglu were screened in MD and YPD/G418 plates,and identified by PCR. In shaking culture condition, methanol was added to a final concentration of 1% to induce the secretion of alpha-glucosidase. RESULTS: Electrophoresis analysis of KM71/pPIC9K-aglu culture supernatant showed that there were two major protein bands corresponding to 98 kDa and 33 kDa respectively in SDS-PAGE, and there was only one band in Native PAGE; while in the control experiment of KM71/pPIC9K, there were no visible bands. Transglucosidation reaction from crude enzyme revealed that contents of isomaltooligosaccharides were up to 26.0% under the optimal conditions of pH 5 and 60 degrees C at 24 h. CONCLUSION: A. niger alpha-glucosidase was expressed in P. pastoris with transglucosidation activity. PMID- 19445186 TI - [Immunogenicity comparision of Listeria monocytogenes inactivated by gamma irradiation or traditional treatments]. AB - OBJECTIVE: Listeria monocytogenes (LM) is a gram-positive facultative intracellular pathogen that can cause animal and human listeriosis. In order to use killed LM in vaccination, we compared, in a mouse model, the immunogenicity of LM that were lethally inactivated by gamma-irradiation, traditional heat or formalin treatment. METHODS: BALB/c mice were inoculated intraperitoneally with these killed vaccine candidates. We detected the serum antibody titers with indirect enzyme-linked immunosorbent assay (ELISA) and evaluated the protective efficacy of each vaccine candidates by the resistance to lethal dose challenge of homologous live LM and the effect of bacterial elimination in the spleen and liver of immunized mice. Adoptive transfer of Flow Cytometry sorted T splenocytes from immunized mice to naive recipients, subsequently challenged with high dose of LM, we determined the possible role of T cell. RESULTS: The serum antibody level of mice inoculated with gamma-irradiated LM was the highest, up to 1:1280 as determined by ELISA, while the level of mice immunized with heat-killed or formalin-killed LM was 1:640 or 1:160, respectively. The protective efficacy of gamma-irradiated,heat-killed or formalin-killed vaccines candidates were 100%, 35% or 30%. As judged by the bacterial elimination in the organs, mice inoculated with gamma-irradiated LM were the most efficiently protected group. Adoptive T cell transfer assay showed that gamma-irradiated LM can trigger T cell protective immune response. CONCLUSION: All the results indicated the superiority of gamma irradiation over traditional heat or formalin treatment in generating LM killed vaccine candidate. gamma-irradiation may be applied to numerous bacterial vaccine candidates, and could have important potential in development of killed vaccines. PMID- 19445187 TI - [Characterization of an atmospheric pressure DC microplasma jet]. AB - In the present work, a simply designed and easy made micrometer plasma jet device operating under atmospheric pressure was characterized. The microplasma jet operates in many kinds of working gas at atmospheric pressure, such as Ar, He, N2 etc, and is powered by a direct current power source. It can generate high current density glow discharge. In order to identify various excited species generated by the direct current microplasma jet device, the optical emission spectra of the jet with argon or nitrogen as working gas were studied. Based on the optical emission spectroscopy analysis of argon microplasma jet, the electron excitation temperature was determined to be about 3 000 K by the intensity ratio of two spectral lines. It is much lower than the electron excitation temperature of atmospheric pressure plasma torch, and hints that the atmospheric pressure direct current microplasma jet is cold compared with the atmospheric pressure plasma torch. The emission spectra of the N2 second positive band system were used to determine the vibrational temperature of the atmospheric pressure direct current microplasma jet. The experimental result shows that the molecular vibrational temperature of N2 is about 2 500 K. The electron density of the microplasma jet is about 10(13) cm(-3), which can be estimated from the electrical parameters of the discharge in the microplasma jet. A simple example of application of the microplasma jet is given. General print paper surface was modified with the microplasma jet and afterwards a droplet test was carried out. It was shown that the microplasma jet is more efficient in changing the hydrophilicity of general print paper. PMID- 19445188 TI - [Detection of binding of antibodies with recombinant house dust mite allergen (rDer p2) by surface plasmon resonance technique]. AB - In the present paper, the authors aimed to detect the binding of monoclonal antibody and polyclonal antibodies in sera of patients with recombinant house dust mite allergen (rDer p2) by surface plasmon resonance (SPR) technique. This technique is superior to other methods, like enzyme-linked immunosorbent assays (ELISAs) in studying the interaction between biomolecules because no labeling and sample separation are needed. The allergen rDer p2 was immobilized on carboxymethyldextran-modified sensor chip surface by amine coupling. Surface plasmon resonance measurements of monoclonal antibody and polyclonal antibodies in patients' sera revealed that their bindings diverge widely; the binding of patients' sera was remarkably lower than that of monoclonal antibody. At the same time, the binding of patients' sera with rDer p2 varied among patients allergic to dust mite. This study could provide an easy, fast and real-time way for clinical allergic diseases diagnosis. PMID- 19445189 TI - [Comparative study on current and light emission for different modes in dielectric barrier discharge]. AB - In the present study, a device of water electrodes was used to get different discharge modes in air and Ar respectively, including stochastic filament mode, hexagon pattern mode and homogeneous diffusion mode. By comparing the waveforms of light emission and current for the three different modes, the relationship between the waveforms of light emission and current in dielectric barrier discharge was investigated. Research results show that the waveforms of light emission and current are similar when the discharge signal is very strong. However, the discharge current signal can not be discerned from the displacement current when the discharge current is very weak, because the current signal includes discharge current and displacement current. Under this circumstance, discharge dynamics can be investigated by studying the waveform of light emission. In addition, the light emission signal of single filament was obtained because spatial resolved measurement can be easily realized for the light emission signal measurement. Consequently, the research results indicate that it is a good method to investigate the discharge dynamics by analyzing the waveform of light emission in dielectric barrier discharge. PMID- 19445190 TI - [Effect of inorganic host MCM-41 doped with Yb3+ on the photoluminescence properties of guest Tb(aspirin) 3phen]. AB - Assembly system with MCM-41 doped with Yb3+ as a host, and Tb(aspirin) 3phen, which had been heat treated, as an active optical guest, was synthesized at room temperature. The structure and physical properties of the composites were characterized by a combination of different techniques such as XRD, N2 adsorption desorption and IR, while the photoluminescence properties of the composites were analyzed by PL. Excitation and emission spectra were examined to explore the PL properties of the prepared samples and the relationship between the optical guest and the inorganic host. The present paper reports a new synthesis method called "Direct-Calcination" to avoid the loss of rare earth ions in the process of synthesis. Strong reflections at 2theta = 2.6 attributed to (100) reflection were presented in XRD patterns of both Yb/MCM-41 and Tb(aspirin) 3phen-Yb/MCM-41, which always can be observed for regular, spherical structure of MCM-41 materials, and the inorganic framework order increased after Tb(aspirin) 3phen being incorporated into the channels of Yb/MCM-41. The intensity of the band at 963 cm(-1) decreased in IR spectrum of Yb/MCM-41, relative to that in IR spectrum of MCM-41, implying that Yb3+ had been banded with the framwork. And a sharp band at 1 384 cm(-1) in IR spectrum of Tb(aspirin) 3phen-Yb/MCM-41 also gives the characteristic information about the bands in Tb(aspirin) 3phen-MCM-41. The results from the characterization of PL show that the wide excitation band over 240-375 nm of Tb(aspirin) 3phen is assigned to the carbonyl group n --> pi* transition absorption, benzene ring pi --> pi* transition absorption of aspirin, and phenanthrene absorption of phen. The luminescence intensity of Tb(aspirin) 3phen incorporated into the channels of MCM-41 can be enhanced by heat treating in the synthesis process of Tb(aspirin) 3phen, while the intensity also can further increases by doping Yb3+ in the silicon framework of MCM-41. The luminescence intensity of the assembly system gets to maximum when Yb/Si ratio is 7.579 x 10(-3). PMID- 19445191 TI - [Preparation and spectrum properties of ZnS : Ag nanocrystals]. AB - In the present paper, ZnS : Ag nanoparticles were prepared with simple chemicals by hydrothermal method. XRD patterns indicated that the products have cubic zinc blende crystal structure. The particle diameters were calculated using the Scherer's formula, and the particle size showed a nonlinear increase with the rise of reaction temperature. TEM images demonstrated the approximate sphere shapes of products, and the crystal sizes approached the estimated ones respectively. The luminescence properties were investigated with PL and PLE spectra. Emission peaks were at about 450 nm. This emission was ascribed to the recombination between the sulfur vacancy-related electron trap donor having an energy level just below the conduction band and the Ag-related hole trap acceptor above the valence band. Excitation peaks were at about 333 nm, and the excitation was attributed to the near-band-edge absorption of ZnS matrix. The luminescence intensity was strongly influenced by the reaction temperatures and time. It increased, decreased, and then increased again with the rise of reaction temperature, and increased then decreased with the increase in reaction time. ZnS : Ag nanoparticles synthesized at 200 degrees C for 6 hours have a well luminescence intensity. PMID- 19445192 TI - [Studies on detection of E. coli O157:H7 by ATP bioluminescence]. AB - In the present paper, a quantitative linear model betweena series of concentrations of E. coliO157 : H7 and counts by BPCL ultra weak luminescence analyzer was built up. And the influences of four different buffers with the same pH (pH = 7.4), Tris-HCl, PBS, KH2PO4-NaOH and Na2 HPO4-C6H8O7, and five different chemical substances with the same mass concentration (10 g x L), NaCl, KCl, NaOH, MgCl2 and NaH2PO4 on ATP bioluminescence were compared. The results showed that Tris-HCl was a suitable buffer for dilution, since it could distinguish well between different concentrations and had the lowest background signals. And MgCl2 could intensify luminescence distinctly, while the other four chemical substances decreased luminescence, of which NaOH decreased luminescence most obviously. Moreover, ATP bioluminescence was correlated well with conventional culture methods (r = 0.96), and the detection limit was 10(3) cells x mL(-1). PMID- 19445193 TI - [Study of Tripterygium hypoglaucum Hutch and Celastrus orbiculatus thunb by FTIR spectrum]. AB - The FTIR spectra of Tripterygium hypoglaucum Hutch (THH) and Celastrus orbiculatus Thunb were studied. The result shows that the two herbs have different ratio of main substance calcium oxalate and dulcitol, so their absorption frequency and form are different as well. In addition, there is an obvious difference between Celastrus orbiculatus stem and root, and both the peak forms of calcium oxalate and dulcitol in the FTIR spectra of roots are sharper and stronger than those of stems. Therefore FTIR can be a fast and reliable method to identify THH and Celastrus orbiculatus. PMID- 19445194 TI - [FTIR study of adsorption of PCP on hematite surface]. AB - The adsorption of pentachlorophenol on hematite was studied through adsorption experiments and FTIR analysis. The pH adsorption isotherms of pentachlorophenol onto hematite were obtained by the static state experiments. The largest adsorption quantity occurred at about pH 6. The adsorption quantity at pH 8.5 of the isoelectric point of hematite was about 31% of the largest adsorption quantity. Fourier transform infrared (FTIR) spectroscopy was used to analyse the change of hematite before and after PCP adsorption, and the species of PCP on hematite. It was discovered that: (1) the typical peak at 565 cm(-1) of the Fe-O bond in alpha-Fe2O3 did not change before and after adsorption, and the adsorption occurred on the surface of hematite. (2) At pH 6.0, the stretching vibration peak at 3 438 cm(-1) due to the hydrogen bond formed between O-H on the surface of alpha-Fe2O3 and water molecules shifted to 3 417 cm(-1). The bending vibration peak of H-O-H+ on the surface at 1 643 cm(-1) was weakened because of complex reaction. The peak owing to Fe-OH bond was displaced from 1 050-1 100 cm( 1) to 950 cm(-1) with increased intensity. The C-O bond stretching vibration peak of PCP was displaced from 1 215 to 1 122 cm(-1). The main interaction between PCP and hematite was static electric interaction. (3) At pH 8.5, the stretching vibration peak of the hydrogen bond formed between O-H on the surface of alpha Fe2O3 and water molecules was displaced from 3 438 to 3 428 cm(-1). The bending vibration peak at 1 643 cm(-1) was obviously weakened because of the hydrogen bonding. The H-O-H+ bending vibration peak at 1 050-1 100 cm(-1) was displaced to 947 cm(-1) with obviously increased intensity, indicating that the interaction was mainly through hydrogen bond. PMID- 19445195 TI - [Isomap-PLS nonlinear modeling method for near infrared spectroscopy]. AB - For modeling the nonlinear relationship existing between samples' near infrared (NIR) spectra and their chemical or physical properties, a novel modeling method was put forward in the present paper, which builds model by combining Isomap and partial least squares (PLS). Isomap is a newly proposed nonlinear dimension reduction algorithm, and belongs to the algorithm family of manifold learning, which is a new branch of machine learning. Isomap is based on multidimensional scaling (MDS) algorithm; however, it replaces the Euclidean distance in MDS with an approximated geodesic distance, so it can effectively find out the intrinsic low dimensional structure from high dimensional data. By combining Isomap and PLS, refered to as Isomap-PLS, a novel nonlinear modeling method for NIR spectra analysis was proposed. In this method, Isomap was used to extract nonlinear information from high dimensional NIR spectra while keeping the invariance of geometric property, and then PLS was adopted to remove linear information redundancy and build a calibration model. The parameters of the Isomap, i.e. the number of the nearest neighbor k and output dimension d, can affect the performance of the method. In this paper, a grid search approach was used for parameter optimization. The Isomap-PLS modeling method was applied to two public benchmark NIR datasets, and the modeling results were compared with that of PLS. The results demonstrated that in both datasets, each model built with Isomap-PLS had a smaller rooted mean square error of cross-validation (RMSECV) than the corresponding model built with PLS. Moreover, for some properties, the RMSECV of Isomap-PLS was significantly reduced by a factor of 2-5 compared with that of PLS. It can be concluded that by taking the virtue that Isomap can reflect the intrinsic nonlinear structure of NIR spectra, Isomap-PLS can effectively model the nonlinear correlations between spectra and physicochemical properties of the samples, and so it gains more power in calibration and prediction than PLS. PMID- 19445196 TI - [Local straight line screening method for the detection of Chinese proprietary medicines containing undeclared prescription drugs]. AB - The present paper constructs a new approach named local straight-line screening (LSLS) to detect Chinese proprietary medicines (CPM) containing undeclared prescription drugs (UPD). Different from traditional methods used in analysis of multi-component spectrum, LSLS is proposed according to the characteristics of original infrared spectra of the UPD and suspected CPM, without any pattern recognition or concentration model establishment. Spectrum-subtraction leads to the variance in local straight line, which serves as a key in discrimination of whether suspected CPD is adulterated or not. Sibutramine hydrochloride, fenfluramine hydrochloride, sildenafil citrate and lovastatin were used as reference substances of UPD to analyze 16 suspected CPM samples. The results show that LSLS can obtain an accurate quantitative and qualitative analysis of suspected CPM. It is possible for the method to be potentially used in the preliminary screening of CPM containing possible UPD. PMID- 19445197 TI - [Application of IR spectrum to the research on mechanism of synthesis of 2,4 toluene dicarbamate catalyzed by zinc acetate]. AB - The methoxycarbonylation mechanism of synthesizing 2,4-toluene dicarbamate from 2,4-toluene diamine and dimethyl carbonate catalyzed by anhydrous zinc acetate was investigated by Fourier transform infrared spectroscopy. The result shows that the new coordination complex was formed by oxygen atom of dimethyl carbonate's carbonyl group attaching to zinc atom of anhydrous zinc acetate to form the Zn-O coordination bond, and the anhydrous zinc acetate changed from a bidentate ligand to a unidentate ligand. Simultaneously, dimethyl carbonate's carbonyl group was activated. 2,4-toluene diamine was a nucleophilic reagent, and it's amidos attacked the activated carbon of dimethyl carbonate's carbonyl group in the new coordination complex to produce the methoxycarbonylation compound 2,4 toluene dicarbamate, then the Zn-O coordination bond in the new coordination complex was broken. At the same time, the anhydrous zinc acetate returned to a bidentate ligand. PMID- 19445198 TI - [Research on reducing mold flux's radiative heat transfer based on FTIR and XRD]. AB - The mold fluxes samples containing transition metal oxides TiO2 were designed based on the composition of commercial mold fluxes in continuous casting of steel, and the relation between radiative heat transfer and the content of TiO2 was obtained through FTIR spectrum analysis and XRD analysis. The result of FTIR analysis indicates that TiO2 has a great negative effect on infrared transmittance of flux samples in the wavelength range of 1-6 microm. The result of XRD analysis indicates that crystallization of cuspidine was restrained with addition of TiO2, and CaTiO3 and other phases were found in the samples. The decrease in cuspidine phase is beneficial to strand lubrication in the mold. Radiation heat flux from the strand to the mold was calculated using a radiative heat transfer model concluded in previous study. Addition of TiO2 was found to result in a remarkable decrease in radiation heat flux for both glassy and crystalline samples, and the heat flux tended to decrease with increasing TiO2, with the maximal decrease reaching 30%. As a result of great refraction and scatter at surface and grain boundaries of samples, the negative effect of crystalline samples was much larger than that of the glassy ones. PMID- 19445199 TI - [The correlation based mid-infrared temperature and emissivity separation algorithm]. AB - Temperature and emissivity separation is the key problem in infrared remote sensing. Based on the analysis of the relationship between the atmospheric downward radiance and surface emissivity containing atmosphere residue without the effects of sun irradiation, the present paper puts forward a temperature and emissivity separation algorithm for the ground-based mid-infrared hyperspectral data. The algorithm uses the correlation between the atmospheric downward radiance and surface emissivity containing atmosphere residue as a criterion to optimize the surface temperature, and the correlation between the atmospheric downward radiance and surface emissivity containing atmosphere residue depends on the bias between the estimated surface temperature and true surface temperature. The larger the temperature bias, the greater the correlation. Once we have obtained the surface temperature, the surface emissivity can be calculated easily. The accuracy of the algorithm was evaluated with the simulated mid infrared hyperspectral data. The results of simulated calculation show that the algorithm can achieve higher accuracy of temperature and emissivity inversion, and also has broad applicability. Meanwhile, the algorithm is insensitive to the instrumental random noise and the change in atmospheric downward radiance during the field measurements. PMID- 19445200 TI - [Active oxygen species of Co-V-O catalysts in propane oxidative dehydrogenation analyzed by FTIR and XPS spectra]. AB - A series of Co-V-O (meta-CoV2O6, pyro-Co2 V2 O7, and ortho-Co3 V2 O8) catalysts were prepared by microwave oxalate co-precipitation method and characterized by (XRD), TEM, BET, FTIR, XPS, H2-TPR and conductivity measurement. The catalytic characters of the catalysts for propane oxidative dehydrogenation were investigated. The FTIR spectra of catalysts were obtained in the range of 400-1 100 cm(-1) and their major bands were assigned. The peak separation fitting of O(1s) XPS spectra was carried out and the quantity of oxygen species was calculated. The results of XRD characterization showed that pure meta-CoV2O6, pyro-Co2 V2O7, and ortho-Co3 V2O8 with nice structure were obtained. The TEM images demonstrated that the catalysts showed uniform particle with the mean particle size of 20-30 nm. The diagram of the relationship between electrical conductivity and oxygen partial pressure of Co3V2O8 and Co2 V2O7 showed dsigma/dPo2 > 0, which implied that these were p-type semiconductor, and CoV2O6 reverse showed dsigma/dPo2 < 0, which implied n-type semiconductor. 48.12%, 47.82% and 35.24% of C3 H6 selectivities were obtained for p-type semiconductor Co3 V2O8, CO2 V2O7 and n-type CoV2O6 catalysts respectively at 10% C3H6 conversion, and the results showed that p-type semiconductor catalysts Co3 V2O8 and Co2 V2O7 showed higher activity than n-type catalyst CoV2O6. The results of FTIR, XPS, H2-TPR and conductivity measurement indicated that transferring between non-stoichiometric and lattice oxygen that easily happened in Co3 V2O8 and Co2 V2O7 catalysts might promote the oxidation-reduction reaction between different valence vanadium species, and promoted the oxygen vacancy formation. Furthermore, the forming of Co-O-V bridge bond that was easy to shift between Co and V increased the mobile oxygen species of O2-, O2(2-) and O- and made the redox reaction among different valence V be realized. It is concluded that high catalytic properties of p-type semiconductor Co3 V2O8 and Co2 V2O7 can be attributed to the abundant oxygen species O- that existed in these catalysts. PMID- 19445201 TI - [Spectral wavelength selection based on PLS projection analysis]. AB - In order to enhance the prediction accuracy of spectral analysis models and reduce their input number, this paper presents a simple and rapid wavelength selection method based on PLS projection correlation coefficients. These correlation coefficients are decided by both the changes in spectra data and the PLS regression coefficients between spectra matrix and concentration vector. Compared with the traditional wavelength selection method based on correlation analysis, the novel proposed method obviously improves the robustness of spectral analysis models and reduces their input number sharply. Applying the proposed method to 208 gasoline samples, the experimental results show that the number of calibration model input decreases to 30% of the original wavelength number, and the root mean square error of cross validation is reduced from 0.44 to 0.34. This method can be widely used in wavelength selection and data compression in spectral quantitative analysis. PMID- 19445202 TI - [FTIR research on new kind of tapioca starch/bentonite composite casting binder]. AB - Tapioca starch was used as the main material and self-developed organic-bentonite used as the modifier to make tapioca starch/bentonite composite binder by melting and solution intercalation technologies. The binder was characterized by means of FTIR, XRD and mechanical performance test. The results showed that the interlamellar spacing of improved organic bentonite was larger than that of organic bentonite and Na-bentonite, and the more the interlayer spacing of bentonite, the more advantageous the binder to the intercalation reaction between starch and bentonite, leading to higher dry tensile strength. The nanometer composite binder also features high bond strength, good humidity resistance, low costs and simple process, and is environment-friendly. PMID- 19445203 TI - [A review on studies and applications of near infrared spectroscopy technique(NIRS) in detecting quality of hay]. AB - The quality of hay can directly affect the price of hay and also livestock productivity. Many kinds of methods have been developed for detecting the quality of hay and the method of near infrared spectroscopy (NIRS) has been widely used with consideration of its fast, effective and nondestructive characteristics during detecting process. In the present paper, the feasibility and effectiveness of application of NIRS to detecting hay quality were expounded. Meanwhile, the advance in the study of using NIRS to detect chemical compositions, extent of incursion by epiphyte, amount of toxicant excreted by endogenetic epiphyte and some minim components that can not be detected by using chemical methods were also introduced detailedly. Based on the review of the progresses in using NIRS to detect the quality of hay, it can be concluded that using NIRS to detect hay quality can avoid the disadvantages of time wasting, complication and high cost when using traditional chemical method. And for better utilization of NIRS in practice, some more studies still need to be implemented to further perfect and improve the utilization of NIRS for detecting forage quality, and more accurate modes and systematic analysis software need to be established in times to come. PMID- 19445204 TI - [Methods of analyzing soybean meal adulteration in fish meal based on visible and near infrared reflectance spectroscopy]. AB - The present study investigated the feasibility of visible and near infrared reflectance spectroscopy (NIRS) method for the detection of fish meal adulteration with vegetable meal. Here the authors collected fish meal and soybean meal (representative vegetable meal) which were common used in our country. Fish meal was adulterated with different proportion of soybean meal and then the doping test samples were prepared. Qualitative discriminant analysis and quantitative analysis were studied with representative fish meal adulterated with soybean meal. Two hundred and six calibration samples and 103 validation samples were used in the qualitative discriminant analysis. The effects of different spectrum pre-treatment methods and spectrum regions were considered when the qualitative discriminant analysis model was established. Based on the smallest standard error of cross validation (SECV) and the correct rate, the spectrum region of visible and NIR was chosen as the best region. The eventually established pre-treatment methods were the standard multi-scatter correction (Std MSC) combined with the second derivative (2, 4, 4, 1). Then the independent external validation set was used to test the model, and there was no false positive samples and false negative samples. The correct discriminant rate was 96.12%. In quantitative analysis, 130 fish meal samples adulterated with soybean meal were used as calibration set. The calibration model was established by partial least squares (PLS). Furthermore, the effect of different spectrum pre treatment methods and the spectrum region were considered. The results showed that the best pre-treatment method was the standard normalized variate (SNV) combined with the second derivative (2, 4, 4, 1). The coefficient of determination (R2) and the standard errors of calibration (SEC) were 0.989 0 and 1.539 0 respectively between the predictive value and the actual value. Sixty five fish meal samples adulterated with soybean meal were used as independent validation set. The coefficient of determination (R2) and the standard errors of prediction (SEP) were 0.988 8 and 1.786 0 respectively, and the ratio of standard deviation of reference data in prediction sample set to the standard errors of prediction (RPD) was 8.61. The results showed that the NIRS could be used as a method to detect the existence and the content of soybean meal in fish meal. PMID- 19445205 TI - [Analysis of roots of soybean (Glycine max Merrill) treated with exogenous citric acid plus short-time aluminum stress by direct determination of FTIR spectrum]. AB - In the present study, 19 soybean (Glycine max L.) cultivars were analyzed and found to differ considerably in aluminum (Al) resistance. The cultivars Zhechun No. 2 (Al-resistant) and Zhechun No. 3 (Al-sensitive) were selected for further analysis. Experiments were performed with plants grown in full nutrient solution for 30 days. Fourier transform infrared spectrometry (FTIR) with OMNI-sampler was applied to the direct determination of different varieties of soybean root tissues, treated with aluminum in a dose-and time-dependent manner plus exogenous citric acid. Then the characteristic absorption peaks of spectra were analyzed and some differences in the FTIR spectra among samples were found from the comparison of the spectra. Results showed that the intensity and the shape of absorption peaks of their FTIR spectra exhibited some differences between different kinds of soybean and different treatment, especially around 1 057, 1 602, 2 927 and 3 292 cm(-1), which mainly reflected the content variety of protein, glucide, nucleic acid and so on. Thus it could be concluded that the effect of aluminum stress and existence of exogenous citric acid did not change the component of chemical substance in soybean roots, although the content of certain substance varied. The two dimensional discriminates analysis chart was drawn by the ratio of area at 2 927 cm(-1) to that at 3297 cm(-1) as the abscissa vs the ratio of area at 1 057 cm(-1) to that at 1 602 cm(-1) as the vertical, to discover the difference between the treatment of aluminum plus exogenous citric acid and that of single aluminum. Result indicates that the difference in the shape of absorption peaks of FTIR spectra became smaller and that presumed the content variety with different treatment was not remarkable under the condition of exogenous citric acid, especially in Zhechun No 3. From all mentioned above it is made clear that exogenous citric acid could really ameliorate distinctly the effect of aluminum on soybean roots which was detected by direct determination of FTIR spectrum, giving the fact that FTIR could reflect the ameliorating effect of exogenous organic acid on plant tissue under aluminum stress. PMID- 19445206 TI - [FTIR study of the endurance to Al of different soybean cultivars]. AB - The spectra of root, stem, leaf of soybean samples with 0, 20, 40, 60 mg x L(-1) Al3+ were determined by Fourier transform infrared (FTIR) spectrometry with OMNI sampler. Little difference was found in the spectra of leaf between two soybean cultivars, aluminum-resistant cultivar Zhechun NO. 2 and aluminum-sensitive cultivar Zhechun NO. 3, except the indices of wave number-absorbance from 928 to 1 200 cm(-1), and similar results were also observed in stem and root samples of the two soybean cultivars with 0 mg x L(-1) Al3+. However, results from the comparison of the spectra showed some distinguishable differences in the intensity and the shape of absorption peaks of their FTIR spectra from 721 to 3 366 cm(-1) of Al-stressed samples and control samples between the two soybean cultivars, and more evident differences of FTIR were exhibited in Al-stressed roots, stems and leaves with higher concentration of Al3+. The increased absorbance at 2 929 and 3 350 cm(-1) was found in root FTIR spectra with 20, 40, 60 mg x L(-10 Al3+, while roots got maximum absorbance at wave number of 1 375 cm(-1) with 20 mg x L(-1) Al3+, which decreased with higher concentration of Al3+, and the same results were showed at wave numbers of 1 410, 1 423, 1 549 and 1 645 cm(-1). Absorption peak showed maximum at wave numbers of 1 051, 2 850, 2 929 and 3 350 cm(-1) in stem FTIR spectra with 60 mg x L(-1) Al3+. There was little difference between the spectra of Al-stressed leaves and controls at wave numbers from 1 750 to 2 750 cm(-1), but visible difference in leaf spectra was exhibited at other wave number. Moreover, the results showed that the FTIR spectra of aluminum-sensitive cultivar Zhechun NO. 3 showed much more observable differences than aluminum-resistant cultivar Zhechun NO. 2 with different concentration of Al, implying that the material metabolic of aluminum-sensitive soybean was evidently affected by Al. Therefore, FTIR spectra could be used broadly for identification of the endurance of different soybean cultivars to Al. PMID- 19445207 TI - [Quantities analysis of the infrared diffuse reflection spectrum of hydrocarbon source rocks by OSC-iPLS]. AB - In many cases, the scattering can be an overpowering contributor to the spectrum, sometimes accounting for most of the variance in the data. Although the degree of scattering is dependent on the wavelength of the light that is used and the particle size and refractive index of the sample, the scattering is not uniform throughout the spectrum. In order to remove the effects of scattering and noise on multivariate calibration of IR spectral signals, orthogonal signal correction (OSC) was used as a method to preprocess the infrared spectra of the hydrocarbon source rocks to be quantitatively determined, thus to establish the calibration model of hydrocarbon source rocks before and after pretreatment by inetval partial least square (iPLS). Pretreatment was smoother and more orderly array. This indicated that the major information in hydrocarbon source rocks spectra could be reserved while part of noise was removed by OSC method. In this study, pretreatment calibration model was obtained, the model's correlation coefficient is 0.994 04 and RMSE is 0.635 2, but with no pretreatment the calibration model's correlation coefficient is 0.770 9 and RMSE is 3.925 7. PMID- 19445208 TI - [Fast discrimination of varieties of sugar based on spectroscopy technology]. AB - Visible and near-infrared reflectance spectroscopy (NIRS) was applied in the discrimination of sugar varieties. NIRS is a pollution-free, rapid, quantitative and qualitative analysis method, with the characteristics of high speed, non destructiveness, high precision and reliable detection data, etc. Four kinds of sugar were gained from the local market and each species was divided into 40 samples. One hundred twenty samples were used as the training set and the remainders (total 40 samples) formed the prediction set. Samples were scanned by a spectroradiometer within a wavelength region of 325-1 075 nm. Three pre processing methods were applied on the spectra prior to building the PLS regression model. The multivariable analysis using partial least square (PLS) was applied to abstract characteristics of the pattern. Through full cross validation, 11 principal components presenting important information of spectra were confirmed. The correlation coefficient (R), residual variance (Rv) and standard error of calibration (SEC) were 0.999 916, 0. 00 985 and 0.014 538 respectively. Then, these 11 principal components were taken as the input of BP neural network. This model was used to predict the varieties of 40 unknown samples. Through training and prediction, the recognition rate of 100% was achieved by BP neural network. This model has come to be reliable and practicable. Thus, it is concluded that PLS analysis combined with BP neural network is an available alternative for pattern recognition based on the spectroscopy technology. PMID- 19445209 TI - [Application of near-infrared reflectance spectroscopy to the discrimination of salt tolerance of alfalfa cultivars]. AB - Near infrared reflectance spectroscopy is a new developed method able to analyse the content of specific compound in the detected sample quickly and efficiently, and has been wildly used in many fields such as evaluation of nutrition value of forage, cultivar discrimination and so on. In the present paper a new method was developed for the discrimination of salt tolerance of alfalfa cultivars by Fourier transform near infrared reflectance spectroscopy. Firstly absorbance spectrum generated by Fourier transform near infrared spectrometry was used to classify twenty alfalfa cultivars. These cultivars were obviously clustered into two groups: salt tolerant and salt sensitive, similar to the result, screened by the traditional methods. Based on these results, a discrimination model was built for identification of salt tolerant cultivars. And then, six other cultivars were used to verify the function of the discriminating model. Result showed that the distinguishing rate of 100% was achieved with the performance index of 85.7%. It is concluded that Fourier transform near infrared spectrum is useful for classification and discrimination of salt tolerance of alfalfa cultivars. The method can be applied to estimate salt tolerance of alfalfa cultivars, and works more quickly and efficiently than the traditional screening methods. Application of Fourier transform near infrared spectrum to discriminating salt tolerance of alfalfa cultivars is significant in both academic and technical areas. PMID- 19445210 TI - [Differentiation of Amanita hemibapha (Berk. & Broome) Sacc. subsp. hemibapha and Amanita hemibapha var. ochracea Zhu L. Yang by Fourier transform infrared spectroscopy]. AB - In order to demonstrate the ability of Fourier transform infrared (FTIR) spectroscopy for the differentiation of macro-fungi at variety level, FTIR spectroscopy was used to obtain vibrational spectra of Amanita hemibapha (Berk. & Broome) Sacc. subsp. hemibapha and Amanita hemibapha var. ochracea Zhu L. Yang. The results show that their spectra are very similar to each other, with a small difference in the relative intensity of absorbance. For the purpose of enhancing the spectral resolution and amplifying the differences, the first-derivative spectra and second-derivative spectra were selected for evaluating the correlation coefficients respectively. The results show that the second derivative spectra of two fruit bodies of Amanita hemibapha (Berk. & Broome) Sacc. subsp. hemibapha and one fruit body of Amanita hemibapha var. ochracea Zhu L. Yang have obvious differences, the correlation coefficients are only 0.245 and 0.356 respectively, the second-derivative spectra of two fruit bodies of Amanita hemibapha (Berk. &Broome) Sacc. subsp. hemibapha are very similar, and the correlation coefficient is 0.865. The authors' results show that Fourier transform infrared spectroscopy in combination with correlation analysis method can be used to identify Amanita hemibapha (Berk. & Broome) Sacc. subsp. hemibapha and Amanita hemibapha var. ochracea Zhu L. Yang rapidly and accurately. PMID- 19445211 TI - [Purification of sulfolene and its UV-Vis and FTIR spectral analysis]. AB - Purification of raw sulfolene was investigated by adsorption method using activated carbon and exchange resin, and the sulfolene was detected by UV-Vis, FTIR and XRD. FTIR spectra of sulfolene and sulfolane were especially analyzed. The results showed that it was the best way to purify industrial grade sulfolene by activated carbon connected exchange resin. The sulfolane with high quality was synthesized by purified sulfolene through catalytic hydrogenation with catalyst. The conversion efficiency was more than 99.8%. It could provide experimental data for the technical reform of industry equipment. PMID- 19445212 TI - Mechanism of surface-enhanced Raman scattering and its application to highly sensitive protein detection. PMID- 19445213 TI - [SERS spectra of serum from diabetic]. AB - The SERS spectra were measured from normal and the diabetic serum. In the diabetic serum, the band of amide II shifted to 1 585 cm(-1) and the relative intensity increased 14%, while the relative intensity of 593 cm(-1) which belongs to amide VI reduced 33%. For the protein side chain, the band at 1 368 cm(-1) assigned to the "buried" tryptophan shifted to 1 365 cm(-1) of the "exposed" and the relative intensity reduced 59%. The relative intensity of 635 cm(-1) assigned to the gauche conformation of the C-S decrased 15% and the band at 725 cm(-1) increased 58%. These indicate that the structure of the protein changed in the diabetic serum. The relative intensity at 1 449 cm(-1) assigned to the lipids characteristic increased 58%. The relative intensity of the glucide characteristic at 1 331, 1 099 and 740 cm(-1) increased 35%, 100% and 62%, respectively. So it is indicated that the content of lipids, glucide and protein increased in diabetic. These results may offer a powerful experimental basis for diabetes diagnosis and biochemistry mechanism study. PMID- 19445214 TI - [Preparation of DNA silver nanowire and its Raman spectra]. AB - Silver nanoparticles were synthesized by the method of combining heating with UV irradiation. In the authors' work, the shape and size of nanograins which carry positive electrical charges are uniform and their average diameter is 7.8 nm. Based on the electrostatic self-assembly characteristics of DNA, silver nanoparticles were equally assembled on predefined aligned calf thymus DNA to form DNA silver nanowires. The diameter of the wires is about 30 nm and the length is 2 microm. The Raman spectra indicate that the silver nanoparticles mainly attach to the backbone chain of DNA and affect the vibration properties of deoxyribose and base. The intensity of the peaks at 782 and 1 098 cm(-1) assigned to stretch vibration of phosphoric skeleton decreases sharply and the band at 782 cm(-1) shifts to 791 cm(-1). The bands of deoxyribose C-O stretch vibration at 1 011 and 1 050 cm(-1) shift to 1 030 and 1 064 cm(-1) respectively. The characteristic peaks of bases at 1 372, 1 334, 1 304 and 728 cm(-1) shift to 1 368, 1 320, 1 294 and 731 cm(-1), respectively. PMID- 19445215 TI - [Raman spectrum study on turquoise]. AB - The Raman spectrum has been employed to discuss the explanation of the structure of water and the vibration of [PO4(3-)] tetrahedron of the turquoise from Hubei and Anhui province. The Raman spectra are resulted mainly from vibrations of water, hydroxyl units and [PO4(3-)] tetrahedron of turquoise. The 3 510-3 440 cm( 1) bands with the main Raman spectra peak at 3 470 cm(-1) were assigned to the upsilon(OH) stretching vibrations and the 3 290-3 070 cm(-1) bands assigned to the upsilon(H2O) stretching vibrations. The bands observed at 1 200-1 030 cm(-1) with the strong peak at 1 039 cm(-1) were assigned to upsilon3 (PO4) antisymmetric stretching vibrations. And the Raman spectra peaks at 650-540 cm( 1) and 500-410 cm(-1) were attributed to the upsilon4 and upsilon2 bending vibrations of [PO4(3-)] tetrahedron, respectively. The spectra of the turquoise from different localities are basically similar and subtly different. PMID- 19445216 TI - [Effects of forms and level of nitrogen fertilizer on the content of chlorophyll in leaves of maize seedling]. AB - The level and form of nitrogen fertilizer could significantly influence the growth and development of plant. The present paper studied the content of chlorophyll by the instrument SPAD-502 after treated with different nitrogen fertilizer level and different nitrogen fertilizer form. The results showed that the contents of chlorophyll in the last expanding leaf of maize seedling treated by levels of 0, 100 and 200 kgN x hm(-2) respectively had no significant difference, with the value of SPAD ranging from 43.3 to 43.7, but when the nitrogen fertilizer level got to 400 kgN x hm(-2), the content of chlorophyll in the last expanding leaf of maize seedling increased significantly, which can be caused by other components in the nitrogen fertilizer, which needs to be further studied. The experiments of nitrogen form showed that maize seedling treated by ammonia nitrogen ((NH4)2SO4) contained more chlorophyll than that treated by saltpeter nitrogen (Ca(NO3)2), and the statistical analysis was significant. The reason for the effect of nitrogen form on the content of chlorophyll of maize seedling leaf could be: (1) it is easier for plants to absorb ammonia nitrogen ((NH4)2SO4) than saltpeter nitrogen (Ca(NO3)2); (2) ammonia nitrogen ((NH4)2SO4) contains more trace elements which can promote the growth and development of plants. PMID- 19445217 TI - [Ring effect and correction studies while retrieving trace gas concentration with passive DOAS]. AB - The method of retrieving the concentration of trace gases using of the diagnostic absorption of trace gases based on the scattered sunlight is called passive DOAS. It has been developed so fast in recent years because it remains simple and is prone to being combined with different platform. While retrieving the column density of trace gases with the scattered sunlight as light source, it will be affected strongly by solar Fraunhofer lines, which is also called Ring effect. It makes it hard to retrieve trace gases concentration and affects measurement precision, especially for lower concentration. The influence of Ring effect and its relation with solar zenith angle in stable day will be introduced in the present paper, and the modification will be provided so that different Ring spectrum is selected according to different solar zenith angle. The slant column density (SCD) of NO2 for 3 stable days was retrieved with this modification. It was proved that the modification is possible. PMID- 19445218 TI - [Spectroscopy research on synthesis of new desilication reagent-calcium hydroferrocarbonate]. AB - For removing silica from high concentration medium after digestion of the diasporic bauxite by sub-molten salt, the research used calcium hydroferrocarbonate with the new desilication reagent. In the reaction, calcium carbonate, calcium hydroxide and calcium ferrite were by-product, therefore the reaction factors showed significant influence on the synthesis and disilicating efficiency. To explore the synthesis mechanism and optimize the reaction factors, the composition of the intermediate obtained from the synthesis reaction was investigated through the combination of FTIR, ICP-AES and desilication reaction. The FTIR and desilication reaction results revealed that calcium hydroferrocarbonate is metastable compound in solution, and the reaction temperature and reaction time have significant influence on the systhesis. With the temperature and reaction time increasing, the content of calcium hydroferrocarbonate in the composition first increased and then reduced. The optimal factors were: temperature of 30 degrees C, reaction time of 16 hours, the liquid to solid mass ratio of 20 and rpm of 500 r x min(-1). The crystal structure of calcium hydroferrocarbonate was investigated, and was found to be rhombohedral, including H2O bond, -OH bond and Fe-O bond. PMID- 19445219 TI - [Study on the aggregation behavior of cationic porphyrins and their interaction with ctDNA]. AB - Interest in the interaction between cationic porphyrins, particularly derivatives of meso-tetra(N-methylpyridinium-4-yl) porphyrin(TMPyP), and DNA abounds because they are versatile DNA-binding agents that could find application in photodynamic therapy, cancer detection, artificial nucleases, virus inhibition and so on. The interaction of two water-soluble cationic porphyrins, meso-tetrakis(4-N, N, N trimethylanilinium) porphyrin (TMAP) and 5-phenyl-10,15,20-tris[4-(N-methyl) pyridinium]porphyrin (TriMPyP), with calf thymus DNA (ctDNA) was studied by UV Vis absorption spectroscopy, fluorescence spectroscopy and resonance light scattering technique. TriMPyP forms aggregate in water due to the molecular asymmetry while TMAP exists as monomers. At lower concentrations of ctDNA (R > 1, R = c(TMAP)/c(DNA) base pair), the interaction of TMAP with DNA leads to significant hypochromicity and bathochromic shift of absorption spectra. And the fluorescence of TMAP was quenched while it showed enhanced resonance light scattering signals. But the extent of enhancement of resonance light scattering signals is very small, so the aggregate of TMAP is not very high. These observations indicate the self-stacking of TMAP along the DNA surface. At higher concentrations of ctDNA (R < 1), TMAP association with DNA is via outside binding which is accompanied with hyperchromic effect and fluorescence enhancement while the resonance light scattering signals is reduced. DNA addition decreases the fluorescence intensity of TriMPyP and it shifts the peak to the higher wavelengths (red shift). The interaction with DNA promotes the aggregation of TriMPyP and no simple outside binding is observed even at higher concentrations of ctDNA. The steric effect of molecular distortion constrains the intercalation or further binding to DNA. The effect of ionic strength on the interaction was investigated at two DNA concentrations, 1.2 and 24.0 micromol x L(-1), for TMAP. The Interactions of both porphyrins with DNA show high sensitivity to ionic strength. By addition of NaCl, electrostatic attraction is decreased, resulting in the change of binding mode. PMID- 19445220 TI - [Investigation on low power microwave irradiation-assisted enzymatic esterification in organic solvent by fluorescence spectroscopy]. AB - The authors studied the fluorescence change of immobilized lipase from Rhizomucor miehei in the microwave assisted enzymatic esterification of caprylic acid and butanol in organic medium by investigating the fluorescence spectra in solvent or aqueous buffer after incubating the lipase with the solvent, caprylic acid and butanol under microwave irradiation, respectively. A comparison was made with the conventional heated enzymatic esterification in the solvents. Both of the heating modes, the microwave irradiation and conventional heating, can enhance the fluorescence intensity without shifting the emission wavelength of the lipase. In the circumstance that the irradiation can accelerate the esterification, the irradiation can enhance the exposure of the lipase protein molecules in the aqueous environment after incubating the lipase with solvents or the substrates. The effect of the reaction mixture on the fluorescence intensity was dominated by the solvents. The trend of the plot of log P versus the initial reaction rate was similar to that of log P versus fluorescence intensity of lipase in aqueous buffer after esterification; but was different from that of log P versus fluorescence intensity of lipase in organic medium. PMID- 19445221 TI - [Nitrogen status diagnosis of summer maize by using visible spectral analysis technology]. AB - In the present paper, a field experiment with different N rates was conducted to study the possibility of using the visible spectrum of crop canopy to diagnose N status for the summer maize. Visible spectrum parameters were compared with the leaf SPAD readings, total N concentration and vein nitrate concentration. Field measurement data showed that the greenness intensity, blueness intensity, normalized redness intensity, normalized greenness intensity and normalized blueness intensity of the maize canopy have significant relationships with leaf SPAD readings, total N concentration and vein nitrate concentration (under a low N input condition, with vein nitrate concentration < 2 000 mg x L(-1)) at summer maize 10 leaves unfold stage. The greenness intensity, blueness intensity, normalized greenness intensity and normalized blueness intensity have significant relationship with the vein nitrate concentration under a low N input condition (vein nitrate concentration < 2 000 mg x L(-1)). But when the maize vein nitrate concentration is above 2 000 mg x L(-1), there is no spectral parameter showing significant relationship with the vein nitrate concentration. The visible spectrum parameters reached a plateau with the vein nitrate concentration increasing. To sum up, the normalized greenness intensity (NGI) and normalized blueness intensity (NBI) have higher r values (0.45-0.66) than other parameters. PMID- 19445222 TI - [A spatial-distance analysis approach of multi-spectrum feature distribution for remote sensing image land use/cover]. AB - Aiming at the problem that a convenient multivariate statistical model is in general not available for the multi-spectrum feature of land use/cover (LUC) class in remote sensing (RS) image, because the class is made of multiple covered species, a spatial-distance analysis approach of multi-spectrum feature distribution for RS image LUC is present, with the mean vector of samples as LUC class center, with max-min clustering algorithm forming the class multi clustering-centers, the spatial-distances from the class center to these multi clustering-centers were calculated. With the distance as abscissa and the percentage of the clustering-center pixels to the whole sample pixels as ordinate, the intra- and inter-classes distance distribution charts were constructed to analyze the multi-spectrum feature distribution of RS image LUC. The results of these samples classification tally with the conclusions of spatial distance analysis, indicating that this approach is feasible. In this approach the multi-dimensional spectrum information is turned into one dimensional distance information, the spatial-distance calculation and clustering threshold confirmation are realized easily, and the multi-spectrum feature of LUC class is clear, so it is a better approach to solving the multivariate distributing problem of multi-spectrum feature. PMID- 19445223 TI - [Study of cefadroxil and cephradine charge transfer process by fluorescence quenching method]. AB - A simple and sensitive fluorescence quenching method was developed for the examination of cefadroxil and cephradine. The method is based on the reaction of fluorescein with cefadroxil or cephradine, resulting in the formation of complexes with weak fluorescence, i.e. quenching the fluorescence intensity of the system. By the use of absorption spectroscopy, infrared spectroscopy and quantum chemistry calculation the reaction process of the cephalosporins and the bonding of reaction mechanism were basically analyzed. Based on this, the fluorescence spectrometry method for the determination of the contents of cefadroxil and cephradine was developed: The maximum excitation and emission wavelength was at 483 nm, and 517 nm and 519 nm respectively. The linear calibration curves were obtained over the cefadroxil and cephradine concentration ranges of 0.3-13.5 mg x L(-1) and 0.1-1.2 mg x L(-1) respectively. The proposed method has been successfully applied to the examination of the subject drugs in its pharmaceutical dosage with good precision and accuracy. The recoveries are 99.63%-99.91% and 99.71%-100.08% respectively. PMID- 19445224 TI - [Interaction of cucurbit[8]urils with ofloxacin, fleroxacin, gatifloxacin and sparfloxacin]. AB - Interaction between cucurbit[8]urils and ofloxacin, fleroxacin, gatifloxacin and sparfloxacin was detected by UV and fluorometric analysis in details. The experimental results revealed that the acidity of the medium effected the interaction of the title systems. The cucurbit[8]urils could interact with ofloxacin, fleroxacin and gatifloxacin with a ratio of 1 : 1 and with sparfloxacin with a ratio of 2 : 1 when pH < 8.0. Inclusion stability constants of the systems of Q[8] with the guests detected at different pH values were 10(3) 10(4) L x mol(-1), while for SPFX it was 10(11) L2 x mol(-2). The results of the analysis of the four systems showed that the linear relation can reach 2 or 3 orders of magnitude and the limit of detection can be as low as 10(-9)-10(-7) mol x L(-1). PMID- 19445225 TI - [Microscopic infrared spectral imaging of oily core]. AB - In the present paper, the authors examined some oily core by microscopic infrared spectral imaging methods. Those methods can be classified in three modes, referred to as "transmission mode", "reflection mode" and "attenuated total reflection (ATR) mode". The observed oily core samples belong to siltstone. The samples were made of quartz (-20%), feldspar(-50%) and other rock (igneous rock 25%, metamorphic rocks 1%, sedimentary rock 4%); a little recrystallized calcite (-1%) was in the pore, and the argillaceous matter was distributed along the edge of a pore. The experimental work has been accomplished using SHIMADZU Model IRPrestige-21 Fourier transform infrared spectrophotometer plus AIM8800 infrared microscope. For IRPrestige-21, the spectral range is 7 800-350 cm(-1) spectral resolution is 1 cm(-1), and AIM8800 microscope with motorized stages has a resolution of 1 micrometer. The experiment was preformed at room temperature. In "transmission mode" infrared spectral imaging method, the spectral range was limited in wavenumbers greater than 2 000 cm(-1) because the base glass piece has strong light absorption. In contrast with "transmission mode", in "attenuated total reflection (ATR) mode", the depth of penetration into sample is very small (1-2 micrometer), then the absorbance value has nothing to do with base glass piece light absorption. In microscopic infrared transmission spectra, the experimental result shows that there are some strong absorption peaks at 2 866, 2 928, 3 618 and 2 515 cm(-1) respectively. The former two peaks correspond to methyl(methylene) symmetrical and unsymmetrical stretch vibration mode, respectively. The latter two peaks correspond to hydroxyl-stretch vibration mode and S-H, P-H chemical bond stretch vibration mode, respectively. In microscopic longwave infrared ATR spectra, there are other stronger absorption peaks at 1 400, 1 038 and 783 cm(i1)respectively, corresponding to methyl(methylene) widing vibration mode and optical mode of quartz crystal, respectively. On the basis of the above-mentioned experimental result, the authors have separately accomplished microscopic infrared transmission and ATR spectral imaging using mapping procedure. The "transmission mode" and "ATR mode" have their own advantage and disadvantage. According to specific structural and spectral properties of sample and the practical research goall we should select a practical procedure. PMID- 19445226 TI - [Effects of N, K fertilization on the relationship between photosynthetic light use efficiency and photochemical reflectance index (PRI)]. AB - PRI (Photochemical reflectance index) has provided a fast and reliable method for estimating photosynthetic light use efficiency across species. Increasing efforts have been paid to explore the effects of such disturbances as water content and CO2 concentration on the relationship between PRI and LUE. In the present paper, five types of wheat with different nitrogen and kalium fertilization were selected to study the influence of varied fertilization levels on the relationship between PRI and LUE. The results proved that leaf chlorophyll contents as well as canopy PRI increased with the increase in nitrogen and kalium fertilization. For all the nitrogen and kalium fertilization of wheat, the regression coefficients R2 are 0.710 4 and 0.853 4 respectively. When considering different levels of fertilization, the regression coefficients R2 are 0.602 0, 0.640 4 and 0.801 4 for three types of nitrogen fertilization, and 0.379 1, 0.640 4 and 0.676 9 for kalium fertilization. Therefore, PRI not only can be a reliable indicator of LUE but also can reflect the fertilization situation of wheat with different precisions of LUE assessment which can provide important reference for management and precision agriculture. PMID- 19445227 TI - [Nucleoplasmic viscosity of living cells investigated by fluorescence correlation spectroscopy]. AB - In order to non-invasively investigate nucleoplasmic viscosity in real time with good temporal resolution, the present study firstly introduced a new method based on fluorescence correlation spectroscopy (FCS). FCS is a kind of single-molecule technique with high temporal and spatial resolution to analyze the dynamics of fluorescent molecules in nanomolar concentration. Through a time correlation analysis of spontaneous intensity fluctuations, this technique in conjunction with EGFP as a probe is capable of determining nucleoplasmic viscosity in terms of Stokes-Einstein equation as well as its corresponding analysis of the diffusion coefficient for EGFP in the nucleus. The results showed that nucleoplasmic viscosity of ASTC-a-1 cells and HeLa cells were respectively (2.55 +/- 0.61) cP and (2.04 +/- 0.49) cP at pH 7.4 and 37 degrees C, consistent with the results by traditional methods, and nucleoplasmic viscosity was found to be larger than cytoplasmic viscosity. Meanwhile, the real-time analysis of nucleoplasmic viscosity in living cells exposed to hypotonic media proved that FCS could be used to track the changing rheological characteristics of the nucleoplasm in living cells. Taken together, this study suggests that FCS provides an accurate and non-invasive method to investigate the microenvironment in living cells on the femtoliter scale and it can be used as a powerful tool in researches on the dynamical processes of intracellular molecules. PMID- 19445228 TI - [Research on distinguishing weed from crop using spectrum analysis technology]. AB - Automatic detection of weeds is necessary for site--specific application of herbicides or precise physical weed control. Leaf reflectance is mainly determined by photosynthetic pigments, leaf structural properties and water content, so spectral reflectance characteristics can be used for weed discrimination. The spectral reflectance of cotton, rice and weeds was determined in the range from 350 to 2 500 nm using the Analytical Spectral Device Full Range FieldSpec Pro (ASD) in laboratory. The discrimination analysis was done using the statistical software package SAS. The characteristic wavelengths were selected by using STEPDISC procedure. With the selected characteristic wavelengths, discriminant models were developed using the DISCRIM procedure in SAS. For distinguishing spine-greens from cotton, three characteristic wavelengths, 385, 415, and 435 nm, were selected, and good classification performance (100% accuracy) was achieved. The combination of characteristic wavelengths 415 and 435 nm has the biggest contribution to discrimination model. For distinguishing barnyard-grass from rice, five characteristic wavelengths, 375, 465, 585, 705, and 1 035 nm, were selected, and also good classification performance (100% accuracy) was obtained. The transition point from yellow to orange wavelength (585 nm) and the wavelength 705 nm in the red edge contributed more to discrimination model. PMID- 19445229 TI - [Cucumber diseases diagnosis using multispectral imaging technique]. AB - For a reliable diagnosis of plant diseases and insect pests, spectroscopy analysis technique and mutispectral imaging technique are proposed to diagnose five cucumber diseases, namely Trichothecium roseum, Sphaerotheca fuliginea, Cladosporium cucumerinum, Corynespora cassiicola and Pseudoperonospora cubensis. In the experiment, the cucumbers' multispectral images of 14 visible lights channels, near infrared channel and panchromatic channel were captured using narrow-band multispectral imaging system under standard observation environment. And the 5 cucumber diseases, healthy leaves and reference white were classified using their multispectral information, the distance, angle and relativity. The discrimination of Trichothecium roseum, Sphaerotheca fuliginea, Cladosporium cucumerinum, and reference white was 100%, and that of Pseudoperonospora cubensis and healthy leaves was 80% and 93.33% respectively. The mean correct discrimination of diseases was 81.90% when the distance and relativity were used together. The result shows that the method realized good accuracy in the cucumber diseases diagnosis. PMID- 19445230 TI - [Quick determination of formaldehyde remnant in the pharmic intermediates by homemade microspectrometer]. AB - The rapid and real-time analytical system based on photometrical methodology of a homemade holographic flat field concave grating integrated microspectrometer was established, which was applied to detect the remnant formaldehyde in the intermediate of ranitidine synthesis. Based on the chromogenic reaction of formaldehyde with MBTH and NH4Fe (SO4)2 in acid medium, the methodology of formaldehyde detection was developed. Furthermore, factors affecting the chromogenic reaction were optimized in details. Under the optimized conditions, a good linear relationship in the range of 0.04-0.20 microg x mL(-1) (r = 0.993 8) was obtained and the lowest detection limit achieved 0.04 microg x mL(-1). In order to demonstrate the methodology and reliability of the microspectrometer analytical system, comparative experiments were carried on among the homemade microspectrometer, SHIMADZU UV-2550 spectrophotometer and U.S.A. Ocean Optic HR2000 Microspectrometer. The F-test was employed to check the reliability and efficiency of the proposed methodology. No significant difference was shown among them. The experimental results showed that the set up analytical system could satisfy the needs of quick and real-time detection in practical applications for experimental analysis, industrial monitoring and medicinal diagnosis. PMID- 19445231 TI - [Study on the energy transfer fluorescence quenching reaction of acridine orange 4-(2-pyridylazo) resorcinol-V(V) system and analytical application]. AB - An energy transfer technique for 4-(2-pyridylazo) resorcinol (PAR)-vanadium(V) and acridine orange (AO) was studied, and the optimum conditions of energy transfer system were also experimented. It was found that in citrate-Na2 HPO4 buffer solution at pH = 5.5, energy transfers from AO to vanadium(V)-PAR complexes. A new method based on energy transfer fluorescence quenching for the determination of trace vanadium(V) with AO-PAR-V(V) was established. The equation of linear regression is deltaF = 165.4c+2.5, and the determination range of vanadium is 0.012-0.5 microg x mL(-1), with detection limit of 0.004 5 microg x mL(-1). The correlation coefficient is R = 0.998 5, and relative standard deviation is 0.6%. The fluorescence reaction is completed within 15 minutes, and relative fluorescence intensity remains unchanged for 2.5 hours. The influence of foreign ions on the determination of V (0.5 microg x mL(-1)) was examined, with a related error of 5%. The method has been used in the determination of trace vanadium in biological samples with the relative error of 6.98%, which meets the requirements of trace analysis. PMID- 19445232 TI - [Study on experiment of fluorescence spectra detection of organic pesticides in soil]. AB - The fluorescence characteristics of carbamate pesticide, namely carbaryl, was studied based on the basic theory that organic molecules can emit fluorescence as they are excited by rays. Consequently, a fluorescence spectrograph was applied to conduct fluorescence spectrum experiments with standard solution of carbaryl and the hydrolyzed carbaryl, the fluorescence spectra were obtained under the condition of different concentration, and the relation between their fluorescence intensity and concentration was also analyzed. On the basis of this, using the soil as a medium, the fluorescence characteristics of carbaryl and the hydrolyzed carbaryl in the soil were researched as well. The experiment results show that carbaryl and the hydrolyzed carbaryl in the soil can also emit intensive fluorescence which is similar to that in solution as being excited by UV rays. The fluorescence spectra are located between 400 and 750 nm and they all have smooth spectrum forms and fine resolution, so the spectra are suitable for qualitative and quantitative analysis of carbaryl. As a result, it is feasible to carry out the detection and analysis of the concerned pesticides in soil directly or indirectly by fluorescence spectral analysis. PMID- 19445233 TI - [Study of enhancement effect of laser-induced crater on plasma radiation]. AB - Single pulses exported from high-energy neodymium glass laser were used to act on the same position of soil sample surface repeatedly, and the plasma emission spectra generated from sequential laser pulse action were collected by spectral recording system. The experimental results show that the laser-induced soil plasma radiation was enhanced continuously under the confinement effect of the crater walls, and the line intensities and signal-to-background ratios both had different improvements along with increasing the number of acting pulses. The photographs of the plasma image and crater appearance were taken to study the plasma shape, laser-induced crater appearance, and the mass of the ablated sample. The internal mechanism behind that laser-induced crater enhanced plasma radiation was researched. Under the sequential laser pulse action, the forming plasma as a result enlarges gradually first, leading to distortion at the trail of plasma plume, and then, its volume diminishes slowly. And also, the color of the plasma changes from buff to white gradually, which implies that the temperature increases constantly. The laser-induced crater had a regular shape, that is, the diameter increased from its bottom to top gradually, thus forming a taper. The mass of the laser-ablated substance descends along with increasing the amount of action pulse. Atomization degree of vaporized substance was improved in virtue of the crater confinement effect, Fresnel absorption produced from the crater walls reflection, and the inverse bremsstrahlung, and the plasma radiation intensity was enhanced as a result. PMID- 19445234 TI - [Study on stray light in self-reversal background correction for atomic absorption spectrometry--the properties of stray light and its influence on background correction]. AB - In self-reversal background correction the particularity of stray light that is not absorbed by the sample matrix is different from that in deuterium lamp and Zeeman background correction. The stray light is evaluated using the cut-off solution method and its effects were studied by means of simulation background absorption using potassium dichromate solution molecular absorption. Experiments confirmed that the stray light due to light source for the sample beam (Conventional pulse, low Current) and reference beam (narrow pulse, high current) is obviously different, with the former being higher than the latter. Therefore, the difference is an important source in self-reversal background correction errors and the errors can not be ignored in high background correction. The present paper also showed the relationships among stray light and lamp current, light energy, and spectral bandwidth. The results show that the ratio of stray light is much related to the lamp current, and the larger the lamp current, the smaller the ratio of stray light. The ratio of stray light that changes with lamp current is not directly related to the energy of analytical line. Stray light ratio decreases with the decrease in spectral bandwidth and its character is similar to continuous spectrum. PMID- 19445235 TI - [Relationship of Zn content and Na/K ratio to the resistance to pathogen invasion in antisense ACS transgenic tomato fruit and normal tomato]. AB - In the present work, inductively coupled plasma atomic emission spectrometry (ICP AES) was used to determine the content of Zn, Na and K and the ratio of Na/K in antisense ACS transgenic tomato fruit (in which the antisense ACC synthase gene construct was inserted) and in normal tomato fruit of the same variety (Lycopersicon esculentum cv. Lichun). The difference in mineral elements content between the two tomatoes and the involvement of Zn content and Na/K ratio in the disease resistance of postharvest tomato fruit were discussed. The results showed that the ethylene biosynthesis is limited in antisense ACS transgenic tomato fruit. Meanwhile, the resistance to Rhizopus nigricans invasion of this transgenic tomato was higher, the disease incidence and lesion area in transgenic tomato fruit were 20.0% and 33.3% lower than those in control fruit, respectively. In addition, the content of Zn in transgenic tomato fruit was 0.322 microg x g(-1) and was 1.5 times higher than that in Lichun tomato fruit. There was no significant difference in K content between transgenic tomato fruit and Lichun fruit, but the content of Na in transgenic tomato fruit was significant higher than that in Lichun fruit and the Na/K ratio in transgenic tomato fruit was 2.0 times higher than that in Lichun fruit. It is suggested that the content of Zn and the Na/K ratio may be involved in the resistance response to pathogen invasion and the development of antisense ACS transgenic tomato fruit. PMID- 19445236 TI - [Determination of mineral elements in eight pear varieties by ICP-MS after microwave-assisted digestion]. AB - A study was carried out on the contents of mineral elements such as Na, K, Ca, Mg, Zn, Cu, Fe, Mn and B in eight different pear varieties by ICP-MS after microwave-assisted digestion. The results indicated that the main elements of the eight pears are similar, but the content of each element is different. The content of K is the highest in the detected pears, followed by Mg, Ca and Na. Compared with the reference value of AIJN (Association of Industry of Juices and Nectars from fruits and vegetables of the European Union), the range scale of K, Mg, and Ca was higher than that of the AIJN, while the content of Na element was lower than that of the AIJN, and other elements content was consistent with it. PMID- 19445237 TI - [Determination of 23 trace elements in wines by ICP-AES]. AB - In the present paper, the contents of trace elements As, Ba, Co, Ni, Cu, Be, Sr, Cr, Mn, Li, P, Se, Pb, Bi, Cd, B, Zn, Mg, Fe, K, Na, Ca and Al in nineteen wines produced in Jiangxi province were determined by using inductively coupled plasma atomic emission spectrometry (ICP-AES). The differentiation in the trace elements between wines was studied in terms of different producing regions, as well as different alcoholic degrees and qualities from the same manufacturer. The experimental results indicated that with the samples cleared up completely by a small quantity of nitric acid the method could satisfy the request of ICP-AES analysis. The relative standard deviations of the method were between 0 and 5.81%, and the recovery rates were between 90.5% and 107.6%. The measuring method provided better accuracy and precision, and the trace elements showed definite differences between wines produced from different regions and with different alcoholic degrees and qualities from the same manufacturer. For instance, there is small amount of element Bi only in the wines of A factory, the content of elements Co, P and Se is higher in the wines of B factory, the content of elements Cu, Fe, K is higher in the wines of C factory, and the content of element Al in the wines of D factory is obviously higher than others. So the research results in this paper provided the theoretical basis for further study of the relationship between wine qualities and trace elements. PMID- 19445238 TI - [Study on the determination of trace composition and impurity elements in kaolin with ICP-MS]. AB - The direct determination method of trace composition, Fe2O3, TiO2, MnO, K2O, Na2O, CaO and MgO, and impurity elements, Pb, Cr, Cd, Cu and As, in kaolin was studied by using inductive coupled plasma mass spectrometry (ICP-MS). After the samples were dissolved completely in HF-HNO3 at low temperature, silicon was volatilized in the form of SiF4 and separated from the solution. Then the solution was continually evaporated to dry to get the solid substance which was dissolved by the nitric acid (1+3). The internal elements 45Sc, 115In and 205Tl were added on line and the effect of matrix, interface and fluctuation of instrument was overcome effectively by using internal standard calibration method. By choosing the optional operating parameters and appropriate isotopes of element to be detected, the influence of mass spectrometry interference was conquered effectively. The effect of temperature in samples preparation on the determination of arsenic was tested. The recovery for spiking sample is in the range from 95.0% to 101.0% and the relative standard deviation is in the range from 1.1% to 2.01%. In order to check the accuracy of the method, the kaolin standard reference material GBW03122 was also analyzed, and the analytical values conformed to standard values. This method has the characteristics of being simple, rapid and accurate, and can be used in the testing of trace composition and impurity elements in kaolin and ceramic product. PMID- 19445239 TI - [Distribution of six trace elements in Fuji apple]. AB - Trace elements are important nutritional elements for human health. Six trace elements in Fuji apple skin and pulp were analyzed by the method of ICP-MS. The results showed that the concentrations of Ca, Mn, Fe, Se, Mo and I were 197 910, 1 623, 14 400, 2, 47 and 91 ng x g(-1) x FW in apple skin respectively; and 58 360, 281, 550, 4, 18 and 24 ng x g(-1) x FW respectively in apple pulp. The concentrations of most trace elements (Ca, Mn, Fe, Mo and I) in apple skin were several times higher than those in apple pulp, especially the concentrations of Fe, Mn and I in skin was 25.18, 4.78 and 2.79 times higher than those in pulp, except Se (2 ng x g(-1) x FW in skin and 4 ng x g(-1) x FW in pulp). So we should not peel apples before we eat them from regions where were not polluted by pesticides and heavy metals. PMID- 19445240 TI - [Analysis study of trace elements in abalone and sea cucumber]. AB - Abalone and sea cucumbers are useful, which is related with trace elements in them. In the present paper, using high-pressure sealed nitrifying pots for digestion of samples, Orthogonal test was applied to the determination of 15 kinds of trace elements in abalone and sea cucumber such as Fe, Ca, Mg, Zn, Sr, Se, Hg, Cd etc by ICP-AES. The orthogonal table of L16 (4(4)) and experiment programs were designed. More information could be obtained with a small number of experimental times by combining chemistry with mathematical statistics, and the best experimental operation conditions could be chosen by square-error analysis. The method was simple, rapid, highly sensitive and accurate, but also features multi-element determination at the same time, with little environment pollution. The recovery rate of the method is in the range of 91.0%-110.0%, and relative standard deviations is less than 3.55%. The experimental results showed that both abalone and sea cucumber are of nutritional value of seafood, and are rich in Fe, Ca, Mg, Zn, Sr and other kinds of trace elements helpful to the human body. At the same time, because of severe environment pollution, seawater pollution should not be neglected. When seawater was polluted, hazardous substances were deposited in abalone or sea cucumber body with high levels of harmful heavy metals. Therefore, it should be a reminder that people must be careful to eat them. PMID- 19445241 TI - [Speciation analysis of lead and its isotopes in fine particulate matters in Beijing by ICP-MS]. AB - Fine particulate matters (PMZ2.5) collected in Beijing during a period from September 2005 to May 2006 were studied. Sequential extraction procedures were applied to divide the total lead into three fractions, i.e. water soluble, liposoluble and insoluble lead. Lead concentrations and their isotopes in each fraction were then determined by inductively coupled plasma mass spectrometry (ICP-MS). Lead standard reference GBW 09133 was used to investigate the accuracy of lead concentration determination and SRM 981 was used to correct the mass discrimination and instrumental drift. The obtained results showed that the analytical precision of lead isotope ratios for SRM 981 of seven repeat measurements at lead concentration of 10 ng x mL(-1) came to about 0.34, 0.27 and 0.24 percent for the 206 Pb/204 Pb, 206Pb/207 Pb and 206Pb/208 Pb ratios, respectively. In Beijing, the mass concentrations for PM2.5 and lead of ambient air were 125.556 and 0.5415 microg x m(-3) respectively for winter 2005, and 201.6 and 0.475 microg x m(-3) respectively for spring 2006 on average, resembling those published results. It was indicated that the lead in the PM2.5 existed mainly in insoluble form, which accounted for 78.99%, while water soluble lead and liposoluble lead amount were 20.69% and 0.32%, respectively. The mean values of 206Pb/207Pb ratio for water soluble species and insoluble species were 1.152 6 +/- 0.009 3 and 1.219 3 +/- 0.009 1 respectively, with a significant difference (Student's test; p < 0.01) statically. By comparing 206Pb/207Pb ratios between biological specimen and ambient air samples, the 206Pb/207Pb ratios in water soluble fraction coincided very well with those in adult blood, therefore, water soluble lead but not insoluble lead in PM2.5 may be the potential source of adults blood lead in Beijing. More attention should be paid to the effect of soluble lead in fine particle matters on human health. PMID- 19445242 TI - [Determination of six mineral elements in roots, stems, leaves, flowers and seeds of Scutellaria baicalensis by FAAS]. AB - A study was carried out on the contents of six trace elements, Ca, Cu, Fe, Mn, Zn and K, in roots, stems, leaves, flowers and seeds of planted Scutellaria baicalensis, by flame atomic absorption spectrophotometry (FAAS). The results indicated that Scutellaria baicalensis was rich in trace elements, meaning that it has a relatively high nutritive value. In stems of Scutellaria baicalensis, the content sequence of the six trace elements was found to be Fe > Mn > Zn = Cu > K > Ca. In leaves, the content sequence of the six trace elements was Fe> Mn > Zn > Cu > K > Ca. In flowers and seeds it was Ca > Fe > Mn > Zn > Cu > K, and Ca > Fe > Zn > Mn > Cu >K, separately, and in roots it was Ca > Fe > Cu > Mn > Zn > K. The stems, leaves, flowers and seeds are rich in Fe, whose content is higher than that in pork liver, Mn and Zn, but lower in Ca. The flowers, seeds and roots are especially rich in Ca, whose content is higher than that in bone, indicating that different parts of Scutellaria baicalensis may accumulate different mineral element. This study, for the first time, researched into Ca, Cu, Fe, Mn, Zn and K contents in different parts of Scutellaria baicalensis, which helps explain the multifunction of Scutellaria baicalensis and provides theoretical basis for further developing its medical and edible value. PMID- 19445243 TI - [Flame atomic absorption spectrometry determination of cadmium in environmental water with preconcentration and separation by sodium trititanate whisker]. AB - Sodium tertitanate whisker is a new material for preconcentration. The adsorption properties of sodiium trititanate whisker for Cd(II) were studied and a new method for preconcentration and separation of Cd(II) was proposed. The adsorption rate of Cd(II) by sodium trititanate whisker was 98% at pH 5.0 and Cd(II) could be eluted from sodium trititanate whisker with hydrochloric acid (C: 0.1 mol x L( 1)). The Cd(II) in environmental water was preconcentrated with sodium trititanate whisker and determined by flame atomic absorption spectrometry (FAAS). The detection limit (3sigma, n = 9) was 3.1 ng x L(-1), and the relative standard deviation (RSD) was 2.6%. The response of proposed method is linear in the concentration range of 0.01-1.0 microg x mL(-1) of Cd(II). The method was applied to the determination of analytes in real samples, such as Changjiang River water, Canal water, Yudai River water etc. Good results were obtained (relative standard deviations were 1.5%-4.7%, while recoveries were 98%-102.0%). PMID- 19445244 TI - [Application of uniform design in optimizing the condition of arsenic determination by atomic fluorescence spectrometry]. AB - In the present paper, uniform design U10* (10(8)) was used to optimize the condition of arsenic determination in vegetable samples by hydride generation atomic fluorescence spectrometry. Mathematical model was established and regression analysis was done, and the optimized solutions to those equations were obtained by making use of the UD3.0 software. Combining the life-span of hollow cathode filament, noise of negative voltage and other factors, the optimal condition was obtained as follows: negative voltage was 280-360 V; lamp current was 50-70 mA; carrier gas flow rate was 500-700 mL x min(-1); KBH4 concentration was 15.0-20.0 g x L(-1); HCL concentration was 0.6-1.2 mol x L(-1); sample size was 0.5-1.0 mL. Two samples of vegetable were analyzed under the optimized condition. The results showed that the relative standard deviation was less than 3.6%, and the recovery was within 94.1%-101.3%, with their detection limits of 0.42 microg x L(-1). In this paper, as an effective method of experiment design, uniform design was introduced to hydride generation-atomic fluorescence spectrometry analysis with multifactors, which offered a good idea for the optimization of experiment conditions. PMID- 19445245 TI - [Progress in the detection of selenium-containing trace proteins]. AB - Essential trace element selenium (Se) exerts its biological functions in vivo mainly through selenoproteins. Thus highly sensitive detection of Se-containing trace proteins is the key step toward the confirmation of selenoproteins predicted bioinformatically from genomes or separated electrophoretically in the study of selenoproteomics. This review mainly describes the principle of a new technique of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP MS), which has been fast developed in recent years, and its application to the detection of Se in proteins separated by gel electrophoresis. The paper also summarizes the progress of mass spectrometry in the identification and characterization of Se-containing proteins after gel electrophoresis, including the detection of Se-containing peptides by ICP-MS hyphenated with either capillary high performance liquid chromatography or nano HPLC, the identification of Se-containing proteins by matrix-assisted laser desorption/ionization time-of flight mass spectrometry, and the characterization and confirmation of selenoproteins by nano HPLC-electrospray tandem mass spectrometry. Problems presented in those methods are also discussed in this paper for further study. PMID- 19445246 TI - [Study on P forms in extracellular polymeric substances in enhanced biological phosphorus removal sludge by 31P-NMR spectroscopy]. AB - The present paper investigated phosphorus forms in the extracellular polymeric substances (EPS) using 31P-NMR spectroscopy, and analyzed the influential parameters for this method. The results showed that in the three investigated EPS samples five P forms were identified, including orthophosphate, orthophosphate monoesters, DNA, pyrophosphate and polyphosphate. And in the EPS extracted from A/A/O sludge and A/A/O-MBR sludge polyphosphate was the main phosphorus form. This indicated that P is contained in the EPS not only owing to the adsorption of orthophosphate, but also because EPS acting like the bacteria cells contributes to enhanced biological phosphorus removal. Furthermore the transformation of P forms in the EPS during the EPS extraction was found but limited within 1 h. It was found that with the NaOH solution added the polyphosphate in the EPS would partly convert to pyrophosphate but not go further to orthophosphate, while with pure water added P forms in the EPS were very stable. This means that after neutralization, the transformation of phosphorus forms could be avoided. Since the measurement of 31P-NMR spectroscopy was very sensitive to pH, which could affect the chemical shift of the peaks and cause peaks overlapping, the pH of EPS sample must be raised to 13.0 before the measurement. PMID- 19445247 TI - [Study on the hydrolysis distribution of ferric saline by infrared spectrophotometry and single crystal X-ray diffraction method]. AB - The hydrolytic stability of Fe(a), Fe(b) and Fe(c) in different pH values of poly ferric-flocculants was studied by using Fe-ferron time by time complexation colorimetry. The research results showed that Fe(b) was unstable, and all Fe(b) was transformed to Fe(c) after 10-15 d placement. The content of Fe(c) tended towards stability after 10-15 d. Also, the content of Fe(a) tended towards stability after 10 d. The single crystal was synthesized by the method of direct crystallization in Fe(III)-SO4(2-) water solution at normal temperature and its structure characteristic was studied by single crystal X ray diffraction method and IR (infrared spectrophotometry). The research results showed that there was no group of Fe-OH-Fe, Fe-OH and binary ferric complexed with two hydroxyl groups in the single crystal synthesized from the ferric aqueous solution in low pH (pH was about 0.5). The form of Fe in single crystal was all Fe(III). The chemical formula of the single crystal was Fe(H2O)6 (SO4)2NH4 x 6H2O when the ammonia water was used as the alkalinizing agent. One reason was that with the evaporation of water, these single crystals were synthesized at pH 0. 5 despite of different initial pH and different initial alkalinizing agents. Another reason was that the hydrolysis distribution of ferric saline was unstable. Therefore, it was not easy to obtain the single crystal of Fe(III)-hydroxy complexes or Fe(III) polymer at low pH value. The study showed that infrared spectrophotometry and single crystal X ray diffraction method have a good prospect in the research on hydrolysis distribution of flocculants. PMID- 19445248 TI - [XPS analysis of chromium element in chromate passivation film formed on tinplate in different surface state]. AB - X-ray photoelectron spectroscopy (XPS) was used to investigate the content and chemical valence of chromium element, and the content of compounds in chromate passive film formed on commercial tinplate via a cathodic electrolytical treatment. The effect of the content and chemical valence for different surface state was studied by using ultrasonic process. From the results, it was shown that there existed Cr, O and Sn in the passivation film. The chromium element in the film was mainly in the forms of Cr(OH)3, Cr2O3, and Cr in the natural surface. The Cr(VI) changed to lower value in the process of cathodic electrolytical treatment. A small quantity of Cr(VI) was found in the defective surface besides Cr(OH)3 and Cr2O3. The content of chromium element in the defective surface was lower than that in the natural surface. When ultrasonic process was added, the content of chromium element in the defective surface was obviously lower than that when no ultrasonic process was added. When ultrasonic process was used, the small quantity of Cr(VI) originally adsorbed on the defective surface disappeared because of the strong elution produced by ultrasonic. PMID- 19445249 TI - [Preparation of Mo-Fe catalysts by sol-gel method and its XRD, FTIR spectral analysis]. AB - The effect of catalyst atomic ratio on the performance of selective oxidation of p-xylene as a probe reaction over Mo-Fe catalysts prepared by sol-gel method was investigated. The catalyst evaluation results show that the optimum catalyst atomic ratio is n(Mo) : n(Fe) : n(Co) = 2.4 : 1 : 0.02 with a high catalytic activity. The composition of the catalyst is Fe2 (MoO4)3 and a little MoO3 having a cooperative effects during the oxidation of p-xylene, which was detected by XRD and FTIR. This study could provide experimental data for the technical reform of industry equipment. PMID- 19445250 TI - [The local outliers mining system of celestial body spectrum based on constrained concept lattice]. AB - It is one of the main goals in mankinds universe exploration to find unknown and particular celestial bodies. Data mining is an effective way of finding the spectrum data of unknown and particular celestial body in mass celestial body spectrum data. Constrained concept lattice, with characteristics of higher constructing efficiency, practicability and pertinency, is a new concept lattice structure. For local bias data of celestial body spectrum in characteristic subspace, the local outlier mining system of celestial body spectrum based on constrained concept lattice was designed and implemented by using VC++ 6.0 and Oracle 9i as developing tools. At the same time, its software architecture and function modules were outlined. Such key techniques for preprocessing celestial body spectrum data, the constructing method of constrained concept lattice, and the local outlier mining method were discussed in details. The running results show that the system is feasible and valuable for mining local bias data of celestial body spectrum in low dimensional characteristic subspace. Therefore, the system provides an effective means for finding the unknown and particular celestial bodies. PMID- 19445251 TI - [Design and analysis of automatic measurement instrument for diffraction efficiency of plane reflection grating]. AB - A new-style system that automatically measures the diffraction efficiency of plane reflection grating was designed. The continuous illuminant was adopted for illumination, the duplex grating spectrograph structure was applied, and the linear array NMOS was the receiving component. Wielding relevant principle of the grating spectrograph, theoretical analysis principle was carried out for the testing system. Integrating the aberration theory of geometrical optics, the image quality of this optics system was analyzed. Analysis indicated that the systematic device structure is compact, and electronics system is simplified. The system does not have the problem about wavelength sweep synchronization of the two grating spectrographs, and its wavelength repeatability is very good. So the precision is easy to guarantee. Compared with the former automated scheme, the production cost is reduced, moreover it is easy to operate, and the working efficiency is enhanced. The study showed that this automatic measurement instrument system features a spectral range of 190-1 100 nm and resolution is less than 3 nm, which entirely satisfies the design request. It is an economical and feasible plan. PMID- 19445252 TI - [Numerical simulation of a new nonlinear iteration tomography based on deflection spectra]. AB - A new deflection tomography was suggested and verified with a simulated flow field. The deflection programs for projection and inverse-projection were produced based on optical principle of refraction and mathematical, physical significance of tomography. With the authors' home-made simple self-correlative algebraic reconstruction technique (SSART), the program system for the new deflection tomography was worked out and named Nonlinear Iteration Tomography Based on Deflection Spectra. A section of a complex flow field was simulated with Gauss function. The deflection spectra of a beam of parallel rays, as they passed through the field, were figured out according to the deflection program for projection, and the relative projections were acquired from the spectra. The section was reconstructed with the projections by SSART. The reconstructed result was compared with the model in order to test the deflection programs for validity. The reconstruction effect was scaled with mean-square error (MSE) and peak error (PE). As a result, with SSART, the deflection programs could be used to reconstruct the simulated field accurately. The MSE of reconstruction in this case was about 0.000 09 to 0.000 11 after 503 iterations, and PE was about 0.007 to 0.013. So, the program system, Nonlinear Iteration Tomography Based on Deflection Spectra, can accurately reconstruct complex flow fields based on deflection information. PMID- 19445253 TI - [Design and experimentation of marine optical buoy]. AB - Marine optical buoy is of important value in terms of calibration and validation of ocean color remote sensing, scientific observation, coastal environment monitoring, etc. A marine optical buoy system was designed which consists of a main and a slave buoy. The system can measure the distribution of irradiance and radiance over the sea surface, in the layer near sea surface and in the euphotic zone synchronously, during which some other parameters are also acquired such as spectral absorption and scattering coefficients of the water column, the velocity and direction of the wind, and so on. The buoy was positioned by GPS. The low power integrated PC104 computer was used as the control core to collect data automatically. The data and commands were real-timely transmitted by CDMA/GPRS wireless networks or by the maritime satellite. The coastal marine experimentation demonstrated that the buoy has small pitch and roll rates in high sea state conditions and thus can meet the needs of underwater radiometric measurements, the data collection and remote transmission are reliable, and the auto-operated anti-biofouling devices can ensure that the optical sensors work effectively for a period of several months. PMID- 19445254 TI - [Investigation of effect of solvents on C=O Fermi resonance with solvent variation method]. AB - Fermi resonance is one of the general and important phenomena in vibration spectra. The method of solvent variation is one of the main methods to study Fermi resonance. In the present paper, FTIR spectroscopy was used to study the Fermi resonance of p-benzoquinone in thirteen solvents. The results show that there are some function relationships between the dielectric constant of solvent and the intensity ratio of Fermi resonance. And the empirical formula was obtained by curve fitting. The equation of Kirkwood-Bauer-Magat was applied to the study of Fermi resonance. And the authors obtained the relation between the intensity ratio R and the dielectric constant epsilon. This result is in accordance with the empirical formula. In order to confirm our result, the infrared data of R. A. Nyquist and J. K. Seehra were analyzed. These results are in accord with that of p-benzoquinone. PMID- 19445255 TI - What difference do the new WHO child growth standards make for the prevalence and socioeconomic distribution of undernutrition? AB - BACKGROUND: The World Health Organization has recently established revised child growth standards. OBJECTIVE: To assess how the use of these new standards affects the estimated prevalence and socioeconomic distribution of stunting and underweight among children in a large number of low- and middle-income countries. METHODS: We analyzed Demographic and Health Survey data for stunting and underweight in 41 low- and middle-income countries employing these new standards and compared the results with those produced by analyses of the same data using the old growth references. RESULTS: For all 41 countries, the prevalence of stunting increases with the adoption of the new standards, by 5.4 percentage points on average (95% CI: 5.1, 5.7). The prevalence of underweight decreases in all but two of the countries, by an average of 2.9 percentage points (95% CI: 2.7, 3.2). The impact of using the new standards on socioeconomic inequalities is mixed. For stunting, inequalities tend to rise in absolute terms but tend to decline in relative terms. The impact on underweight is inconsistent across countries. Poor children suffer most from undernutrition, but even among the better-off children in developing countries, undernutrition rates are high enough to deserve attention. CONCLUSIONS: These results suggest that the adoption of the new WHO standards in itself is unlikely to affect policies dramatically. They do confirm, however, that different strategies are likely to be required in these countries to effectively address undernutrition among children at different socioeconomic levels. PMID- 19445256 TI - The potential role of private pharmacies in maternal iron supplementation in rural Tanzania. AB - BACKGROUND: The reduction of maternal anemia is an agreed public health goal but one that has been very difficult to achieve. On Pemba Island, Tanzania, more than 90% of pregnant women are anemic, despite government efforts to identify and treat anemia during antenatal clinic visits. OBJECTIVE: To investigate the potential of private pharmacies to be accessed for iron supplements for maternal anemia. METHODS: We compared and contrasted the care given at private pharmacies and public clinics in terms of six characteristics: accuracy, affordability, availability, geographic accessibility, accommodation, and acceptability. We used data from in-depth interviews, surrogate customer encounters, governmental medicine record reviews, and participant observation. RESULTS: The accuracy of health care workers' advice about the treatment of anemia at private pharmacies and government clinics was similar. Supplements purchased at pharmacies were sometimes cheaper than the free supplements from the government, when the costs of transportation and time spent at the clinic were considered. Supplements at private pharmacies were always available, whereas the supply at government clinics was erratic. Private pharmacies were physically closer, socially less distant, and more accommodating than government clinics. Both clinics and private pharmacies were socially acceptable to pregnant women, although government clinics were typically not attended until later in pregnancy. CONCLUSIONS: The private sector probably has untapped potential for the reduction of maternal anemia in settings in which public health services fall short. Private pharmacies can contribute to the reduction of maternal anemia on Pemba Island and beyond. PMID- 19445257 TI - Education and improved iron intakes for treatment of mild iron-deficiency anemia in adolescent girls in southern Benin. AB - BACKGROUND: To our knowledge, the impact of a nutrition education program combined with an increase in bioavailable dietary iron to treat iron-deficiency anemia has never been studied in adolescent girls. OBJECTIVE: To evaluate the impact of an intensive dietary program for the treatment of iron-deficiency anemia in 34 intervention and 34 control boarding-school girls aged 12 to 17 years from Benin. METHODS: A quasi-experimental design consisting of 4 weeks of nutrition education combined with an increase in the content and bioavailability of dietary iron for 22 weeks was implemented in the intervention school, but not in the control school. Data were obtained from both groups from a nutrition knowledge questionnaire, 24-hour dietary recalls, anthropometric measurements, measurement of iron status indices, and screening for malarial and intestinal parasitic infections. RESULTS: Nutrition knowledge scores and mean intakes of nutrients, including dietary iron, absorbable iron, and vitamin C, were significantly higher in the intervention group (p < .05) than in the control group after 26 weeks. Mean hemoglobin and serum ferritin values were also significantly higher in the intervention group than in the control group (122 vs. 112 g/L [p = .0002] and 32 vs. 19 microg/L [p = .04], respectively), whereas the prevalence of anemia (32% vs. 85% [p = .005] and iron-deficiency anemia (26% vs. 56% [p = .04]) was significantly lower in the intervention group than in the control group. No significant differences between the groups were observed in intestinal parasitic infections or malaria status postintervention. CONCLUSIONS: A multidietary strategy aiming to improve available dietary iron can reduce iron deficiency anemia in adolescent girls. PMID- 19445258 TI - Decreasing stunting, anemia, and vitamin A deficiency in Peru: results of the Good Start in Life Program. AB - BACKGROUND: The rates of stunting, iron-deficiency anemia, and vitamin A deficiency in Peru are among the highest in South America. There is little scaled up experience on how to solve these problems countrywide. OBJECTIVE: To evaluate the Good Start in Life Program during the period from 2000 to 2004. METHODS: Data on weight, height, hemoglobin, serum retinol, urinary iodine, and age were obtained from children under 3 years of age during two transverse surveys in 2000 and 2004. RESULTS: In 2004, the program covered 75,000 children, 35,000 mothers, and 1 million inhabitants from 223 poor communities. The rate of stunting decreased from 54.1% to 36.9%, the rate of iron-deficiency anemia decreased from 76.0% to 52.3%, and the rate of vitamin A deficiency decreased from 30.4% to 5.3% (p < .01). The annual cost per child was US$116.50. CONCLUSIONS: Adaptations of this participative program could contribute to decreased stunting, iron deficiency anemia, and vitamin A deficiency at the national scale in Peru and many other countries. PMID- 19445259 TI - Contribution of natural resources to nutritional status in a protected area of Gabon. AB - BACKGROUND: In protected areas, legislation restricts the population's access to natural food resources, which might have an impact on their welfare. OBJECTIVE: To assess the contribution of the individual use of natural resources to nutritional status in the rural population of the Gamba Complex of Gabon. METHODS: Four villages were selected to represent the rural population. All households were invited to participate, and 95% agreed. In each of the two major seasons, data were collected from all individuals (n = 637) in these 95 households during a 7-day period using a weighed food-consumption survey, observations, interviews, and anthropometric measures. RESULTS: Among children 5 to 9 years of age (n = 82) and adolescents (n = 169), their use of natural resources was the best predictor of nutritional status (explaining 8% of the variance), mainly via its contribution to the achievement of nutrient requirements. The use of natural resources was not a predictor for children 6 to 23 months (n = 28) or 24 to 59 months of age (n = 63), where the best predictors were access to care (26%) and health status (15%), respectively. Household food security predicted nutritional status in women caregivers (n = 96), although negatively. CONCLUSIONS: Natural resources contribute to the nutritional status of children 5 to 9 years of age and adolescents but not of other groups. The intrahousehold allocation of food, particularly of natural food resources, needs to be investigated to better appreciate the contribution of natural resources to the population's well-being. Women seem particularly vulnerable. Other than activities related to conservation, work is needed to understand the role of natural resources for populations living within and around protected areas. PMID- 19445260 TI - Undernutrition in the Kora Mudi tribal population, West Bengal, India: a comparison of body mass index and mid-upper-arm circumference. AB - BACKGROUND: Undernutrition among adult tribal women is a major health problem in India. OBJECTIVES: To compare the utility of two different anthropometric indicators of chronic energy deficiency (CED) among tribal Kora Mudi women and to determine which of these two is a better indicator of undernutrition. METHODS: A cross-sectional study of 123 individuals was conducted. The body mass index (BMI) and mid-upper-arm circumference (MUAC) were used to evaluate CED. RESULTS: The prevalence of CED based on BMI less than 18.5 was 55.3%, and the prevalence of CED based on MUAC less than 22.0 cm was 51.2%. Both of these prevalence rates are classified in the very high-prevalence category (> or = 40%) and indicate a critical situation according to World Health Organization recommendations. Mean BMI increased significantly with higher quartile of MUAC. There was a significant difference in the prevalence of CED between the MUAC quartiles. The risk ratio for CED for women in the lowest quartile of MUAC was 9.33 compared with those in the highest quartile. There was a significant positive association between MUAC and BMI. Regression analysis demonstrated that MUAC had a significant positive impact on BMI; the percentage of the variation in BMI explained by MUAC was 52%. Logistic regression analysis demonstrated that overall, 82.11% of cases of CED were correctly classified with the use of MUAC. The use of MUAC correctly diagnosed 82.35% of cases of CED and 81.82% of women with normal nutritional status. CONCLUSIONS: This population was facing severe nutritional stress. With limited resources and in the absence of skilled manpower, it may be more appropriate to use MUAC for human population surveys, particularly among tribal populations of developing countries. PMID- 19445261 TI - The costs and cost-efficiency of providing food through schools in areas of high food insecurity. AB - BACKGROUND: The provision of food in and through schools has been used to support the education, health, and nutrition of school-aged children. The monitoring of financial inputs into school health and nutrition programs is critical for a number of reasons, including accountability, transparency, and equity. Furthermore, there is a gap in the evidence on the costs, cost-efficiency, and cost-effectiveness of providing food through schools, particularly in areas of high food insecurity. OBJECTIVE: To estimate the programmatic costs and cost efficiency associated with providing food through schools in food-insecure, developing-country contexts, by analyzing global project data from the World Food Programme (WFP). METHODS: Project data, including expenditures and number of schoolchildren covered, were collected through project reports and validated through WFP Country Office records. Yearly project costs per schoolchild were standardized over a set number of feeding days and the amount of energy provided by the average ration. Output metrics, such as tonnage, calories, and micronutrient content, were used to assess the cost-efficiency of the different delivery mechanisms. RESULTS: The average yearly expenditure per child, standardized over a 200-day on-site feeding period and an average ration, excluding school-level costs, was US$21.59. The costs varied substantially according to choice of food modality, with fortified biscuits providing the least costly option of about US$11 per year and take-home rations providing the most expensive option at approximately US$52 per year. Comparisons across the different food modalities suggested that fortified biscuits provide the most cost efficient option in terms of micronutrient delivery (particularly vitamin A and iodine), whereas on-site meals appear to be more efficient in terms of calories delivered. Transportation and logistics costs were the main drivers for the high costs. CONCLUSIONS: The choice of program objectives will to a large degree dictate the food modality (biscuits, cooked meals, or take-home rations) and associated implementation costs. Fortified biscuits can provide substantial nutritional inputs at a fraction of the cost of school meals, making them an appealing option for service delivery in food-insecure contexts. Both costs and effects should be considered carefully when designing the appropriate school based intervention. The costs estimates in this analysis do not include all school-level costs and are therefore lower-bound estimates of full implementation costs. PMID- 19445262 TI - Prevalence of undernutrition among children in the Garhwal Himalayas. AB - BACKGROUND: Nutritional status is the best indicator of the global well-being of children. In India every third child is underweight, whereas in the Garhwal Himalayas only one-fifth of the children are nutritionally normal. Information regarding the causes of such low nutritional status in children of Garhwal is lacking. OBJECTIVE: The present study was designed to identify factors that may influence the nutritional status of the children of the Garhwal Himalayas. Stunting, signifying long-term irreversible chronic undernutrition, was studied, along with wasting, which signifies acute undernutrition among children. METHODS: Forty families from one town and one village in each of the three major agroclimatic situations (high, middle, and low hills) were selected at random (total 240 families). The nutritional status of 353 children (0 to 12 years of age) was assessed by nutritional anthropometry and compared with tables of weight for-age and height-for-age z-scores (WAZ and HAZ) identifying wasting and stunting, respectively, and compared with the World Health Organization (WHO) Growth Reference charts 2007. Chi-square test was applied to analyze the effects of age, sex, altitude, and area on the nutritional status of children. RESULTS: Of the 353 children studied, 38.2% belonged to the school-aged group, with 7% more girls than boys. Only 11.3% of the children had normal HAZ while 10.3% had normal WAZ. The largest percentages of children (31.8% HAZ and 29.1% WAZ) were clustered in the SD1 group, that is the severely stunted or wasted group. In every age group except the 9- to 12-year group, most of the children were found in the WAZ SD1 category. Gender appeared to influence the SD1 category significantly. There were 17.0% severely stunted girls (SD1), as compared to 14.8% boys; while the percentages of WAZ girls was 16.1% and boys was 13%. The situation in the urban areas was slightly better: 6.4% of the sample had normal HAZ and 7.1% had normal WAZ, compared with 4.4% and 4.6% of the rural children. In all three agroclimatic situations, the largest percentage of children fell in the HAZ SD1 (stunted) category (15.3% in the high hills, 7.3% in the middle hills, and 9.5% in the low hills). There is a significant effect of area (rural vs. urban) on stunting and wasting among children. The child's sex affects stunting only. The other two variables, altitude and age, do not show a significant relationship with stunting or wasting. CONCLUSIONS: The rate of malnutrition among children in the Garhwal is very high. The majority are severely stunted and wasted, indicating a high prevalence of both chronic and acute malnutrition. Only the area of residence (rural or urban) had an influence on a child's nutritional status. PMID- 19445263 TI - Antioxidant system for the preservation of vitamin A in Ultra Rice. AB - BACKGROUND: Ultra Rice grains are micronutrient-fortified, extruded rice grains designed to address specific nutritional deficiencies in populations where rice is a staple food. Vitamin A and some of the B vitamins, as well as iron and zinc, are target nutrients for fortification through Ultra Rice technology. Vitamin A is sensitive to degradation. Therefore, the original Ultra Rice formulations included stabilizers, some of which were not approved as food additives in all of the receiving markets. OBJECTIVE: To develop a new antioxidant system for improving vitamin A storage stability in Ultra Rice grains, while complying with international food regulations. METHODS: Ten formulations were prepared containing various combinations of hydrophilic and hydrophobic antioxidants, as well as moisture stabilizers. Accelerated vitamin A storage stability tests were conducted at 25 degrees, 35 degrees, and 45 degrees C with 70% to 100% relative humidity. RESULTS: The most stable samples contained one or more phenolic antioxidants, a water-soluble antioxidant, and stabilizing agents. The best results were obtained by using butylated hydroxyanisole (BHA) in combination with butylated hydroxytoluene (BHT) as the hydrophobic antioxidants and ascorbic acid as the hydrophilic antioxidant. Citric acid and sodium tripolyphosphate (STPP) were used to chelate metal ions and to stabilize moisture, respectively. The best formulations retained more than 85% and approximately 70% of the added vitamin A at 25 degrees and 45 degrees C, respectively, after 24 weeks storage. CONCLUSIONS: The best antioxidant system, composed of generally accepted food additives, improved vitamin A stability while reducing the price, thus greatly improving the commercial viability of Ultra Rice grains for use as a ricefortificant. PMID- 19445264 TI - A comparative evaluation of the macronutrient and micronutrient profiles of soybean-fortified gari and tapioca. AB - BACKGROUND: Gari and tapioca are storage-cupboard convenience foods obtained from the tubers of cassava (Manihot esculenta Crantz). They are important staples in Nigeria and many African countries where malnutrition is a major problem. Tapioca is a quick-cooking food made from partly gelatinized starch and gari is a fermented, roasted, granular food made from cassava pulp. OBJECTIVE: Gari and tapioca are nutritionally inferior and need to be fortified. This paper reports the macro- and micronutrient profiles of soybean-fortified gari and tapioca. METHODS: Gari and tapioca were fortified with soybean flour or soybean residue at 25% of dry weight. Standard methods were used for the determination of proximate parameters such as crude protein, fat, ash, carbohydrate and moisture content. All the samples were analyzed for phosphorus, calcium, magnesium, potassium, sodium, manganese, iron, copper and zinc. RESULTS: Unfortified tapioca had significantly lower (p < .05) proximate values (protein: 0.31%; fat: 0.17%; ash: 0.34%) than unfortified gari (protein: 1.50%; fat: 1.56%; ash: 1.35%). The fortification of both gari and tapioca significantly (p < .05) increased the contents of crude protein, phosphorus, fat, and ash as well as all the monitored macro- and micronutrients. These values (%) increased from 1.50-9.31, 0.06-0.11, 1.56-4.31 and 1.35-1.64 for gari-soybean fortified gari; and 0.31-12.56, 0.03 0.12, 0.17-5.45 and 0.34-1.41 for tapioca to soybean fortified tapioca respectively. Soybean flour increased the nutrient content of the fortified gari and tapioca compared to soybean residue. Data from this study suggest that both soybean flour-fortified tapioca and soybean flour-fortified gari are effective means of meeting the daily requirements of minerals, protein, and energy. CONCLUSIONS: Both soybean flour-fortified tapioca and soybean flour-fortified gari could be used to fight macronutrient and micronutrient deficiencies, not only in Nigeria and other African countries where these two cassava products are staples, but also in other cassava-consuming developing nations. PMID- 19445265 TI - Euthanasia policy and practice in Belgium: critical observations and suggestions for improvement. AB - The essay opens with some background information about the context of euthanasia in Belgium. It proceeds by discussing the Belgian law on euthanasia and concerns about the law, its interpretations and implementation. Finally, the major developments and controversies since the law came into effect are discussed. Suggestions as to how to improve the Belgian law and circumscribe the practice of euthanasia are made, urging Belgian legislators and the medical establishment to reflect and study so as to prevent potential abuse of vulnerable patients. PMID- 19445266 TI - Other people's lives: reflections on medicine, ethics, and euthanasia. PMID- 19445267 TI - [Parkinson treatment--where to begin?]. PMID- 19445268 TI - [Measles]. AB - Measles are a systemic infectious disease caused by a single stranded ribonucleic acid virus (measles virus) from the paramyxovirus family. Typically, the disease is characterized by a two-phase course. After an average incubation period of 8 to 11 days, initial symptoms such as fever, cough, coryza and conjunctivitis appear. Two thirds of the patients shows a white-marked enanthema on the buccal mucosa (Koplik's spots). After disappearance of these symptoms, a second increase of temperature and the typical measles exanthema, a brownish-red maculopapular rash, appear. Infection with measles virus induces transient immunodeficiency that favours the formation of several complications. Some of them, e. g. encephalitic diseases, are severe and associated with a high mortality. Measles are world-wide distributed and belong to the ten most frequent infectious diseases in some less developed countries. The disease is associated with a high mortality in some African and South-East Asian countries, in particular in children aged less than 12 months. Of particular note, measles are the most important cause of blindness in children in population with borderline vitamin A status. In Germany, the number of reported measles cases has been declined dramatically since the introduction of a vaccine more than four decades ago. However, regional outbreaks or small epidemics still occur. Because there is no specific antiviral treatment, therapy of measles is symptomatic and depends on the manifestation of the disease. The most important prevention strategy is immunization with a life-attenuated vaccine that can be applied as monovaccination or in combination with mumps and rubella virus (MMR vaccination) or mumps, rubella and varicella virus (MMRV vaccination). PMID- 19445269 TI - [Molecular, cellular and physiological responses to resistance training]. AB - Resistance training induces differenciated adaptions. Depending on the applied method, neural or anabolic adaptions may dominate. Neural adaptions already reveal in the early stage of a training program, since force improvements can be seen even without muscle hypertrophy. During this phase, upcoming adaptions on myofibrilliar protein level are initiated on mRNA level. These adaptations may be described mainly as an increase of myofibrillar proteins and fibre type transformation, respectively. The article describes adaptations against specific methods of resistance training like maximum power, speed strength and strength endurance and shortly discusses the therapeutic use of resistance training. PMID- 19445270 TI - [Combination treatment in osteoporosis. Basic treatment plus specific osteoporosis medication]. PMID- 19445271 TI - [Fixed drug combinations--the pros and the cons]. AB - In a number of applications, more than one drug has to be prescribed to achieve the desired therapeutic goal. Most often, it is the treatment of chronic diseases (like hypertension, type 2 diabetes mellitus, allergic asthma, but also chronic infectious diseases like tuberculosis or AIDS) which requires the combination of drugs with different mechanisms of action. Multimorbidity, often present in old age, increases the number of drug intakes per day while the ability to do so correctly declines. It appears thus plausible that a fixed combination of drugs, by decreasing the number of drug intakes per day, may lead to an improved compliance and eventually to an improvement of clinical endpoints. However, there is scarce evidence that this assumption is generally valid. For each of the above diseases the use of fixed combinations has to be evaluated separately with respect to an improvement in clinical endpoints as well as to an increased risk of adverse effects. Finally, the pharmacoeconomic aspect as to how the cost of fixed combinations compares to that of free combinations has to be taken into account. PMID- 19445272 TI - [Interactions between the 3-Month Syringe and antibiotics]. PMID- 19445273 TI - [The thyroid papillary microcarcinoma, a frequent scenario with a not well known biological behaviour]. AB - The advent of high resolution ultrasonography resulted in the increased detection of small thyroid nodules and, consequently, in the diagnosis of thyroid microcarcinoma (mPTC). This agrees with the reduced mortality rate from thyroid cancer recently recorded in several European countries. Contrary to the hypothesis that thyroid cancer progression should be due to the progressive accumulation with time of molecular alterations, in different reports mPTC age was significantly higher than other thyroid cancers. Recently, a report suggested that "papillary microtumor" sounds the more appropriate for a low aggressive lesion. This term could reduce the large use of overtreatment, unchanging the patient's expected life. PMID- 19445274 TI - [Computerized medical records in monitoring hypertension. Longitudinal and horizontal evaluation of 25 general practitioners in a primary care setting of Modena, Italy]. AB - This study aims at evaluating the effectiveness of a computerized-based Clinical Record in monitoring hypertension in a Primary Care Setting. Blood pressure (BP) recording increased by 62% to 70% in the years 2004 to 2006. No improvement, however, was noticeable in the achievement of gold-standard targets in BP control (62% in all period). At the end of 2006 BP was recorded in 65% of patients. Among them, 2/3 of the non diabetics reached < 140/90 mmHg standard, while only 23% of diabetics reached < 130/80 mmHg standard. In conclusion, using a computerized clinical record appears not to be sufficient to obtain good clinical performances, yet it is a necessary first step to clinical audit. PMID- 19445275 TI - [Polypharmacy and psychotropic drugs as risk factors for falls in long-term care setting for elderly patients in Lombardy]. AB - Aim of the study was to investigate polypharmacy and psychotropic drugs as risk factors for falls in a Long-term Care Setting for elderly patients. In a cross sectional study we investigated the characteristics of 414 subjects: 207 fallen patients 44 (21.3%) male e 163 (78.7%) female mean age 84.16 +/- 8.3 y.o. First generation neuroleptics (OR 1.739 CI 95% 1.047-2.889), benzodiazepines (OR 2.357 CI 95% 1.5-3.702) and mood stabilizers (OR 1.889 CI 95% 1.091-3.270) were associated to falls when adjusted for age, sex and comorbidities. Polypharmacotherapy (> or = 4 drugs) was a risk factor for falls when associated to a risk medication in the daily regimen only (OR 2.157 CI 95% 1.447-3.217). What raised has to be taken into account in the prescriptive activities in a Long term Care Setting for elderly patients. PMID- 19445276 TI - [Adverse drug reactions: a common cause of hospitalization of the elderly]. AB - Aging is associated with various physiological changes and multiple diseases which alter the pharmacological response to a drug in elderly patient. Moreover, elderly people are more sensitive to frequently used drugs like NSAIDs, benzodiazepines, opioids, etc. There is an urgent need to develop better preventive strategies to reduce the burden of adverse drug reactions. PMID- 19445277 TI - [The whole world in a cup of coffee. Case reports]. AB - There is a rising interest for clinical cases in medicine. Actually, they don't necessarily conflict with the evidence-based medicine approach; rather, as several authors made clear, EBM-oriented case reports and clinical trials could be complementary. Cases and case series could even represent the first line of evidence and they are extremely valuable in discovering new pathologies and monitoring unexpected drug effects. They also play a relevant role in continuing medical education. The new section of Recenti Progressi in Medicina is edited by a prominent Italian research Institute (Istituto di Fisiologia Clinica, CNR). It focuses on a single case, guiding the physicians' decision-making from differential diagnosis to the treatment options. PMID- 19445278 TI - [The mysterious case of an intracardiac mass]. AB - The authors describe the case of a 73-year old patient, with multiple cardiovascular risk factors and severe renal insufficiency, presenting with an intracardiac mass, as shown at echocardiography. Differential diagnosis and use of different imaging tests are discussed. PMID- 19445279 TI - [Neutropenia induced by ticlopidine: a delayed onset case]. AB - Authors describe a case of neutropenia induced by ticlopidine. Attention must be taken for this case because the adverse effects of the drug usually occur within the first three months since the start of the therapy; instead, in our case the neutropenia occurred about 18 months. PMID- 19445280 TI - [Pierre Robin syndrome treated by physiotherapy electromyography assisted]. AB - Pierre Robin syndrome is characterized by the triad: micrognathia, cleft palate and glossoptosis. This syndrome, which often undermines several organs and systems, is treated with a multidisciplinary approach that involves several specialists. The AA. present a case of Pierre Robin syndrome in neuromuscular rehabilitation by physiotherapy EMG-assisted. PMID- 19445281 TI - [Immunomodulatory properties of statins and cancer risk]. AB - Statins are cholesterol-lowering drugs widely prescribed for cardiovascular prevention. They are also immunomodulatory and increase peripheral regulatory T cell numbers and function, in vivo. This may be beneficial by decreasing inflammatory response within the atheroma and stabilizing atherosclerotic plaque, however this novel pleiotropic effect might impair host tumor-specific effector T cell responses. Indeed, in some randomized trials, notwithstanding their short duration, statins have been found to increase cancer incidence especially in the elderly and women. In these situations, the decrease in cardiovascular mortality can be matched by an equal increase in cancer mortality, leaving all-cause mortality unchanged. Furthermore, statins have been shown to interfere with cancer immunotherapy. Preventive pharmacological treatment can sometimes be justified because of reduced cardiovascular events even if total mortality does not change, but if it leads to an increase in cancer incidence, it might be not easily accepted. Physicians need to weigh the global risks and benefits when prescribing statins. PMID- 19445283 TI - Advancements in cardiopulmonary resuscitation: increasing circulation and improving survival. AB - Clinicians, as well as lay people, have realized the importance of resuscitative maneuvers throughout recorded history. Cardiopulmonary resuscitation has evolved from a relatively primitive technique to one now dictated by data from evidence based medicine. Recent advancements include changes in life support guidelines, the development of an impedance threshold device, and the initiation of therapeutic hypothermia. We can only expect continued advancements in cardiopulmonary resuscitation through new technology with resultant improved outcomes. PMID- 19445282 TI - [Probiotics. A review]. AB - Probiotics are defined viable microorganisms which in sufficient amount reach the intestine in an active state, to be able to exert positive health benefit on the host. Thus far, they have shown particular promise on prevention or treatment of various pathologic conditions. Our aim has been to report the most recent articles (until October 2008), resulting from randomized, double controlled trials, according to the conventional and molecular methods. In this review we have taken into consideration almost all the fields in which the probiotics have been given, either with a prophylactic or therapeutic intent. So far we have summarized the actual results concerning lactose intolerance, acute rotavirus diarrhea, traveller's diarrhea, antibiotic associated diarrhea, Clostridium difficile infection, and the role as adjuvant in Helicobacter pylori eradication. Furthermore, we have synthesised articles concerning the probiotic connection in irritable bowel syndrome, and in inflammatory bowel diseases. Last but not least, the prevention by probiotics of allergic diseases, of bacterial vaginosis, of respiratory infections, and the possible advantage in hypercholesteremic subjects. PMID- 19445284 TI - Symptomatic splenomegaly in polycythemia vera: a review of the indications for splenectomy and perioperative considerations. AB - Polycythemia vera is a condition that surgeons do not commonly encounter. Advances in medical management have largely led to avoidance of surgical intervention in most patients. Indications and timing of splenectomy have been the subject of debate since the disease was first described in the late 19th century. Though anemia and thrombocytopenia associated with polycythemia vera only transiently respond to splenectomy, painful splenomegaly with infarction or compression of surrounding viscera are presently accepted indications for surgery. Special consideration must be given to polycythemia vera patients both preoperatively and postoperatively due to altered coagulation and anatomy. We present a review of the pathophysiology, medical treatment, indications for surgical intervention, and perioperative considerations for polycythemia vera. PMID- 19445285 TI - Does shave biopsy accurately predict the final breslow depth of primary cutaneous melanoma? AB - Shave biopsy (SB) is used for the diagnosis of suspicious skin lesions, including melanoma. Its accuracy for melanoma has not been confirmed. We examined our experience with SB to determine its ability to predict true Breslow depth (BD). We performed a retrospective review of the tumor registry for all patients diagnosed with melanoma by SB from 1995 to 2004. Site and depth of lesion, tumor stage, correlation of BD between SB and wide local excision (WLE), and changes in surgical management due to discordance were examined. Melanoma-in-situ was defined as a depth of 0 for this analysis. One hundred thirty-nine patients were diagnosed with melanoma by SB. Pathology after WLE were as follows: 54 (39%) patients had no residual disease, 67 (48%) had a BD equal to or less than the SB, and 18 (13%) had a thicker BD compared with the SB. For these 18 patients, the median BD by SB and WLE was 1.1 mm (range 0-6.5) and 3.5 mm (range 0.5-20.5), respectively (P = 0.0017). Upstaging of final BD from SB to WLE was significantly associated with increasing tumor depth and higher stage of melanoma (P < 0.0001). Only seven of the 139 patients (5%) required further surgery because of the increased depth of the WLE. SB underestimated the final BD of melanoma in 13 per cent of patients, but changed the management of few patients. SB is a valuable tool for practitioners in the diagnosis of melanoma. Nevertheless, patients diagnosed with melanoma by SB should be counseled about the rare need for additional surgery. PMID- 19445286 TI - Pneumomediastinum in the injured patient: inconsequential or predictive? AB - Free air in the peritoneum is a portent of significant pathology in the patient with abdominal trauma. The finding of a pneumomediastinum (PM) on a thoracic computed tomography scan (CT) of a trauma patient is, however, not clinically well-defined. The objectives of this study were to evaluate the incidence, pattern, and outcome of CT-diagnosed PM in a cohort of injured patients. The trauma registry and radiology reports were reviewed retrospectively for all injured patients admitted over an 8-year period to determine the incidence of PM. Medical and radiological records of patients with a PM on thoracic CT were then reviewed to determine the pattern and outcome of the injuries. There were 1364 thoracic CTs performed in the study-period. The prevalence of PM was 5.2 per cent (71/1364). For the cohort of patients with a PM, the mean age was 34.8 years, and 14.7 per cent (10/68) had penetrating injuries. Of these 68 patients, 10.3 per cent (7/68) presented with nine clinically significant injuries to the esophagus, trachea, larynx, or bronchus. These injuries were suspected clinically by an associated open wound or significant symptoms, and only 5.8 per cent of (4/68) patients required surgical repair. The remaining 89.7 per cent (61/68) of patients with a PM did not develop any sequelae nor require further directed treatment. A finding of a pneumomediastinum on a thoracic CT in injured patients is rare and clinically nonspecific. Pneumomediastinum alone does not seem to be predictive of severe injury and warrants detailed investigation only when clinical symptoms are present. PMID- 19445287 TI - Impact of hollow viscus injuries on outcome of abdominal gunshot wounds. AB - Abdominal gunshot wounds (GSW) are a source of morbidity and mortality. Limited data are available on the effect of hollow viscus injuries (HVI) secondary to gunshot wounds. GSW sustained in the Louisville area from 2004 to 2007 were reviewed. Attention was given to the impact of HVI from abdominal GSW. Statistical significance was determined. One-hundred ten patients sustained GSW with peritoneal violation. Eighty-six had HVI. Eighteen died after laparotomy with 15 having an HVI. Patients undergoing damage control (DC) have a significant increase in mortality compared with those not requiring DC. Exsanguination was the major cause of mortality (67%). Mortality directly related to HVI was found in 11 per cent. Twenty patients underwent DC with 11 deaths. Isolated HVI did not show a significantly increased mortality compared with other injury patterns involving solid organ or major vascular structures. Various methods of repair showed no significant survival advantage. Recognition and repair of HVI in abdominal GSW is crucial to patient salvage. Definitive repair of HVI at the initial operation should be considered. Primary repair of HVI is preferred although no survival disadvantage is seen in other forms of repair in marginally stable patients. Definitive repair at the initial operation decreases complications. PMID- 19445288 TI - Surgical treatment for right colon cancer directly invading the duodenum. AB - Right colon carcinoma with duodenal invasion is rare, and optimal management remains controversial. Twenty patients demonstrating right-colon carcinoma directly invading the duodenum presented at the Second Xiangya Hospital between 1990 and 2006. Different surgical management strategies were selected based on duodenal involvement, and patient outcomes were evaluated. There was no perioperative death in this series, but three major complications presented during the perioperative period: one case of duodenal stenosis and two duodenal leaks due to gastric or duodenal drainage. Eight of 13 patients treated by en bloc resection survived more than 3 years, including one 10-year survivor and four 5-year survivors. Of the seven patients treated with palliative resection, no patients survived more than 18 months. In conclusion, duodenal invasion by a right-sided colon carcinoma does not necessarily represent incurable disease. If carefully applied based on the extent of duodenal invasion, active surgical management is very useful for improving patient prognosis without increasing the risks associated with surgery. PMID- 19445289 TI - Long-term morbidity, pain, and disability after repair of severe chest wall injuries. AB - Long-term morbidity after severe chest wall injuries is common. We report our experience with acute chest wall injury repair, focusing on long-term outcomes and comparing our patients' health status with the general population. We performed a retrospective medical record review supplemented with a postal survey of long-term outcomes including the McGill Pain Questionnaire (MPQ) and RAND-36 Health Survey. RAND-36 outcomes were compared with reference values from the Medical Outcomes Study and from the general population. Forty-six patients underwent acute chest wall repair between September 1996 and September 2005. Indications included flail chest with failure to wean from the ventilator (18 patients), acute, intractable pain associated with severely displaced rib fractures (15 patients), acute chest wall defect/deformity (5 patients), acute pulmonary herniation (3 patients), and thoracotomy for other traumatic indications (5 patients). Three patients had a concomitant sternal fracture repair. Fifteen patients with a current mean age of 60.6 years (range 30-91) responded to our surveys a mean of 48.5 +/- 22.3 months (range 19-96) postinjury. Mean long-term MPQ Pain Rating Index was 6.7 +/- 2.1. RAND-36 indices indicated equivalent or better health status compared with references with the exception of role limitations due to physical problems when compared with the general population. The operative repair of severe chest wall injuries is associated with low long-term morbidity and pain, as well as health status nearly equivalent to the general population. Both the MPQ and the RAND-36 surveys were useful tools for determining chest wall pain and disability outcomes. PMID- 19445290 TI - Industry support of graduate medical education in surgery. AB - The role of pharmaceutical and medical device companies ("industry") in graduate medical education (GME) is under debate. We surveyed program directors in general surgery and surgical specialties to determine industry activities in surgical GME. We used an internet-based questionnaire regarding industry marketing and educational activities in surgical programs, and their effects on surgical education. We received 65 responses to 377 requests (17%). Nearly two-thirds reported industry-sponsored meals. Industry-supported travel was infrequent ("never" and "seldom" in 56% of device workshops, 69% of lectures, and 74% of conferences). More than one-half reported support for academic events: paid lecturers and exhibition fees (both 58%), and unrestricted grants (62%). More than one-half (54%) reported industry-sponsored research. One-fourth believed their programs to be dependent on industry for their educational missions. Most disagreed that industry support posed a problem, either in general (55%) or for their program (71%). One-fourth of respondents (25%) advocated profession-wide restrictions of industry involvement with GME. Equal numbers agreed (39%) and disagreed (35%) with the view that pharmaceutical and medical device industries have motivations that are in conflict with those of doctors and their patients. Industry activities are widespread in surgical residencies, with approval of many program directors. PMID- 19445291 TI - Epidemiology of sternal fractures. AB - The epidemiology of sternal fractures has been poorly described. The objective of this study was to examine the demographics, outcomes and injuries associated with sternal fractures. The trauma registry at a level I trauma center was retrospectively reviewed to identify all patients with sternal fractures over a 10 year period. Demographic data collected included age, gender, mechanism of injury and injury severity score. Patients were analyzed according to age < or = 55 or > 55 years. During the 10-year study period, a total of 37,087 patients were admitted to the emergency department. Of these, 125 (0.33%) had a sternal fracture. The average age was 44 +/- 17 years, with 76.0 per cent being male. The most common mechanism of injury was motor vehicle collision (68%) followed by auto vs. pedestrian (18%). Associated rib fractures occurred in 49.6% of the population, cardiac contusions in 8.0%, thoracic aortic injuries in 4.0 per cent and heart lacerations in 2.4 per cent of patients. Associated rib fractures were more likely to occur in patients over the age of 55 (66.7% vs 44.2%, P = 0.032) as well as a traumatic hemothorax (15.8% vs 40.0%, P = 0.005). However, no significant difference in mortality was observed between the two age groups (16.8% vs. 26.7%, OR: 0.56, 95% CI, 0.21 to 1.47; P = 0.234). Sternal fractures are a rare sequela of blunt trauma. Associated injuries are common, including rib fractures and soft tissue contusions. Associated cardiac and aortic injuries are rare but highly lethal and should be screened for on the initial chest CT scan. After appropriate exclusion of associated injuries, the majority of patients diagnosed with a sternal fracture following blunt trauma can be safely discharged to home. PMID- 19445292 TI - Fever and leukocytosis in critically ill trauma patients: it is not the blood. AB - The diagnosis of bacteremia in critically ill patients is classically based on fever and/or leukocytosis. The objectives of this study were to determine 1) if our intensive care unit obtains blood cultures based on fever and/or leukocytosis over the initial 14 days of hospitalization after trauma; and 2) the efficacy of this diagnostic workup. An 18-month retrospective cohort analysis was performed on consecutively admitted trauma patients. Data collected included demographics, injuries, and the first 14 days maximal daily temperature, leukocyte count, and results of blood and catheter tip cultures. Fever was defined as a maximum daily temperature of 38.5 degrees C or greater and leukocytosis as a leukocyte count 12,000/mm3 or greater of blood. Five hundred ten patients were evaluated for a total of 3,839 patient-days. The mean age and injury severity score were 49 +/- 1 years and 19 +/- 1, respectively. Four hundred twenty-five blood culture episodes were obtained and 25 (6%) bacteremias were identified in 23 patients (5%). A significant association was found between obtaining blood cultures in patients with fever (relative risk [RR], 7.7), leukocytosis (RR, 1.3), and fever + leukocytosis (RR, 3.2). However, no significant association was found between these clinical signs and the diagnosis of bacteremia. In fact, fever alone was inversely associated with bacteremia. Our intensive care unit follows the common "fever workup" practice and obtains blood cultures based on the presence of fever and leukocytosis. However, fever and leukocytosis were not associated with bacteremia, suggesting inefficiency and that other factors are more important after trauma. PMID- 19445293 TI - Pregnancy during otolaryngology residency: experience and recommendations. AB - Pregnancy during graduate medical training became a pertinent issue in the United States during the 10-year interval between 1992 and 2002 as the number of female residents trended steadily upward to over 25 per cent. Surgical training programs characteristically present unique challenges and stressors for all trainees, and pregnancy introduces additional physical, professional, and emotional demands for the pregnant woman and her coworkers. A qualitative study was performed using in person interviews of female otolaryngology residents who had given birth within the previous 12 months. Items addressed included the pregnancy course and its complications, specific stressors during and after pregnancy, and solutions implemented by the resident and her program director. Reactions and level of support from coworkers were also discussed. Five pregnancies were reported among three residents interviewed. One resident experienced preterm delivery, which necessitated a week-long stay in the neonatal intensive care unit for her infant. Another had chorioamnionitis during delivery of two infants. One child had low birth weight. The third resident had a miscarriage during the first trimester of her first pregnancy and sustained a minor head injury after fainting in the operating room during her second pregnancy. Overall, long hours, unpredictable work demands, and guilt over colleagues' increased workloads and altered schedules were noted as significant sources of stress among these residents; the women also described high expectations of themselves, along with misgivings over their ability to balance pregnancy and parenthood with career demands. The most significant postpartum stress indicator was the matter of child care, especially as it related to finding adequate coverage for on-call periods ranging from 3 to 14 days per month. Maintaining breastfeeding was an additional concern in the postpartum period. Pregnancy during surgical residency is a significant source of conflict for the pregnant resident and her colleagues. Our study illustrates how program directors can pre-emptively address challenges this event presents. When policies on maternity leave, call issues during pregnancy, and flexible rotation schedules are in place before pregnancy occurs, the process may be smoother and more rewarding for all involved. PMID- 19445294 TI - The impact of intoxication on the number of organs available for transplantation after brain death. AB - A significant number of head-injured trauma patients are likely to present with a positive toxicology. The purpose of this study is to investigate whether intoxication with substances such as cocaine, amphetamine, alcohol, and opiates on admission has any influence on the number of organs that are recovered after brain death in these patients. We conducted a retrospective review of all organ donor patients admitted to a Level I trauma center over a 4-year period (2002 to 2005). Patients with positive toxicology screens on admission were compared to counterparts with negative screens with regard to the number of organs harvested. There were 90 organ donor patients during the 4-year period. There were 63 (70%) patients to negative toxicology screens. The remaining 27 (30%) were found to be intoxicated with a variety of substances, including alcohol (18%), cocaine (4%), amphetamines (9%), benzodiazepines (4%), opiates (4%), and polysubstances (10%). A comparison of total organs and individual organs donated by both intoxicated and nonintoxicated patients showed no overall statistical difference in the number or type of organs donated between the two groups. Thus, the prospect of organ procurement should not be overlooked in intoxicated patients. PMID- 19445295 TI - Infrahepatic vena cavocavostomy, a modification of the piggyback technique for liver transplantation. AB - We describe our experience with a modification of the piggyback (PB) technique for orthotopic liver transplantation in which the donor infrahepatic vena cava is used as the venous outflow tract. From May 1997 to January 2006, a total of 109 cases using this technique were performed in 101 patients. Collected data included recipient demographics and diagnosis, warm ischemia time, use of venovenous bypass or temporary portacaval shunt and complications related to the venous outflow and graft, and patient survival. Data were compared with the patients undergoing standard PB technique during the same period. The reasons for using the technique were grouped according to whether there was a problem with the recipient hepatic veins or a concern about the length or diameter of the donor suprahepatic vena cava. These included the presence of a transjugular intrahepatic portosystemic shunt (eight cases), retransplantation (22 cases), thin-walled, friable hepatic veins (32 cases), Budd-Chiari syndrome (two cases), domino liver procurement (six cases), reduced or split liver grafts (five cases), and graft inferior vena cava to recipient hepatic veins size discrepancy (34 cases). There was no graft loss. The warm ischemia time was 39.65 minutes compared with 37 minutes in the standard PB group. The long-term graft and patient survival rates were similar in the two groups. Infrahepatic vena cavocavostomy is a useful variation of the standard PB technique. PMID- 19445296 TI - Retrievable inferior vena cava filters are rarely removed. AB - There has been an increasing nationwide trend of inferior vena cava (IVC) filter placement over the past 3 years. Most of these have been the newer, removable variety. Although these are marketed as retrievable, few are removed. The purpose of this study was to examine the practice pattern of IVC filter placement at Huntington Hospital. This study is a retrospective chart review of all IVC filter placements and removals between January 1, 2004, and December 31, 2006. The primary data points include indication for placement, major complications (migration, caval thrombosis, pulmonary embolus [PE]), attempted removal, and successful removal. Three hundred ten patients received IVC filters at our institution during this period. Eighty-four were placed in 2004, 95 in 2005, and 131 in 2006. Of those, only 12 (3.9%) were documented permanent filters, whereas the remainder (298) were removable. Of the retrievable filters placed, only 11 (3.7%) underwent successful removal. There were four (1.3%) instances in which the filter could not be removed as a result of thrombus present within the filter and two (0.67%) in which removal was aborted as a result of technical difficulty. Our use of IVC filters has increased steadily over the last 3 years. Despite the rise in use of "removable" filter devices, few are ever retrieved. Although IVC filter insertion appears an effective method of PE prevention, it comes at a cost, both physiological and monetary. It would be wise to devise more stringent criteria to identify those patients in the various populations who truly require filter placement and to be cautious in altering our indications for placement. PMID- 19445297 TI - Systemic mastocytosis as a rare cause of diffuse gastrointestinal hemorrhage. PMID- 19445298 TI - Isolated metastasis to the gallbladder arising from adenocarcinoma of the prostate. PMID- 19445299 TI - Transdiaphragmatic cardiac resuscitation. PMID- 19445300 TI - Carcinoma of the prostate with aggressive rectal invasion. PMID- 19445301 TI - Limb salvaging treatment in a rare case of spontaneous necrotizing myositis. PMID- 19445302 TI - Massive abdominal distension resulting from a giant hepatobiliary cystadenoma. PMID- 19445303 TI - Massive recurrence of cyst hydatid disease in the proximal thigh: unsuccessful conservative treatment with percutaneous aspiration, ethanol injection, and reaspiration. PMID- 19445304 TI - Does ICP monitoring in children with severe head injuries make a difference? PMID- 19445305 TI - HIT or miss. PMID- 19445306 TI - Botanical briefs: trumpet vine (Campsis radicans). PMID- 19445307 TI - What is your diagnosis? Acute herpes simplex virus type 1 stomatitis. PMID- 19445308 TI - Childhood vesicular pemphigoid mimicking severe atopic dermatitis: a case report. AB - Bullous pemphigoid (BP) is an autoimmune blistering disorder that typically affects elderly patients. Rarely, it can occur in childhood. Vesicular pemphigoid is an atypical variant of BP. We report a case of childhood vesicular pemphigoid in an infant aged 6 months that was initially misdiagnosed as severe atopic dermatitis (AD). To the best of our knowledge, only one other case of childhood vesicular pemphigoid has been reported in the literature. PMID- 19445309 TI - Tinea imbricata. AB - Tinea imbricata (TI) is a chronic superficial mycosis caused exclusively by Trichophyton concentricum. Characteristically, the lesions are composed of multiple concentric annular plaques that have thick adherent peripheral rims of scale. A brief review of this infection is presented. PMID- 19445310 TI - Steroid-induced rosacealike dermatitis: case report and review of the literature. AB - Steroid-induced rosacealike dermatitis (SIRD) is an eruption composed of papules, pustules, papulovesicles, and sometimes nodules with telangiectatic vessels on a diffuse erythematous and edematous background. It results from prolonged topical steroid use or as a rebound phenomenon after discontinuation of topical steroid. There are 3 types of SIRD that are classified based on the location of the eruption: perioral, centrofacial, and diffuse. Diagnosis of this disease entity relies on a thorough patient history and physical examination. Treatment involves discontinuation of the offending topical steroid and administration of oral and/or topical antibiotics. Topical calcineurin antagonists should be considered as alternative or adjunctive therapies for patients who do not respond to traditional treatments. Dermatologists may need to provide psychological support during office visits for patients who have difficulty dealing with the discontinuation of topical steroid and/or the psychological impact of a flare. Epidemiology, pathogenesis, histopathology, and differential diagnosis of the entity also are reviewed. PMID- 19445311 TI - Calcitriol ointment 3 microg/g is safe and effective over 52 weeks for the treatment of mild to moderate plaque psoriasis. AB - Topical vitamin D3 agents have emerged as important options for the treatment of psoriasis. Calcitriol, a naturally occurring and biologically active form of vitamin D3, has been developed in an ointment formulation for topical psoriasis therapy in the United States. The product has been used outside of the United States for years. Several short-term (< 6 months) clinical trials have demonstrated that calcitriol ointment 3 microg/g improves symptoms of psoriasis in participants with mild to moderate plaque psoriasis without demonstrating clinical evidence of alterations in calcium homeostasis, but little information has been available about the safety and effectiveness of continuous long-term use of calcitriol ointment. In this open-label, multicenter study, 324 participants with primarily mild to moderate chronic plaque psoriasis were treated with calcitriol ointment 3 microg/g twice daily for up to 52 weeks. A total of 136 participants completed 52 weeks of treatment. Serious adverse events (AEs) (reported by 1 participant each unless otherwise noted) included a pretibial skin ulcer (study drug was used only on the upper body), a joint disorder, metrorrhagia (2 participants), heart failure, hospitalization due to arteriosclerosis, breast carcinoma, and an infection (due to a dog bite). Clinical improvement in psoriasis symptoms was assessed by an investigator-rated global severity score (GSS) and participant-rated global assessment of improvement in psoriasis symptoms from baseline. Improvements in GSS were seen over the course of treatment. Calcitriol ointment 3 microg/g is a safe, effective, and well-tolerated option for the long-term treatment of chronic plaque psoriasis. Clinical improvement was maintained for up to 52 weeks, with no clinical effect on calcium homeostasis or other relevant laboratory test parameters. PMID- 19445312 TI - Improving adherence to topical treatment. AB - The efficacy of topical medications generally increases when they are used as directed. To help patients achieve optimal therapeutic outcomes, it is worthwhile for physicians to utilize strategies that may improve patient adherence. Effective strategies include positive patient-physician relationships, patient education, follow-up visits or calls, and patient participation in treatment decisions. PMID- 19445313 TI - Fundamentals and health benefits of xanthohumol, a natural product derived from hops and beer. AB - In recent years, there has been a growing interest in phenolic compounds and their presumed role in the prevention of various degenerative diseases, such as cancer and cardiovascular diseases. Xanthohumol, a prenylated chalcone from hops and beer, is among the phenolic compounds which have received the most attention in recent years. This compound has a range of interesting biological properties that may have therapeutic utility. Based on the health-promoting properties of xanthohumol, the production of a beer enriched in this substance would be of huge interest to the brewing industry, for the benefits this could bring to consumer's health. This paper reviews recent and important data with respect to the health benefits or biological activities of xanthohumol and beer. In addition, an overview of the chemistry and biotechnological aspects of xanthohumol is presented. PMID- 19445314 TI - Bioactivity of grape chemicals for human health. AB - Grapevine (Vitis vinifera) products, grape and grape juice, represent a valuable source of bioactive phytochemicals, synthesized by three secondary metabolic pathways (phenylpropanoid, isoprenoid and alkaloid biosynthetic routes) and stored in different plant tissues. In the last decades, compelling evidence suggested that regular consumption of these products may contribute to reducing the incidence of chronic illnesses, such as cancer, cardiovascular diseases, ischemic stroke, neurodegenerative disorders and aging, in a context of the Mediterranean dietary tradition. The health benefits arising from grape product intake can be ascribed to the potpourri of biologically active chemicals occurring in grapes. Among them, the recently discovered presence of melatonin adds a new element to the already complex grape chemistry. Melatonin, and its possible synergistic action with the great variety of polyphenols, contributes to further explaining the observed health benefits associated with regular grape product consumption. PMID- 19445315 TI - Wine, resveratrol and health: a review. AB - Several studies have cited the Mediterranean diet as an example of healthy eating. In fact, the Mediterranean diet has become the reference diet for the prevention of cardiovascular disease. Red wine seems to be an essential component of the diet, since moderate consumption of wine is associated with lower risk and mortality from cardiovascular disease. Evidence is also accumulating that wine helps prevent the development of certain cancers. Of all the many components of wine, resveratrol, which is a natural component specifically present in wine, has been identified as being mainly responsible for these health-promoting properties. Many valuable properties such as cardioprotective and anticarcinogenic activity have been attributed to resveratrol; however, its bioavailability is quite low. The bioactivity of metabolites derived from resveratrol, and the accumulation of resveratrol in vital organs are still under study, but there are high expectations of positive results. Other stilbene compounds are also considered in this review, despite being present in undetectable or very small quantities in wine. The present paper reviews all aspects of the health properties of wine, bioactive compounds found in wine, and their concentrations, bioavailability and possible synergistic effects. PMID- 19445316 TI - Apple-products phytochemicals and processing: a review. AB - Epidemiological studies have linked the consumption of apples with reduced risk of some cancers, cardiovascular disease, asthma, and diabetes. Extensive research exists on apples and the health benefits of their beverages and phytochemicals. The purpose of this paper is to review the most recent literature in this area focusing on phytochemicals, phytochemical bioavailability and antioxidant behavior. PMID- 19445317 TI - Bioactive compounds of selected fruit juices. AB - Fruits are one of the most important sources of phenolic compounds in our diet. Many of these compounds exhibit a wide range of biological activities, especially antioxidant activity. The objective of this study was to determine the composition and antioxidant activity of phenolic compounds found in fruit juice obtained from buckthorn, flowering quince, rowanberry and hawthorn. Hydroxycinnamic acids (neochlorogenic and chlorogenic acid) and procyanidins were the main phenolics in rowanberry juice. The highest level of flavonols (quercetin derivatives) was found in sea buckthorn. All juices showed strong free-radical scavenging activity against ABTS*+ radicals and ferric reducing ability measured by the FRAP method. The strongest antioxidant activity was found in rowanberry juice, but the lowest was measured in hawthorn and sea buckthorn juices. PMID- 19445318 TI - Vitamin C and the role of citrus juices as functional food. AB - The literature on the content and stability of vitamin C (ascorbic acid, AA) in citrus juices in relation to industrial practices is reviewed. The role of vitamin C from citrus juices in human diet is also reviewed. Citrus fruits and juices are rich in several types of bioactive compounds. Their antioxidant activity and related benefits derive not only from vitamin C but also from other phytochemicals, mainly flavonoids. During juice processing, temperature and oxygen are the main factors responsible for vitamin C losses. Non-thermal processed juices retain higher levels of vitamin C, but economic factors apparently delay the use of such methods in the citrus industry. Regarding packing material, vitamin C in fruit juice is quite stable when stored in metal or glass containers, whereas juice stored in plastic bottles has a much shorter shelf-life. The limiting step for vitamin C absorption in humans is transcellular active transport across the intestinal wall where AA may be oxidized to dehydroascorbic acid (DHAA), which is easily transported across the cell membrane and immediately reduced back to AA by two major pathways. AA bioavailability in the presence of flavonoids has yielded controversial results. Whereas flavonoids seem to inhibit intestinal absorption of AA, some studies have shown that AA in citrus extract was more available than synthetic ascorbic acid alone. DHAA is reported to possess equivalent biological activity to AA, so recent studies often consider the vitamin C activity in the diet as the sum of AA plus DHAA. However, this claimed equivalence should be carefully reexamined. Humans are one of the few species lacking the enzyme (L-gulonolactone oxidase, GLO) to convert glucose to vitamin C. It has been suggested that this is due to a mutation that provided a survival advantage to early primates, since GLO produces toxic H2O2. Furthermore, the high concentration of AA (and DHAA) in neural tissues could have been the key factor that caused primates (vertebrates with relative big brain) to lose the capacity to synthesize vitamin C. Oxidative damage has many pathological implications in human health, and AA may play a central role in maintaining the metabolic antioxidant response. The abundance of citrus juices in the Mediterranean diet may provide the main dietary source for natural vitamin C. PMID- 19445319 TI - Phenolic contribution of South African herbal teas to a healthy diet. AB - South African herbal teas, rooibos and honeybush, are increasingly enjoyed as healthy alternatives to Camellia sinensis teas. They contribute to the diet with bioactive phytochemicals not commonly found in foods. Major compounds of rooibos are the unique dihydrochalcone, aspalathin, and its flavone isomers, orientin and isoorientin. Honeybush contributes the xanthones, mangiferin and isomangiferin and the flavanones, eriocitrin, narirutin and hesperidin. All these compounds are either C-glucosides or O-rhamnoglucosides, which are poorly absorbed. Phase II metabolism and degradation by intestinal bacteria are important factors in their absorption. Modulation of drug metabolising enzymes is indicated which not only could affect the therapeutic window of drugs, but also the bioavailability of other dietary flavonoids. PMID- 19445320 TI - Ingredients for functional drinks in neurodegenerative diseases: a review. AB - Several studies have indicated that oxidative stress is a major risk factor for the initiation and progression of neurological disorders like Parkinson's disease (PD) and Alzheimer's (AD). Therefore, reducing oxidative stress appears to be a rational choice for the prevention and reduction in the rate of progression of these neurological disorders. The brain utilizes about 25% of respired oxygen even though it represents only 5% of the body weight. Free radicals are generated during the normal intake of oxygen, during infection, and during normal oxidative metabolism of certain substrates. Although experimental data are consistent in demonstrating the neuroprotective effects of antioxidants in vitro and in animal models, the clinical evidence that antioxidant agents may prevent or slow the course of these diseases is still relatively unsatisfactory, and insufficient to strongly modify clinical practice. In this paper, natural possible substances that could be added to a beverage to prevent or decrease the developing of neurodegenerative diseases are reviewed. PMID- 19445321 TI - Impact of high-intensity pulsed electric fields on bioactive compounds in Mediterranean plant-based foods. AB - Novel non-thermal processing technologies such as high-intensity pulsed electric field (HIPEF) treatments may be applied to pasteurize plant-based liquid foods as an alternative to conventional heat treatments. In recent years, there has been an increasing interest in HIPEF as a way of preserving and extending the shelf life of liquid products without the quality damage caused by heat treatments. However, less attention has been paid to the effects of HIPEF on minor constituents of these products, namely bioactive compounds. This review is a state-of-the-art update on the effects of HIPEF treatments on health-related compounds in plants of the Mediterranean diet such as fruit juices, and Spanish gazpacho. The relevance of HIPEF-processing parameters on retaining plant-based bioactive compounds will be discussed. PMID- 19445322 TI - Horizontal-flow biofilm reactors for the removal of carbon and nitrogen from domestic-strength wastewaters. AB - This study investigated the performance of a horizontal-flow biofilm reactor in treating domestic-strength synthetic wastewater (SWW) under three hydraulic and chemical oxygen demand (COD) loading rates (phases 1 to 3) ranging from 152 L/m2 x d and 58.9 g COD/m2 x d to 497 L/m2 x d and 192.7 g COD/m2 x d, respectively; the rates were based on the top surface plan area (TSPA) of the reactor. The reactor comprised a stack of 30 horizontal polystyrene sheets. The SWW, intermittently dosed onto the unit, flowed over and back along sequential sheets in the stack before exiting at the bottom of the unit. Maximum average removals of > 98% biochemical oxygen demand and 96.2% total ammonium-nitrogen (NH4-N) were observed. The TSPA COD and NH4-N removal rates were high for all phases. The unit provides a high-performance, economic, low-maintenance, and flexible alternative for removing carbon and ammonium from low-flow point sources. PMID- 19445323 TI - Simulation of coagulation, flocculation, and sedimentation. AB - The computer program ZB2 was used to study simulated coagulation, flocculation, and sedimentation. The effect of the initial velocity of soil particles on the values of reaction-rate constants was investigated. In this respect, the results obtained with the program ZB2 corresponded to the theory and realities of coagulation carried out under practical conditions. The effect of coagulant excess/deficiency on the formation of the first floc and on the rate of coagulation of 50% of a soil was also estimated. An increase in simulated coagulant excess caused a decrease in the simulated rate of soil coagulation. In this respect, the results obtained with the program ZB2 did not correspond to the realities of coagulation carried out under practical conditions. An attempt was made to explain this inconsistency referring to the coagulation-flocculation theory. The simulation program ZB2 may provide a basis for developing "local" programs simulating coagulation-flocculation, which can be successfully applied at wastewater treatment plants. PMID- 19445324 TI - Membrane bioreactor treatment of a simulated metalworking fluid wastewater containing ethylenediaminetetraacetic acid and dicyclohexylamine. AB - Membrane bioreactors (MBRs) have been installed at automotive plants to treat metalworking fluid (MWF) wastewaters, which are known to contain toxic and/or recalcitrant organic compounds. A laboratory study was conducted to evaluate treatment of a simulated wastewater prepared from a semisynthetic MWF, which contains two such compounds, dicyclohexylamine (DCHA) and ethylenediaminetetraacetic acid (EDTA). Primary findings were as follows: During stable operating periods, almost all chemical oxygen demand (COD), total Kjeldahl nitrogen (TKN), and EDTA were removed (by > 96%). During somewhat unstable periods, COD removal was still extremely robust, but removal of EDTA and TKN were sensitive to prolonged episodes of low dissolved oxygen. Nitrogen mass balance suggested 30 to 40% TKN removal by assimilation and 60 to 70% by nitrification (including up to 34% TKN removal via subsequent denitrification). Dicyclohexylamine appeared to be readily biodegraded. Maximum DCHA and EDTA degradation rates between pH 7 and 8 were found. An Arthrobacter sp. capable of growth on DCHA as the sole source of carbon and energy was isolated. PMID- 19445325 TI - Modeling of hydrogen sulfide oxidation in concrete corrosion products from sewer pipes. AB - Abiotic and biotic oxidation of hydrogen sulfide related to concrete corrosion was studied in corrosion products originating from a sewer manhole. The concrete corrosion products were suspended in an acidic solution, mimicking the conditions in the pore water of corroded concrete. The removal of hydrogen sulfide and dissolved oxygen was measured in parallel in the suspension, upon which the suspension was sterilized and the measurement repeated. The results revealed the biotic oxidation to be fast compared with the abiotic oxidation. The stoichiometry of the hydrogen sulfide oxidation was evaluated using the ratio between oxygen and hydrogen sulfide uptake. The ratio for the biotic oxidation pointed in the direction of elemental sulfur being formed as an intermediate in the oxidation of hydrogen sulfide to sulfuric acid. The experimental results were applied to suggest a hypothesis and a mathematical model describing the hydrogen sulfide oxidation pathway in a matrix of corroded concrete. PMID- 19445326 TI - Numerical modeling of dissolved oxygen in an ultra-urban best management practice. AB - Stormvault (Jensen Precast, Sparks, Nevada) is a retention-type ultra-urban best management practice, which has been tested extensively for pollutant reduction. As the first step to understand the internal water quality change during a dry weather condition, dissolved oxygen was monitored in a Stormvault system. A diffusion-reaction model was developed to diagnose the contributions of organic materials floating on the water surface, in the water column, and in the sediment, to dissolved oxygen decrease. The mathematical model was calibrated using the observed dissolved oxygen data recorded at a 0.15-m interval along the water column depth. Three scenarios were simulated, and the results confirmed that sediment oxygen demand (SOD) is the governing factor controlling a dissolved oxygen decrease in the system. The SOD rate reaches 0.8 g m(-2) d(-1) at 20 degrees C, with an average sediment accumulation depth of 0.05 m, which is lower than the recommended cleanup depth of 0.15 m. PMID- 19445327 TI - Color removal from acid and reactive dye solutions by electrocoagulation and electrocoagulation/adsorption processes. AB - In this study, electrocoagulation of Marine Blue Erionyl MR (acid dye) and electrocoagulation followed by adsorption of Brilliant Blue Levafix E-BRA (reactive dye) from aqueous solutions were investigated, using aluminum electrodes and granular activated carbon (GAC). In the electrocoagulation and adsorption of dyestuff solutions, the effects of current density, loading charge, pH, conductivity, stirring velocity, contact time, and GAC concentration were examined. The optimum conditions for the electrocoagulation process were identified as loading charges 7.46 and 1.49 F/m3, for a maximum abatement of 200 mg/L reactive and acid dye, respectively. The residual reactive dye concentration was completely removed with 700 mg/L GAC. The results of this investigation provide important data for the development of a combined process to remove significant concentrations of recalcitrant dyes from water, using moderate activated carbon energy and aluminum consumption, and thereby lowering the cost of treatment. PMID- 19445328 TI - Removal of steroid estrogens from wastewater using granular activated carbon: comparison between virgin and reactivated carbon. AB - This research was set up in response to new European legislation to identify cost effective treatment for removal of steroid estrogens from effluent. This study aimed to compare estrogen removal of two types of granular activated carbon: virgin (F400) and reactivated (C401) carbon. Rapid, small-scale column tests were conducted with a total bed volume of 24.9 cm3 over three columns, and analysis was carried out using high-performance liquid chromatography. Results demonstrated that C401 performed more efficiently with greater than or equal to 81% estrogen removal in wastewater compared to F400 which produced greater than or equal to 65% estrogen removal. Estrogen removal can be affected by competitive adsorption from natural organic matter present in wastewater. In addition, the physical properties of each carbon had the potential to influence adsorption differently, thus resulting in the observed varied adsorption capability of the two carbons. PMID- 19445329 TI - Comparison of plate counts, Petrifilm, dipslides, and adenosine triphosphate bioluminescence for monitoring bacteria in cooling-tower waters. AB - Effective bacterial control in cooling-tower systems requires accurate and timely methods to count bacteria. Plate-count methods are difficult to implement on site, because they are time- and labor-intensive and require sterile techniques. Several field-applicable methods (dipslides, Petrifilm, and adenosine triphosphate [ATP] bioluminescence) were compared with the plate count for two sample matrices--phosphate-buffered saline solution containing a pure culture of Pseudomonas fluorescens and cooling-tower water containing an undefined mixed bacterial culture. For the pure culture, (1) counts determined on nutrient agar and plate-count agar (PCA) media and expressed as colony-forming units (CFU) per milliliter were equivalent to those on R2A medium (p = 1.0 and p = 1.0, respectively); (2) Petrifilm counts were not significantly different from R2A plate counts (p = 0.99); (3) the dipslide counts were up to 2 log units higher than R2A plate counts, but this discrepancy was not statistically significant (p = 0.06); and (4) a discernable correlation (r2 = 0.67) existed between ATP readings and plate counts. For cooling-tower water samples (n = 62), (1) bacterial counts using R2A medium were higher (but not significant; p = 0.63) than nutrient agar and significantly higher than tryptone-glucose yeast extract (TGE; p = 0.03) and PCA (p < 0.001); (2) Petrifilm counts were significantly lower than nutrient agar or R2A (p = 0.02 and p < 0.001, respectively), but not statistically different from TGE, PCA, and dipslides (p = 0.55, p = 0.69, and p = 0.91, respectively); (3) the dipslide method yielded bacteria counts 1 to 3 log units lower than nutrient agar and R2A (p < 0.001), but was not significantly different from Petrifilm (p = 0.91), PCA (p = 1.00) or TGE (p = 0.07); (4) the differences between dipslides and the other methods became greater with a 6-day incubation time; and (5) the correlation between ATP readings and plate counts varied from system to system, was poor (r2 values ranged from < 0.01 to 0.47), and the ATP method was not sufficiently sensitive to measure counts below approximately 10(4) CFU/mL. PMID- 19445330 TI - A procedure to estimate proximate analysis of mixed organic wastes. AB - In waste materials, proximate analysis measuring the total concentration of carbohydrate, protein, and lipid contents from solid wastes is challenging, as a result of the heterogeneous and solid nature of wastes. This paper presents a new procedure that was developed to estimate such complex chemical composition of the waste using conventional practical measurements, such as chemical oxygen demand (COD) and total organic carbon. The procedure is based on mass balance of macronutrient elements (carbon, hydrogen, nitrogen, oxygen, and phosphorus [CHNOP]) (i.e., elemental continuity), in addition to the balance of COD and charge intensity that are applied in mathematical modeling of biological processes. Knowing the composition of such a complex substrate is crucial to study solid waste anaerobic degradation. The procedure was formulated to generate the detailed input required for the International Water Association (London, United Kingdom) Anaerobic Digestion Model number 1 (IWA-ADM1). The complex particulate composition estimated by the procedure was validated with several types of food wastes and animal manures. To make proximate analysis feasible for validation, the wastes were classified into 19 types to allow accurate extraction and proximate analysis. The estimated carbohydrates, proteins, lipids, and inerts concentrations were highly correlated to the proximate analysis; correlation coefficients were 0.94, 0.88, 0.99, and 0.96, respectively. For most of the wastes, carbohydrate was the highest fraction and was estimated accurately by the procedure over an extended range with high linearity. For wastes that are rich in protein and fiber, the procedure was even more consistent compared with the proximate analysis. The new procedure can be used for waste characterization in solid waste treatment design and optimization. PMID- 19445331 TI - Study on mechanism of wet air oxidation of emulsification wastewater. AB - Wet air oxidation (WAO) can effectively be used to treat high-concentration, non biodegradable emulsification wastewater that contains nonionic matters. Gas chromatograph analysis of emulsification wastewater after oxidation indicated that a catalyst increased production of fatty acids but could not promote its oxidation between 160 and 180 degrees C. When the temperature was greater than or equal to 220 degrees C, the catalyst not only increased production of fatty acids initially but effectively promoted its oxidation in later stages and significantly reduced the concentration of residual surfactants. Experiments proved that fatty acids (especially acetic acid) were the primary intermediate products and that oxidation of these acids was the rate-limiting step. During the process of catalytic WAO of emulsification wastewater, active oxygen molecules attacked organic matters resulting in production of fatty acids, ketone, alcohol, hydrocarbon, and oligo-polyether through radical chain reactions. PMID- 19445332 TI - Nitrification-denitrification biological treatment of a high-nitrogen waste stream for water-reuse applications. AB - This research was conducted to evaluate the use of biological nitrification denitrification systems as pre-processors for recycling wastewater to potable water in support of space exploration. A packed-bed bioreactor and membrane aerated nitrification reactor were operated in series with a 10:1 recycle ratio over varying loading rates. The dissolved organic carbon (DOC) removal exceeded 80% for all loading rates (theta = 1 to 6.8 days), while total nitrogen removal generally increased with decreasing retention time, with a maximum removal of 55%. The degree of nitrification generally declined with decreasing retention time from a high of 80% to a low of 60%. Maximum DOC and total nitrogen volumetric removal rates exceeded 1000 and 800 g/m3 x d, respectively, and maximum nitrification volumetric conversion rates exceeded 300 g/m3 x d. At low hydraulic loading rates, the system was stoichiometrically limited, while kinetic limitations dominated at high hydraulic loading rates. Incomplete nitrification occurred at high loading rates, likely as a result of the high pH and large concentrations of ammonia. PMID- 19445333 TI - Comparison of the modeling approach between membrane bioreactor and conventional activated sludge processes. AB - Activated sludge models (ASM) have been developed and largely applied in conventional activated sludge (CAS) systems. The applicability of ASM to model membrane bioreactors (MBR) and the differences in modeling approaches have not been studied in detail. A laboratory-scale MBR was modeled using ASM2d. It was found that the ASM2d model structure can still be used for MBR modeling. There are significant differences related to ASM modeling. First, a lower maximum specific growth rate for MBR nitrifiers was estimated. Independent experiments demonstrated that this might be attributed to the inhibition effect of soluble microbial products (SMP) at elevated concentration. Second, a greater biomass affinity to oxygen and ammonium was found, which was probably related to smaller MBR sludge flocs. Finally, the membrane throughput during membrane backwashing/relaxation can be normalized and the membrane can be modeled as a continuous flow-through point separator. This simplicity has only a minor effect on ASM simulation results; however, it significantly improved simulation speed. PMID- 19445334 TI - Short-term effect of capping on microbial communities in freshwater sediments. AB - Because biogas bubbles can influence cap integrity, the effect of capping and cap material on the ebullition potential in sediments must be studied. The goal of this comprehensive study was to determine the short-term effect of capping regime on the activity, metabolic potential, and community structure of sediment microorganisms. To evaluate the effect of capping (sand, synthetic aggregate, and no cap) on microbial communities (i.e., nitrifiers and methanogens), sediments were collected from the Anacostia River (Washington, D.C.). Microbial communities in sand-capped sediments exhibited the highest activity (tetrazolium redox dye, fluorescein diacetate hydrolysis assay, and biogas production), while communities in uncapped sediments exhibited the highest metabolic diversity. Substantial changes in microbial community structure (denaturing gradient gel electrophoresis) did not occur as a result of capping. Our data showed that the nature and magnitude of the effect that capping can have on microbial activity (biogas production) will likely be dependent on the capping materials chosen. PMID- 19445335 TI - Treatment of phenol wastewater using hydroxyl radical produced by micro-gap discharge plasma technique. AB - Hydroxyl radical produced by non-equilibrium plasma, which was induced by micro gap dielectric barrier discharge, was used for the treatment of phenol wastewater. The advantage of this method was that chemicals and catalysts were not involved when hydroxyl radical was generated from water and oxygen. A proportional efficiency of phenol removal was observed with the hydroxyl radical increasing. The removal efficiency was higher in a basic condition than in an acidic condition, which was enhanced with the pH value of the solution increasing from 3.6 to 11.2. It was rational to adjust the pH value between 9.0 and 10.0. The removal efficiency of phenol was reduced when the conductivity of the solution increased from 0 to 200 micros x cm(-1); the highest was found in the solution without Na2CO3. The UV spectral absorption in the process indicated that few organic compounds with a conjugated structure were included in the treated wastewater. PMID- 19445336 TI - The dying can teach us? PMID- 19445337 TI - Palliative sedation at home. AB - A large number of dying patients receive palliative care at home, and although palliative sedation (PS) may be indicated, literature describing PS at home is scarce. This study is a retrospective description of PS delivered to terminal patients at home from December 2000 to March 2006. A total of 36 patients (with a median age of 65) received home PS. Cancer was the diagnosis for 35 patients, and most patients suffered more than one symptom--most commonly, intractable pain, followed by agitation and existential suffering. Drugs used included midazolam, morphine, haloperidol, fentanyl TTS, and promethazine. Median duration of sedation was three days; median time to symptom control was 24 hours. Good symptom control was achieved in 28 out of 36 patients, and 34 of the patients died at home. In conclusion, PS was a feasible and successful treatment option, improving the care of terminal patients whose preference is to die at home. PMID- 19445338 TI - Patients' experiences of physical therapy within palliative cancer care. AB - INTRODUCTION: Few studies have analyzed patients' experiences of physical therapy within palliative cancer care. OBJECTIVE: To describe how patients with incurable cancer experience physical therapy. METHOD: Seventeen patients were interviewed. Data was analyzed according to a contextual analysis within a phenomenographic approach. RESULT: Two aspects were identified: "clear and satisfactory" and "unclear and unsatisfactory". Descriptive categories were: "participation", "motivation and encouragement", "independence", "relief and well-being", "security and hope", "unclear part of the care", and "insufficient number of interventions". "Participation" was a core category interrelated with patient satisfaction. CONCLUSION: Physical therapy was important: it enabled independence, provided relief from distressing symptoms, and offered support. However, communication and coordination within the palliative care team has to improve if it is to minimize the negative impact of symptom distress on patient well-being and quality of life. Also, physical therapists must develop strategies for patient empowerment and methods for assessing and evaluating qualitative aspects of physical therapy in palliative cancer care. PMID- 19445339 TI - The "good" rural death: a report of an ethnographic study in Alberta, Canada. AB - Much concern has centred on the "good" death since the modern hospice/palliative care movement began, and considerable progress has been made in urban services to promote the good death. Little is known about the perspectives of people who live in rural and remote areas of Canada on the good death and how this good death might be enabled in those areas. This report is of an ethnographic study in rural Alberta involving English-speaking Albertans. An identical study in Quebec will be reported elsewhere. The 2006-07 Alberta study involved 13 interviews with individuals to understand their personal viewpoints or perspectives and how they were shaped by their experiences, followed by focus group discussions in two representative rural communities for additional insights from rural policy-makers and care providers. Four themes in the Alberta data highlight critical elements of the good rural death. These findings are expected to contribute to rural/remote palliative and end-of-life care developments. PMID- 19445340 TI - Volunteers in palliative care make a difference. AB - Family care giving is important for the quality of life of terminally ill patients and their family members. Although family caregivers are generally eager to provide palliative care, at some point it may become too demanding, and then volunteers can make a difference. This four-study paper presents the experiences of families of terminally ill patients with volunteer support. In four sequential studies, information was gathered from focus groups (n = 22), a survey (n = 237), individual interviews (n = 6), and an Internet panel (n = 1,712). The focus groups revealed that volunteers can make the last phase of life less stressful for family caregivers by offering practical and emotional support, and this was confirmed by the survey; however, one improvement is needed: every volunteer support should be concluded with a closing contact. The individual interviews showed that in the end-of-life stage the crucial decision is whether the patient can remain at home, not whether the caregiver needs volunteer support; and in such extreme situations, it is understood that volunteer support must involve more than one volunteer. The Internet panel revealed that in the Netherlands the general public is aware that volunteers can provide palliative care support, but many people don't know how to contact these volunteers. We must find ways to extend volunteer support in palliative care in the Netherlands and elsewhere. We must also study further the experiences of caregivers of terminally ill patients with volunteers and others who provide palliative care. PMID- 19445341 TI - A quality end of life from a palliative care patient's perspective. AB - This qualitative study explored the meaning of quality of life (QOL) from the perspective of palliative care patients by examining their lived experiences and their perceptions of what contributes to their QOL. Ten in-patients--five women and five men--took part in in-depth, semi-structured interviews. When asked about their QOL, they spoke about three distinct aspects: the meaning of a quality life at this stage in their illness trajectory, the experience of living with the illness, and factors that contributed to their QOL. Patients' approach to life, illness life, and ideal quality life were found to create a sphere of influence that shaped their end-of-life experience. At the heart of living a quality end of life for these patients was their ability to "do the things that I usually do," "be helpful to others," and "live in a caring environment," The findings highlight the importance of understanding each of these factors: patients' approach to life, illness life, and ideal quality of life, and what they mean to patients in order to tailor interventions to enhance their QOL. PMID- 19445342 TI - A palliative care intervention in forgiveness therapy for elderly terminally ill cancer patients. AB - Palliative care is now considered an essential part of end-of-life care, yet little research examines the efficacy of interventions addressing the psychological treatment of dying patients. Forgiveness therapy has been shown to be effective in improving psychological well-being and may provide a valuable addition to a terminal cancer patient's overall treatment plan. This study experimentally tested the effectiveness of a four-week forgiveness therapy in improving the quality of life of elderly terminally ill cancer patients. Participants (n = 20) were randomly assigned to a forgiveness therapy group or to a wait-list control group, which received forgiveness therapy in the second four week period. All participants completed instruments measuring forgiveness, hope, quality of life, and anger at pre-test, post-test 1, and post-test 2. The forgiveness therapy group showed greater improvement than the control group, with one-tailed t-tests, on all measures. After receiving forgiveness therapy, participants in both forgiveness treatment conditions demonstrated significant improvements on all measures. The aggregated effect size was large. The four-week forgiveness therapy demonstrated psychological benefits for elderly terminally ill cancer patients and thus may be an appropriate addition to the treatment plan for terminal cancer patients. PMID- 19445343 TI - What is a good death? Stories from palliative care. AB - The components of good and bad deaths have not been well elucidated in the literature. Furthermore, the value of using narratives in palliative care research has not been extensively explored. We invited people involved in palliative care (patients, caregivers, physicians, and nurses) to tell us their stories of good and bad deaths, and 15 responded. We asked them to tell us about the good and bad deaths that they had witnessed and to describe what a good death and a bad death would be like for them, personally. Several common themes emerged from their good death narratives: a death free from pain, the sense of a life well lived, and a sense of community. Common bad death themes included a painful death and a loss of control and independence. We found that the use of story in palliative care provided an opportunity to create meaning and to heal for both the teller and the listener. PMID- 19445344 TI - Caregiver empowerment and music therapy: through the eyes of bereaved caregivers of advanced cancer patients. PMID- 19445345 TI - Spousal perceptions of marital stress and support among grandparent caregivers: variations by life stage. AB - Few studies have examined how raising grandchildren influences the marital relationship of grandparent caregivers although half of such caregivers are married. This study used national survey data from Midlife Development in the United States (MIDUS) to contrast perceptions of spousal support and strain for grandparents who had recently provided care for grandchildren along with their own young children (n=16), and grandparents who had recently cared for grandchildren only (n=96). Results revealed an interaction between caregivers' sex and family situation with grandmother caregivers who were raising both their own minor children and grandchildren reporting less spousal support than grandfathers in the same situation. Differences on the spousal strain dimension were not significant. Grandmother caregivers occupying 2 caregiving roles appear to have a unique experience with caring for grandchildren. These results parallel other studies that show that grandparent caregivers have poorer outcomes when they hold multiple caregiving roles simultaneously. PMID- 19445346 TI - Parenthood, stress, and mental health in late midlife and early old age. AB - Using 2 waves of the Wisconsin Longitudinal Study, I examine psychological consequences of potentially stressful, non-normative, or "off-time" aspects of the parental role in late midlife and early old age, including coresidence with adult children, stepparenthood, and parental bereavement. Additionally, I analyze gender differences in psychological implications of these characteristics of parenthood. Findings from random-effects pooled time-series models indicate that having stepchildren is unrelated to older parents' mental health. Moreover, the psychological consequences of step-parenthood do not depend on parental gender or the quality of parent-child relationships. Conversely, having at least 1 coresidential adult child of post-college age decreases psychological well-being among mothers but not among fathers. Death of a child has a detrimental effect on parents' mental health; yet, fathers are affected more adversely than mothers. The findings are interpreted with respect to family stress, parental role, and gendered role perspectives. Distinct experiences of this cohort of mothers and fathers are discussed. PMID- 19445347 TI - Why do older men report low stress ratings? Findings from the Veterans Affairs Normative Aging Study. AB - We examined the interplay between three explanatory hypotheses for why older adults appear to rate their problems as less stressful than do younger adults: age-related differences in personality, in types of problems, and in the appraisal process-specifically, the number of primary stress appraisals. A sample of 1054 men from the Normative Aging Study (mean age = 65.02; range = 45 to 92) were interviewed about a problem in the past week. Personality did not mediate the effect of age on stress ratings. While general hassles and health problems both increased with age, they had opposite influences on stress ratings. Accounting for covariates, older men reported fewer appraisals, and the number of appraisals mediated the association between age and stress ratings. We found no moderating effects of problem type on these processes. Thus, lower stress ratings for everyday problems in later life may result from developmental changes in primary appraisal processes. PMID- 19445348 TI - Age and workers' perceptions of workplace safety: a comparative study. AB - The study examined the relationship between age and (i) safety perception; (ii) job satisfaction; (iii) compliance with safety management policies; and (iv) accident frequency. Participants were Ghanaian industrial workers (N=320) categorized into 4 age groups: 19-29 years; 30-39 years; 40-50 years; and 51 years and above. Workplace safety perception was assessed with Hayes, Perander, Smecko, and Trask's (1998) 50-item Work Safety Scale (WSS): a scale that effectively captures the dimensions identified by safety experts to influence perceptions of workplace safety. ANOVA was used to test for differences in the mean scores of the 4 groups. Post Hoc analysis revealed differences of statistical significance between the 2 younger cohorts and the 2 older cohorts. The results indicated a positive association between age and safety perception. Older workers had the best perceptions on safety, indicated the highest level of job satisfaction, were the most compliant with safety procedures, and recorded the lowest accident involvement rate. From a practical perspective, understanding age-related perceptions of workplace safety would benefit management's decisions regarding workers' adaptability, general work effectiveness, accident frequency, implementation of safety management policies, and handling of age-related accident characteristics. PMID- 19445349 TI - [Culture and psychological concepts of self-harm]. AB - The paper reveals cultural and psychological concepts of self-harm. The authors tried to describe many, particular functions attached to self-mutilation activity, specially so-called 'normal' and 'pathological' functions. In the author's views there are no firm limits between these to the kinds of self-harm, because so-called 'normal' functions frequently co-occur with 'pathological' ones. From a therapeutic perspective it's beneficial to attempt to understand the subjective meaning of self-injury, what are the 'pathological' and 'normal' functions, how self-mutilations mirror the actual situation and history of the patient's development, what is the cultural context. In therapeutic intervention, the subjective attitude of the physician / psychiatrist / therapist is crucial, especially in the context of limiting negative aspects of coutertransference. These negative aspects can disturb the contact with patients by a high level of feelings of inefficacy, anger, withdrawal, intrusive interpretations, rejecting patients or limiting effective forms of interventions. The authors of the paper describe some aspects of self-injury such as tattooing, piercing, communication functions, role of traumatic experiences, psychoanalytical and cultural views. PMID- 19445350 TI - [Self-harm done by young patients during their psychiatric hospitalization in relation to the presence of specific mental disorders and chosen environmental factors]. AB - AIM: The objective of the study was to assess the relation between the occurrence of deliberate self-harm (DSH) in young patients during their psychiatric treatment and the presence of specific mental disorders, or the history of suicide attempts, the exposure to abuse and their family situation. METHOD: The studied group consisted of 187 in-patients aged 13-19 years, hospitalized at the Adolescent Ward of the Central Clinical Hospital, Medical University of Lodz, during the 2 quarters on the turn of 2005 and 2006. All patients were examined psychiatrically, and on discharge they were also assessed with the "Questionnaire for the Assessment of Self-Harm" designed for the purpose of this study. RESULTS: Forty-seven percent of the psychiatrically treated in-patients had performed DSH acts. A strong relationship (p < 0.001) was found between the occurrence of SH and the previous history of suicidal attempts, the presence of an alcohol problem in the family, the exposure to sexual and physical abuse and the lack of support from close family members. CONCLUSIONS: There was no relation between the occurrence of deliberate self-harm in young in-patients and the presence of a specific psychiatric disorder. PMID- 19445351 TI - [Emotional disturbances in children and adolescents from the attachment theory perspective]. AB - Emotional disturbances in children and adolescents may be explained basing on different aetiological theories. One of them is the attachment theory created by Bowlby. It stresses the relationships between the characteristic of children's relations with caregivers and their behaviours, which might be described as symptoms in certain circumstances. Attachment behaviours should not be treated as the only explanation of disturbances but rather as a risk factor. Another advantage of the theory is that it might be helpful in the integration of different theories referring to the aetiology of emotional disturbances, taking into consideration both intrapsychic and interpersonal factors. PMID- 19445352 TI - [Change in self-image in the population of adolescents in 15 years--comparative study]. AB - The image of the self changes over time. The changes are conditioned by the culture and the social structure that the adolescents live in. AIM: The study aimed to compare self-image in the non- treated 17 y.o. population of adolescents during 15 years. METHOD: In 1987 and 2001, a representative sample of school attending adolescents was screened with OSIQ (The Offer Self-Image Questionnaire for Adolescents). RESULTS: In the period surveyed, the self-image of 17-year-olds improved. In the boys' group, there is still an incoherence of the self-image, while in girls the coherence grows. CONCLUSIONS: As a result ofmacrocultural factors, favourable changes take place in the area of mental health and coping that are reflected in the improvement of the self-image. PMID- 19445353 TI - [The actual image of male patients with paranoid schizophrenia in perception of the patients themselves and their parents]. AB - AIM: The aim of this study was to answer following questions: Does the self-image of male schizophrenics differ from the image their parents have? Do parents judge their sons more negatively or more positively than they themselves do? Are opinions of the mothers and fathers different or consistent? METHODS: 30 unmarried male patients with paranoid schizophrenia (diagnosis based on ICD-10) were included in the study. All subjects lived with their parental families. In all cases, families were complete. Subjects were aged 18-23 (x = 23.23). The mean time of duration of disease was 2.37 (range 0.5-5 years) and the mean hospitalization number was 1.7 (range 1-4). All subjects had completed primary education. 3 subjects graduated from university and the rest of them continued education in vocational or secondary schools as well as universities. The study was carried out during the last week before discharge from the hospital. The Adjective Check List (ACL) of Gough and Heilbrun was used in the study. Subjects filled out the questionnaire in accordance with instructions "I am" and parents in accordance with the instruction "My son is". Three different types of present images of patients were obtained: patient self-image, the image their mother and their fathers have and they were compared using ANOVA. RESULTS: Comparison of actual self-images of male schizophrenics with present images of schizophrenics their mothers have revealed 26 statistically significant differences, and with present images of schizophrenics their fathers have revealed 23 statistically significant differences. The differences between images of schizophrenics obtained from their mothers and their fathers were statistically significant in 2 cases only. CONCLUSIONS: Self-opinion of the males diagnosed with paranoid schizophrenia is more positive than the opinion their mothers and fathers have of them. Self-images of the males diagnosed with paranoid schizophrenia and images their mothers have are different. Mothers have a more negative opinion of their sons than their sons have of themselves. Self-images of males diagnosed with paranoid schizophrenia and images their fathers have are different. Fathers have a more negative opinion of their sons than their sons have of themselves. Generally fathers and mothers perceive their sons in the same way. PMID- 19445354 TI - [The assessment of personality traits and coping style level among the patients with functional dyspepsia and irritable bowel syndrome]. AB - AIM: The aim of the study was the assessment of personality traits level (neuroticism, extraversion, openness to experiences, agreeableness, conscientiousness) and coping styles among patients with functional dyspepsia and irritable bowel syndrome. METHODS: The Neo-Five Factor Inventory of Personality (NEO-FFI) and Coping Inventory for Stressful Situation (CISS) were used in the study. RESULTS: The subjects had a high level of agreeableness and conscientiousness and an average level of neuroticism, extraversion, openness to experiences. Moreover, the avoidance--oriented coping style dominated among the patients with functional dyspepsia and the highest level of the emotional oriented coping style was characteristic for the irritable bowel syndrome patients. CONCLUSION: Lack of the effective coping is characteristic for patients with functional dyspepsia and irritable bowel syndrome. Significant differences between groups were noted in the conscientiousness level. Patients with functional dyspepsia had a high and patients with irritable bowel syndrome--an average level of conscientiousness. PMID- 19445355 TI - [Severe COPD and gender of patients versus the presence of profound psychological trauma]. AB - The authors examined psychiatrically a group of 45 patients suffering from severe COPD. The special interest of the study was the careful analysis of the time, context and content of different psychological traumas that the patients had experienced throughout their lives. METHODS: The authors examined 45 patients suffering from severe COPD (according to GOLD classification) during the present hospitalisation. There were 19 women (42%) and 26 men (58%). The average age was M = 64.56 years (SD = 10.64), and average duration of illness was M = 10.53 years (SD = 10.18). Mini International Neuropsychiatric Interview, Polish version 5.0.0, Panic and Agoraphobia Scale, Beck's Depression Inventory, Family Functioning Questionnaire (KOR), Sense of Coherence Scale (SOC-29), Defence Style Questionnaire (DSQ-40) and Life Inventory were used. RESULTS: Although the proportion of women in the group of 45 patients with severe COPD was 42%, they seem to be more prone to depression and panic than men. It may be due to specific trauma of suffering and/or death of an emotionally close person, which occurred in 64.4% of the study group. This trauma may have an impact on the intensity of anxious and depressive symptoms, catastrophic interpretation of bodily symptoms and also the sense of coherence of patients with COPD. CONCLUSIONS: It is possible, that strictly psychological and psychiatric problems affect the course and severity of COPD in women. PMID- 19445356 TI - [Links between panic disorder, depression, defence mechanisms, coherence and family functioning in patients suffering from severe COPD]. AB - Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressive lung disorder characterised by airflow obstruction. It is one of the major causes of morbidity, disability and mortality in the older population. Comorbid psychiatric and psychological impairments (depression and anxiety, most often panic disorder) are common in COPD. They impair the quality of life in COPD severely and are often not fully explored in the clinical management of COPD patients. AIM: The aim of our study was to assess the prevalence of anxiety (especially panic disorder) and depression among patients with COPD. A secondary objective was to find out a correlation between the psychological aspects (defence style, sense of coherence and family functioning) and psychiatric symptoms. METHODS: The authors examined 45 patients suffering from severe COPD (according to GOLD classification) during their present hospitalisation. There were 19 women (42%) and 26 men (58%). The average age was M = 64.56 years (SD = 10.64), and the average duration of illness was M = 10.53 years (SD = 10.18). Mini International Neuropsychiatric Interview, Polish version 5.0.0, Panic and Agoraphobia Scale, Beck's Depression Inventory, Family Functioning Questionnaire (KOR), Sense of Coherence Scale (SOC-29), Defence Style Questionnaire (DSQ-40) and Life Inventory were used. RESULTS: The study revealed that 44.4% of the group with severe COPD were patients who suffered also from panic disorder and 40% from depression. Depression was linked with more severe panic symptoms. All psychiatric symptoms were associated with a psychological problems. CONCLUSION: It is highly possible, that psychiatric and psychological problems affect the quality of life, self management and treatment outcome in patients with COPD. PMID- 19445357 TI - [The position of psychooncology in contemporary psychiatry]. AB - Growing evidence indicates that it is not possible to understand carcinoma taking into account only the biological basis, without the psychological and social aspects of the disease. Contemporary psychooncology represents a holistic approach to the disease, integrating theoretical models, clinical and sociological observations as well as current scientific data. Psychooncological research concentrates on the influence of psychological factors on the risk of developing cancer (the model of "personality promoting carcinoma" and the model of "loss and depression"), on psychological processes as predictive factors in the course of an already existing illness and on psychological distress during diagnosis and treatment of the cancer. PMID- 19445358 TI - [European measure of best practice for people with long-term mental illness in institutional care--DEMoB.inc]. AB - The article depicts the international scientific project-DEMoB.inc. which aims to develop a European tool kit for assessing quality of care provided by long-term psychiatric and social care facilities. Positive aspects of rehabilitation of people with profound and chronic mental disturbance, as well as health care system shortcomings leading to patients' social exclusion, abuse and violation of basic human rights have been shown. While describing the six phases of the research, special attention has been paid to the first one based on the Delphi method. The implementation of the method in the development the tool kit's international core and local "clip-ons" as well as its general characteristics have been presented. Association between tool kit assessments and patients' quality of life, autonomy, markers of recovery as well as the MANSA and the Resident Choice Scale have been described. Economic analysis--value for money (VfM), the CSRI scale and potential dissemination activities on an international and local level have been proposed. PMID- 19445359 TI - [Delphi application in medical science teaching]. AB - Teaching constitutes part of a psychiatrist's work. The essential determinants of best practice in psychiatric education as well as proven teaching methods are still lacking. The authors have presented the application of the Delphi technique to under- and postgraduate teaching programmes in diverse fields of medical knowledge. The Delphi method is based on systematic and anonymous refinement of expert opinion on defined scientific issues. The conventional approach of the method relies on questionnaires filled in by chosen experts in at least 3 or 4 rounds. Answers are assessed quantitatively and qualitatively during subsequent rounds in order to refine and specify opinions and--when expected--to achieve consensus. Innovative methods of the Delphi analysis have been presented. Patients' and physicians' opinions as well as electronic methods have been applied in curricula development. Both the positive experience of practical Delphi method application and methodological flexibility might be useful in construction of modern teaching programmes in psychiatry. PMID- 19445360 TI - [Sickle cell disease in France in 2008. Achievements and challenges]. AB - Much progress has been made in the past two decades in the diagnosis and management of sickle-cell disease. Clinical, pathophysiological and therapeutic studies have given rise to national procedures for all patients. Life expectancy has improved dramatically in industrialized countries, and the number of sickle cell patients reaching adulthood is growing. Neonatal diagnosis began in France in 1995 and is crucial for early prevention. Crisis management and long-term surveillance both require dedicated drepanocytosis centers for children and for adults. PMID- 19445361 TI - [A center in Paris for screening and counselling sickle cell patients and carriers]. AB - Prevention of sickle cell anemia, a severe and painful disease, relies on carrier detection and information, and on prenatal diagnosis with the possibility of medical abortion. Here we report the first results of a medical and welfare program launched in Paris 20 months ago and dedicated to sickle cell carrier screening and information. PMID- 19445362 TI - [Sickle cell disease in Africa: current situation and strategies for improving the quality and duration of survival]. AB - The prevalence of sickle cell disease is extremely high in Africa, where 150,000 to 300,000 homozygous individuals are born every year. Africans were well aware of the disease before its first description in America. Spectacular progress has been made in our knowledge of the pathophysiology of SCD, and patient management has vastly improved in northern countries where the prevalence of the disease is low. We describe the current situation of sickle cell disease in Africa and propose strategies for improving disease prevention and patient management. PMID- 19445363 TI - [Advances in sickle cell disease]. AB - Generation of transgenic mice have identified new pathophysiological mechanisms in sickle disease, including a permanent proinflammatory state and dysregulation of vascular tone. Treatment is no longer solely symptomatic. New agents target red cell hydration and the kinetics of deoxyhemoglobin S polymerization. Hydroxyurea, which reactivates fetal hemoglobin synthesis, is now widely used. Anti-adhesion molecules and agents modulating vascular tone are being tried in sickle mice. Bone marrow transplantation is widely used to cure patients with HLA identical siblings, and gene therapy looks promising for those without a donor. PMID- 19445364 TI - [Stroke prevention in sickle-cell disease: results, hurdles and future perspectives]. AB - Sickle cell disease (SCD) is the most frequent cause of stroke during infancy, and stroke is the most serious complication of SCD in children. Sludge-induced distal vasculopathy explains 25% of strokes in SCD, while proximal vasculopathy is responsible for 75% of cases. The stenoses observed in SCD-related proximal vasculopathy are progressive and can be detected by transcranial Doppler (TCD), a reliable, non-invasive and low-cost imaging method. High velocities (> 2 mls) are associated with a 40% risk of stroke within 36 months, but initiation of a transfusion program maintaining the HbS level under 30% reduces the risk to less than 2%. TCD must be performed in all children at 12-18 months of age to detect cerebral vasculopathy and prevent stroke. This approach has been adopted in our institution, based on a cohort of SCD newborns screened at birth: the risk of stroke was reduced from the expected 11% to less than 2% at 18 years. Genoidentical stem cell transplantation, which safely obviates the need for transfusion programs and provides a 95% chance of cure, should be offered early to patients at risk of stroke. When possible, sibling cord blood cryopreservation is recommended PMID- 19445365 TI - [New issues in adult sickle sell disease]. AB - Over the past 20 years, early medical treatment has significantly increased the life expectancy of children with sickle cell disease. More than 90% of patients now reach the age of 20, and the median life expectancy of sickle cell patients is at least 50 years in countries with advanced healthcare systems. The increase in the number of adults with homozygous sickle cell disease is accompanied by increasingly frequent chronic osteoarticular, renal, cardiorespiratory, ocular, cutaneous and cerebral complications. Pregnancy is a high-risk situation for the mother and child The efficacy and safety of hydroxyurea and long-term blood transfusions in adults with sickle cell disease are currently under investigation. PMID- 19445366 TI - [Update on counterfeit drugs: a growing risk for public health]. AB - Drug counterfeiting is a growing danger, and not only in developing countries where it can account for up to 40% of the market. Counterfeit drugs can be both ineffective and toxic. They are becoming more and more common in the USA and even in Europe. France seems to have escaped this problem for the time being. The drug distribution chain (producer-wholesaler-retail pharmacist) is both the gatekeeper and the weak point of the system. Counterfeiting is more frequent in countries where drug distribution is badly organized or excessively deregulated The increasing use of the Internet for self-diagnosis and self-medication is adding to the problem, particularly in countries where social security coverage is limited The IMPACT initiative, launched in 2006 by WHO and other stakeholders worldwide (health authorities, healthcare professionals, patients, customs, police, industry), is aimed at developing precise legislative, regulatory and technical measures, and at increasing global awareness of this threat to public health. PMID- 19445367 TI - [Whooping cough from infants to adults]. AB - Neither natural nor vaccine-induced immunity to pertussis lasts for life. Before intensive vaccination of toddlers, pertussis was essentially a pediatric disease. Mortality and morbidity have fallen drastically in parts of the world where toddlers have been systematically protected with efficacious whole-cell vaccines. The infection is now more common in adults with waning specific immunity, who can go on to infect newborns too young to be vaccinated, with potentially dramatic consequences. For these reasons, the vaccine strategy was recently modified in several countries, with the introduction of vaccine boosters for children, adolescents and young adults, as well as for healthcare workers in contact with newborns. In France, vaccine boosters were introduced for adolescents in 1998 and for adults in contact with newborns in 2004, leading to a decrease in morbidity in adolescents and very young adults. It is important to inform the medical community, and the families with neonates, of these changes in vaccine strategy. Efficient surveillance and notification systems are needed in all countries. Surveillance must include the use of standardized diagnostic tests and reagents. Bacterial isolates should be thoroughly characterized at the genomic, transcriptomic and proteomic levels. PMID- 19445368 TI - [CD4 lymphocytes as targets and actors in the pathogenesis of HIV infection- therapeutic implications]. AB - CD4 T lymphocytes play a central role in the pathogenesis of human immunodeficiency virus (HIV) infection. In viremic patients, these cells are direct targets for the virus: HIV multiplies intensely in this subpopulation during the acute phase of the disease and continues to propagate in these same cells during the clinical latency phase. Uninfected CD4 T lymphocytes are also indirectly affected during this second phase: they are activated, become anergic, then disappear by apoptosis, ultimately contributing to CD4 lymphopenia. Our studies have shown that dysfunction of the interleukin-2 system and its receptors largely explain the early immune deficiency seen in viremic patients. Later, blockade of the homeostatic interleukin-7/CD4 loop contributes to rendering this CD4 lymphopenia irreversible. Our studies suggest that the inflammatory reaction which accompanies this infection gives rise to a state of abnormal activation, with receptor desensitization to the main cytokines regulating CD4 lymphocyte functions and numbers. In the few rare patients who manage to control HIV in the absence of any treatment, the CD4 T cell compartment has a very characteristic configuration. We have shown that an extensive subpopulation of "central memory" CD4 T lymphocytes expresses large quantities of the CCR7 homing receptor and that this helps drive these lymphocytes to infected lymph nodes. Also, these "central memory" CD4 T lymphocytes produce large quantities of IL-2, that they use in an autocrine manner, stimulating their self-renewal and ensuring their long-term survival. Our studies have opened the door to cytokine-based immunotherapy and to the development of new drug- and vaccine-based strategies. PMID- 19445369 TI - [Immunological aspects of anticancer chemotherapy]. AB - For over 40 years, four therapeutic modalities, namely surgery, radiotherapy, chemotherapy and hormone therapy have formed the core of anticancer treatments. Their mode of action is thought to involve a direct cytotoxic action on tumor cells. Recently, the discovery of tumor-associated immunosuppression and tumor immunosurveillance has led to cancer being reconsidered not only as an organ disease but also as a host disease. This new concept is supported by the recent discovery of the immunogenic effects of tumor cell death induced by a variety of cytotoxic drugs. This work describes a new pathway of tumor-derived antigen presentation mediated by the alarmin HMGB1 (released by dying tumor cells in response to chemo/radiotherapy) and by TLR4 on dendritic cells. In this model, TLR4 recognizes? tumor-derived antigens, leading to T cell activation and to the induction of an antitumor immune response. Accordingly, we show that breast cancer patients bearing a loss-of-function mutation of the TLR4 receptor have shorter disease-free survival, confirming the major role of the immune system in the response to cytotoxic treatments. The response to chemotherapy and/or radiotherapy may thus combine both direct cytotoxic effects and the development of long-term antitumor immunity. We anticipate that these new results will have major impact on cancer management. PMID- 19445370 TI - [Limbic encephalitis--evolving concepts]. AB - Limbic encephalitis is an inflammatory disease localized to the "grand lobe limbique" defined by Broca in 1878, sometimes restricted to the hippocampus, but sometimes including extralimbic abnormalities. The main features are subacute onset, short-term memory disorders and cognitive impairment, temporal seizures, and hippocampic changes on MRI. A list of underlying causes has recently been published Infectious causes used to be frequent (mainly herpes simplex virus). Paraneoplastic limbic encephalitis is characterized by the presence of various onconeural antibodies, such as AntiHu and ANNA3 (bronchial small cell carcinoma), AntiMa2 (testicular tumor), AntiCV2 (lymphoma, thymoma,...). No such antibodies are detected in 40% of patients. The prognosis of these forms is poor. Voltage gated potassium channel-associated limbic encephalopathies are due to antibodies targeting potassium channels. Mutations of the genes encoding the Kv11 and Kv12 subunits are responsible for several Shaker syndromes, including neuromyotonia, Morvan's disease, type I episodic ataxia, and limbic encephalitis with hyponatremia. Plasma exchanges and immunotherapy are effective. In patients without detectable antibodies, hippocampic anti-neuropil antibodies should be sought, particularly those targeting N-methyl-D-aspartate receptors. Ovarian teratoma is the usual cause of this type of encephalitis. Surgery and immunotherapy are effective. These disorders have been categorized into those associated with antibodies targeting intracellular antigens (poor-prognosis paraneoplastic encephalitis) and those associated with antibodies targeting antigens reacting with cellular membranes (potassium channelopathies and antineuropil antibodies), which respond to immunotherapy and carry a better prognosis. Limbic encephalitis can also reveal Hodgkin's disease, as in a case observed by the authors. PMID- 19445371 TI - [Periodic paralysis: new pathophysiological aspects]. AB - Periodic paralyses are neuromuscular disorders characterized by attacks of muscle weakness coinciding with changes in blood potassium levels. They are thus classified as hypokalaemic, normokalaemic or hyperkalaemic. Most forms are genetic, with autosomal dominant inheritance. These diseases are channelopathies, i.e. caused by mutations in ion channel genes. The culprit genes encode muscle sodium, calcium and potassium channels. Mutations in calcium or potassium channels cause periodic paralyses of the same type (hypokalaemic periodic paralysis or Andersen-Tawil Syndrome). In contrast, distinct mutations in the gene encoding the sodium channel can cause the entire range of periodic paralysis (hypokalaemic, normokalaemic or hyperkalaemic). The physiological consequences of mutations have been studied with patch-clamp techniques and electromyography. Generally speaking, mutations alter the excitability cycle of the muscle membrane, resulting in a loss of function (paralysis). Electromyographic studies have demonstrated a good correlation between symptoms and physiological parameters, giving rise to a classification that can help orient the molecular diagnosis. Work on the genetics and pathophysiology of periodic paralyses has helped to improve the diagnosis and management of these syndromes. PMID- 19445372 TI - [A new type of periodic paralysis: Andersen-Tawil syndrome]. AB - Andersen-Tawil syndrome includes a clinical triad consisting of periodic paralysis, cardiac arrhythmia, and usually mild but diagnostically useful dysmorphic features. This potassium channelopathy is due to mutation of the KCNJ2 gene encoding the protein Kir 2.1. The main muscular manifestation is periodic paralysis, usually of the hypokalemic type. Muscle biopsy may reveal tubular aggregates or be normal, as in our patient. Cardiac manifestations are variable and may include a long QT syndrome, premature ventricular contractions, complex ventricular ectopy, and polymorphic or bidirectional ventricular tachycardia. Imipramine therapy had a positive effect on arrhythmia in our patient. Dysmorphic features provide a diagnostic clue but may be difficult to identify and should thus be methodically sought. Clinical expression is variable, even within the same family. Since the culprit gene KCNJ2 was identified, locus heterogeneity has been shown in Andersen-Tawil syndrome. Kindreds without KCNJ2 mutations are clinically indistinguishable from those with mutations. Kir2.1 is an inward rectifier K+ channel with important roles in maintaining membrane potential and during the terminal phase of cardiac action potential repolarization. Several studies show a dominant negative effect of KCNJ2 mutation on Kir 2.1 channel function. PMID- 19445373 TI - [MRI and fetal multidetector CT in the diagnosis of fetal malformations]. AB - Prenatal imaging has benefitted from rapid technological progress in the last ten years. Ultrasound remains the standard screening method for fetal malformations but can be hindered by the bony structure of the skull. In particular, it can be difficult to distinguish between white and grey matter. MRI is a useful complementary method for detecting brain malformations. In particular, MRI is necessary to detect associated malformations and to obtain a precise diagnosis when ultrasound examination shows ventricular dilation. MRI is taking an increasingly important place in the assessment and prognostication of extracranial malformations such as congenital diaphagmatic hernia. We reviewed 2885 fetal MRI examinations. Fetal computed tomography is gradually replacing plain maternal abdominal radiography. We examined 90 CT films for fetal bone malformations. PMID- 19445374 TI - [Twin-to-twin transfusion syndrome: diagnosis and treatment]. AB - Multiple pregnancies represent 2% of all pregnancies but account for 20% of admissions to neonatal intensive care units. The outcome of multiple pregnancies is mainly dependent on chorionicity. Most perinatal complications are 3 to 12 times more prevalent in monochorionic pregnancies. The increased mortality and morbidity in this setting are mainly related to vascular anastomoses on the chorionic plate, joining the two fetal circulations. Intrauterine death of a monochorionic twin leads to exsanguination of the survivor, with fatal outcome in 20 to 30% of cases and a similar rate of severe ischemic complications. The most severe and acute complication is the twin-to-twin transfusion syndrome (TTTS). The main clinical manifestations of TTTS are the polyuric polyhydramnios- oliguric oligohydramnios sequence in the recipient and donor twin, respectively. TTTS is associated with a perinatal mortality rate of around 90%, and neurological sequelae are present in 20-40% of survivors born at around 25 weeks. Serial amnioreduction was long the only fetal therapy for TTTS, improving the survival rate to around 50% for at least one twin delivered at around 28 weeks, and reducing the risk of sequelae to around 20% among survivors. We have developed an intrauterine fetoscopic surgical treatment for TTTS. A 2-mm endoscope and a diode laser fiber are introduced percutaneously, under local anesthesia, through a single 3-mm trocard Coagulation of feto-fetal anastomoses on the chorionic plate leads to the survival of at least one twin in around 80% of cases at 33 weeks. Fewer than 10% of survivors have sequelae, mainly related to prematurity. We conducted a randomized controlled trial that confirmed the superiority of laser therapy over amnioreduction. The long-term outlook of these infants is good, with up to 6 years of follow-up. PMID- 19445375 TI - [Antenatal prediction of pulmonary hypoplasia and intrauterine treatment by endoscopic fetal tracheal occlusion in severe isolated congenital diaphragmatic hernia]. AB - Congenital diaphragmatic hernia (CDH) affects one in 2500 to 5000 births and can be detected in utero by means of ultrasound screening Associated structural problems aggravate the prognosis. The survival rate is 70% or more for cases managed in tertiary care centers. The commonest causes of neonatal death in this setting are pulmonary hypoplasia and pulmonary hypertension. Prenatal imaging findings can now accurately predict postnatal outcome, based mainly on ultrasound determination of the lung-to-head ratio and liver position. This information can be used to counsel patients. In severe cases, prenatal intervention can reverse pulmonary hypoplasia. We review current data on prenatal prediction of neonatal survival. We also discuss experimental and clinical data on the benefits of fetal tracheal occlusion. The TOTAL trial (Tracheal Occlusion To Accelerate Lung growth) is currently ongoing in Europe. PMID- 19445376 TI - [Recent developments in fetal surgery. Technical, organizational and ethical considerations]. AB - Progress in prenatal diagnosis has led to more frequent detection of fetal abnormalities which, if left untreated, would be fatal or cause severe disabilities despite optimal postnatal care. Intrauterine surgery is possible in selected cases. Most procedures involve microendoscopy with local or regional analgesia. Fetal analgesia is indicated for procedures that are directly invasive for the fetus. Surgical treatment of twin-to-twin transfusion is so far the only example of successful fetal therapy, as demonstrated in a randomized controlled trial. The most severe forms of congenital diaphragmatic hernia may also benefit from temporary occlusion of the fetal trachea in order to allow lung growth and prevent pulmonary hypoplasia. The future of open fetal surgery will depend partly on the results of the ongoing MOM study of intrauterine coverage of myelomeningocele. These developments also raise ethical questions, including the competence of the surgical team, and the borderline between therapeutic innovation, experimental surgery, and standard of care. The possibility of therapeutic termination should not be overlooked. PMID- 19445377 TI - [Chronic hepatitis B: current therapy]. AB - HBV cannot be fully eradicated from the body because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. True cure is infrequent, but persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Treatment options for chronic hepatitis B include pegylated interferon and 4 licensed oral nucleosides/nucleotides (lamivudine, adefovir entecavir and tenofovir). Interferon is the only drug with a defined duration of treatment. It is effective in 30% to 40% of patients but is poorly tolerated. In contrast to interferon, nucleotide/nucleoside analogs have only minor adverse effects. However, a resurgence of the infection may occur when these drugs are withdrawn, implying that treatment may have to continue indefinitely. The onset of viral resistance to these agents also limits their long-term use but can be minimized by ensuring potent suppression of viral replication. PMID- 19445378 TI - [Medical follow-up, personal experiences and everyday life of young adults after liver transplantation during childhood]. AB - Over the last two decades liver transplantation for children (pLT) with life threatening acute or chronic liver diseases has yielded high long-term success rates. Long-term follow-up of pLT recipients has focused mainly on somatic complications (infections, chronic rejection, biliary problems, cancer occurrence, etc.). Other studies have examined precise aspects of everyday life, and particularly health-related quality of life. In contrast, no global surveys of everyday life, including educational and vocational issues, academic performance, personal feelings and concerns and at-risk behaviors have yet been carried out among adults who received liver grafts during childhood. We conducted a global survey of these young adults' everyday lives. POPULATION AND METHODS: The study was based on a structured questionnaire administered during phone interviews. One hundred sixteen pLT patients managed in a single pediatric liver unit since 1986 were interviewed between April 2005 and July 2006 by the same pediatrician (JPD), who was not involved in their personal medical management. Mean age at interview was 21 +/- 4 (17-33) years; mean age at pLT was 7.0 +/- 4.6 (0.5-16) years; and the mean and median follow-up periods after LT were respectively 13.9 +/- 3.9 years and 15 years. Three-quarters of the patients said they were satisfied with their quality of life and 81% were satisfied with their health status. A significant difference in the age at which LT was performed was found between patients reporting "good or very good" quality of life and patients reporting "neither good nor bad" quality of life (mean age at LT 6.2 +/- 4.1 vs 9.4 +/- 1.4 years; p = 0.0002). Two-thirds of the patients were still attending school. One-third were in age-appropriate school grades, and 31%, 23% and 13% were respectively 1, 2 and 3 years behind. Twenty-five per cent of patients were in paid employment and 12% were unemployed. Reported at-risk behaviors (tobacco and cannabis use) were not more frequent than among these patients' peers, and alcohol consumption was significantly lower (p<0.0001). Strict adherence to medications was reported by only 55% of patients. Concerns about their future health were expressed by 53% of patients. Many patients were reluctant to speak openly to their peers about their LT status. The vast majority of patients wished to discuss personal problems with a physician (quality of life, vocational problems, future health, sexuality, pregnancy), and also wanted more medical information from caregivers. A large majority of young adults transplanted during childhood have good quality of life. Educational level and academic performance are lower than among these patients' peers. This study highlights personal difficulties encountered by a noteworthy proportion of young adults transplanted during childhood. This needs to be taken into account both by pediatricians and by adult medical care providers. PMID- 19445379 TI - [Novel strategies for preventing viral hepatitis C recurrence after liver transplantation]. AB - Hepatitis C virus (HCV) is a major cause of chronic liver disease. About 170 million people worldwide are chronically infected. No preventive or therapeutic vaccine is available. Current antiviral combinations based on pegylated interferon alpha (IFN-alpha) and ribavirin have limited efficacy, poor tolerability and high cost. End-stage liver disease due to chronic HCV infection is a leading indication for liver transplantation (LT). However, re-infection of the liver graft is inevitable, with a high risk of cirrhosis within 5 years. To infect the graft, circulating virions need to attach to and enter hepatocytes, via viral envelope glycoproteins E1-E2. E1-E2 can react with cell receptors despite the presence of neutralizing antibodies. [corrected] A better understanding of the early steps of viral attachment and escape from neutralizing antibodies could lead to novel antiviral strategies. PMID- 19445380 TI - [Event-related potentials and performance errors during falling asleep]. AB - Sound is the most adequate external stimulus for studying information processes in the brain during falling asleep and at different sleep stages. Common procedure of analysis of the event-related potentials (ERPs) averaged for a group of subjects has some drawbacks because of the ERP interindividual variability. Therefore in our work, we determined parameters of the auditory ERP components selectively summed up for individual subjects in different series of a psychomotor test with their subsequent group analysis. Search for the ERP parameters which would allow us to quantitatively estimate brain functional states during performance errors associated with a decrease in the level of wakefulness and falling asleep was the aim of our work. The ERPs were recorded in healthy volunteers (n = 41) in the evening from eight EEG derivations (F3, F4, C3, C4, P3, P4, O1, O2) in reference to a linked mastoid electrode. The analysis was performed in 14 subjects with a sufficient number of falling asleep episodes. A monotonous psychomotor test was performed in a supine position with the eyes closed. The test consisted of two alternating series: calculation of sound stimuli from 1 up to 10 with simultaneous pressing the button and calculation from 1 up to 5 without pressing the button and so on. Computer-generated sound stimuli (50-ms pulses with the frequency of 1000 Hz, 60 dB HL) were presented binaurally through earphones with interstimulus intervals in 2.4-2.7 s. Comparison of the ERP parameters (latency and amplitude of components N1, P2, N, and P3) during correct and erroneous performance of the psychomotor test showed that a decrease in the level of wakefulness caused a statistically significant increase in the amplitude of components of vertex complex N1-P2-N2 in series without pressing the button. The greatest changes in the ERPs in different series of the psychomotor test were observed for component N2 (latency 330-360 ms), which has the common origin with the EEG theta rhythm and is characteristic of the first sleep stage. PMID- 19445381 TI - [Event-related synchronization/desynchronization of cortical theta- and alpha electrical activity and cognitive set to emotionally negative face expression]. AB - Alpha- and theta-band EEG synchronization/desynchronization, induced by the presentation of emotionally negative stimulus (angry faces), was studied in 35 healthy adults. In subjects with a plastic set induced theta-synchronization was greater, and its latency was shorter, than in subjects with a rigid set. This difference is particularly apparent in temporal and parieto-occipital brain regions. A sufficiently high level of theta-synchronization is essential for a quick set-shifting. This synchronization reflects the activity of cortico hippocampal feedback system and its participation in the perception of emotional faces. In subjects with a plastic set this process induces alpha-synchronization, and in subjects with a rigid set--desynchronization. W. Klimesh (2007) suggests, that induced alpha-synchronization reflects processes of inhibition in cognitive activity. This inhibition plays an important role in the set-shifting. The role of tonic and phasic forms of cortex activation, produced by cortico-hippocampal and fronto-thalamic systems, in the shifting of a cognitive set to facial face expression is discussed. PMID- 19445382 TI - [Cortex biopotential coherence changes in men and women during performance of verbal creative task]. AB - Patterns of EEG coherence changes induced by performance of a verbal creative task were studied in 14 male and 13 female university students. EEG coherence was computed for six frequency bands in the range from 4 to 30 Hz. Experiment consisted of two series: in the first series, the task was performed under the instruction "to create sentences", in the second series under the instruction "to create original sentences". Independently of the instruction, coherence reactivity values (data of the experiment minus corresponding baseline data) were negative in the tetal and alpha2 ranges and positive in the beta2 range in all subjects. Sex differences related to the type of instruction were found in changes in the total reactivity values of intrahemispheric coherence (sum of intrahemispheric coherence reactivity values for the all frequency bands studied). The task performance under the instruction "to create original sentences" vs. the task performance under the instruction "to create sentences" was accompanied by changes of the right-hemispheric dominance (i.e. higher values of coherence in the right hemisphere than in the left hemisphere) to the left hemispheric dominance in women and the opposite effect in men. PMID- 19445383 TI - [Comparison of parameters of stress and trait anxiety in teenagers who are brought up in full, incomplete families, and families with the replaced parents]. AB - 166 teenagers in the age of 15-17 years were investigated on the influence of socially adverse conditions of education upon the level of trait anxiety and presence of stress. Teenagers who were brought up in socially unsuccessful conditions (in family with registered cases of alcoholism, violence, suicide, etc.; in family of relatives; with trustees) and also teenagers who were brought up in incomplete families show higher level of trait anxiety (even if initially they have low congenital parameters of neurotism) and more expressed stress both on psychological and physiological level in a greater degree than teenagers from family with mother and stepfather. Teenagers living in family with stepfather have parameters of anxiet similar to teenagers living in complete families. PMID- 19445384 TI - [The dynamics of modification of electrical activity of the rabbit brain during consistent "animal hypnosis" series]. AB - The dynamics of modification of individual rhythms of electrical activity in both hemispheres was studied under condition of chronic experiments in rabbits during "animal hypnosis" sessions. It was shown that, after the first "animal hypnosis" session, significant changes in the spectral power of electrical activity appeared only in the right premotor cortical area. They consisted in an increase in the spectral power of the delta1 and delta2 rhythms and a decrease in the spectral power of the other rhythms. During the next "animal hypnosis" sessions, changes in the electrical activity became stronger, especially in the right hemisphere. Significant changes in the spectral power of the delta and theta rhythms appeared not at the beginning of the "animal hypnosis" session but 4-6 min later. During the third "animal hypnosis" session, the power of the alpha and beta rhythms in the premotor and sensorimotor cortical areas of both hemispheres varied in an undulatory way. PMID- 19445385 TI - [Visual deprivation affects the development of auditory sensitivity during the period of maturation of freezing response in pied flycatcher nestlings]. AB - Recording of evoked potentials (EP) from the higher auditory center of birds field L of the nidopallium was used to study the development of the auditory sensitivity in normally developing vs visually deprived pied flycatcher nestlings aged 6-9 days. The visual deprivation was shown to induce a significant decrease in the absolute auditory EP thresholds in the frequency range of species-typical food call (1-3 kHz) during the period corresponding to the time of the vision involvement into the feeding behavior in the normal young (6 days post-hatching). In the frequency range of species-typical alarm call (4-5 kHz), EP thresholds in visually deprived nestlings were significantly lower than in the control birds during the period corresponding to the time of the vision involvement into the defense behavior of the latter (8-9 days post-hatching). With account made for the previous data demonstrating the decrease of efficiency of acoustic signals provoking freezing in visually-deprived nestlings, it is reasonable to suggest that defense behavior develops not just as a response to alarm call or imitating tone pips, but as a whole system, whose norma maturation and functioning requires integration of numerous factors visual afferentation being one of them. PMID- 19445386 TI - [Involvement of dopamine receptors of different types in formation of latent inhibition of passive avoidance reaction in Wistar rats]. AB - The effect of the intraperitoneal injection of dopaminergic agents on normal and weak latent inhibition of step-through passive avoidance task was studied in rats. Normal latent inhibition was caused by 20-fold preexposure (four times daily) of environmental conditional stimulus before training. For modeling of the weak latent inhibition 10-fold preexposure was used. Effects of D2 agonist quinpirole (1 mg/kg) and selective D1 agonist SKF 38393 (1 mg/kg) injected individually and in combination with haloperidol (0.5 mg/kg) were tested. Quinpirole caused a significant potentiation of the normal latent inhibition (20 fold preexposures) but did not affect the weak latent inhibition. Haloperidol reinforced the weak latent inhibition but reduced the normal latent inhibition. The agent SKF 38393 was not able to affect the latent inhibition independently of the preexposure number. Injected in combination with haloperidol, SKF 38393 prevented the normal latent inhibition from being impaired by haloperidol. These findings suggest that D1 receptors do not appear to participate in the modulation of the latent inhibition as an independent substrate, but D1 receptors are essential for the full manifestation of the D2-mediated modulation of the latent inhibition. PMID- 19445387 TI - [Effect of positive and negative social experiences on sucrose solution intake by male mice]. AB - Hedonic reactions to various rewards play a key role in various forms of motivated behavior. The influence of repeated experience of social victories or defeats in daily agonistic interactions between male mice on voluntary consumption of 1% sucrose solution supplemented with vanillin (0.2%) was studied. Intake of sucrose solution was shown to be decreased in the winners and losers exposed to social confrontations as compared with the controls. Three days of deprivation restored the intake of sucrose solution to the control level in the winners and failed to restore the baseline intake in the losers. The results imply that similar reaction of animals to a hedonic non-drug reinforcer may have different motivational origin depending on positive or negative social experience. PMID- 19445388 TI - [Immobility and hyperthermia in tail suspension test: the association with Porsolt test and startle response in 11 inbred mouse strains, and the effect of MAO A knockout]. AB - The tail suspension test (TST)-induced immobility and hyperthermia and acoustic startle response were studied in 11 mouse inbred strains and in MAO A knockout Tg8 mice. Significant genotypic differences in TST-induced immobility rather than hyperthermia and the lack of correlation between the expression of immobility and hyperthermia were found. Positive genotypic correlation between immobility in the TST and Porsolt test as well as TST-induced immobility and acoustic startle response was shown. Genetic knockout of the main enzyme in serotonin and catecholamines metabolism, MAO A, decreased the startle response and TST-induced hyperthermia but had no effect on TST-induced immobility in Tg8 mice indicating the differences in neurochemical regulation of these TST-induced responses. The results support the validity of the TST as dry-land version of the forced swimming test and draw attention to TST-induced hyperthermia as an animal model of response to uncontrollable, inescapable stress demonstrated in humans. PMID- 19445389 TI - [Involvement of presynaptic 5-HT1A receptors in immunomodulation under conditions of psychoemotional state]. AB - The development of the immune reaction after the activation or blockade of presynaptic 5-HT1A receptors, respectively, with a selective agonist or antagonist depends on specific behavioral patterns. Agonist of 5-HT1A receptors 8 OH-DPAT (0.1 mg/kg 15 min prior to immunization) did not change the number of IgM plaque-forming cells in the spleen of aggressive mice at the peak of the immune response (the 4-th day after immunization) but increased their number in submissive animals, in which the baseline immune response was lower than in aggressive animals. Administration of WAY-100635 (0.1 mg/kg 30 min prior to immunization) resulted in a decrease in the immune reaction in aggressive mice and led to its increase in submissive animals. It is suggested that the immunomodulatory effects of drugs affecting the activity of presynaptic 5-HT1A receptors are related to changes in the functional state of these receptors and the interaction between serotonin- and dopaminergic systems. PMID- 19445390 TI - [Active avoidance learning in rats and morphological changes in the hippocampus after pentylenetetrazole kindling]. AB - The relationship between parameters of active avoidance conditioning and morphological changes in the hippocampus was investigated using pentylenetetrazole kindling animal model of epilepsy. Pentylenetetrazole kindling impaired learning of escape reaction and increased the number of intertrial crossings in a shuttle box during active avoidance conditioning. Kindling decreased the number of neurons in the hippocampal CA1 and CA3 fields and in the dentate gyrus and increased the number of abnormally changed neurons, which displayed cell shrinkage and chromatophilic staining. Negative linear correlations were found between seizure severity and the number of normal neurons in the hippocampus (CA1 and CA3) and dentate gyms in the kindled rats. Positive correlations between the number of damaged neurons and seizure severity were revealed in the CA1 field of the hippocampus and dentate gyrus in the same group. No correlations could be found between the seizure score or behavioral indices in the active avoidance test, or between the indices of the active avoidance learning and the number of undamaged cells in the hippocampus. However, in the control animals, negative correlations were demonstrated between the number of damaged cells in the CA1 and CA3 field and the number of avoidance reactions in the first and last learning sessions. PMID- 19445391 TI - [Effect of the exposure to factors inducing diffuse damage of cerebral tissue on sleep structure in laboratory rats]. AB - Effects of strong stress inducing diffuse damage of the brain tissue on subsequent sleep were studied in rats preliminary implanted with chronic electrodes for the neocortical and hippocampal EEG as well as EMG of the neck muscles. An acute and three chronic experimental models were used: general cerebral ischemia induced by a permanent unilateral occlusion of the common carotid artery, hypoxic hypoxia, hypoglycemia, and "penicillinium" epilepsy. Polysomnographic recording was performed either continuously within 24 hrs (in case of the chronic stress model) or 3 hrs daily: from 09 to 12 a.m. (for three acute stress models). In all the models, a significant increase in the paradoxical sleep (PS) percentage was found which reached its maximum within 1-3 days since stress exposure. The following changes were found to be dependent upon the character of the stress factor. In acute stress models, the PS percentage returned to the baseline level within 5-6 days. In the chronic model, the PS percentage returned to baseline level on the 40-45th day after the day of occlusion. The sharp increase in the PS percentage following the exposure to stress factors inducing cerebral tissue damage corroborate the hypothesis of an increase in neural tissue restitution processes during PS periods. PMID- 19445392 TI - [Post-stress alteration of attractiveness of female mice chemosignals for intact males]. AB - In early period (1-4 day) after exposure to stress, CBA and C57B1/6 female mice excrete (with urine) volatile components (chemosignals) more attractive for intact males of the same strain than excretions of intact females irrespective of the genotype. In later period, attractiveness of excretions of these mice varies in an undulatory way. The difference in attractiveness between compared groups of females disappears within the period of a month after exposure to stress. Comparison of CBA and C57BL/6 strains shows that, within the period of 1-14 days, males prefer syngenic chemosignals (from mice of the same strain). Thus, a post stress reversion of the genotype-dependent female olfactory attractiveness for males was observed. Such kind of attractiveness substantially differs from that in intact mice, for which the male preference to allogenic chemical signals (female mice of the same genotype) is natural. Features of male preference to chemical signals of females after their exposure to stress were demonstrated in direct comparison with the attractiveness of allogenic female signals. The normal chemosignalization is becoming restored from two to three weeks after the exposure to stress. The biological significance of the described phenomenon is discussed. PMID- 19445393 TI - [Effects of chronic fluoxetine treatment on catalepsy and immune response in mice genetically predisposed to freezing reaction: the role of 5-HT1A and 5-HT2A receptors and tph2 and SERT genes]. AB - ASC/Icg (Antidepressant Sensitive Catalepsy) mouse strain selected for high predisposition to pinch-induced catalepsy is characterized by depressive-like behavior and impaired immune response. Chronic treatment with SSRI fluoxetine attenuated catalepsy manifestation and normalized a decreased number of rosette forming cells (RFC) in spleen in ASC mice. Chronic fluoxetine administration had no effect on catalepsy and RFC number in mice of parental cataleptic CBA/Lac strain. Fluoxetine failed to alter 5-HT1A receptor functional activity in mice of both strains and diminished 5-HT2A receptor functional activity in CBA but not in ASC mice. No effect on cortical 5-HT1A and 5-HT2A receptor mRNA levels and on 5 HT1A receptor, tph2 (tryptophan hydroxylase-2) and SERT (serotonin transporter) mesencephalic gene expression was observed in ASC mice. Other possible serotonergic mechanisms of fluoxetine effect on catalepsy and immune response in mice with depressive-like state are discussed. PMID- 19445394 TI - [Efficiency of the "disk-over-water" method without feedback for sleep deprivation in rats]. AB - The "disk-over-water" method, where animals are awakened by disk rotation triggered by sleep EEG signals, was efficiently used in many studies involving sleep deprivation. Recently, the modification of this method has been developed where, during the period of deprivation, the disk was rotated in accordance with a pre-set program (the "disk-over-water" method without feedback). We considered this modification as a potentially promising one for investigation of relationship between maternal sleep and litter development. However, none of these methods has been used in experiments on female rats, and efficiency of the method without feedback has never been tested using electrophysiological estimation of sleep-wake states either. Performing these tasks was the goal of the present study. Cortical EEG, hippocampal theta-activity and locomotor activity were recorded in 14 female Wistar rats underwent sleep deprivation in the "disk-over-water" setup without feedback. Three days long during the deprivation periods from 11:00 to 14:00 the disk was rotated for 8 s with 15 s intervals. REM sleep was totally eliminated during these periods, and amounts of slow wave sleep did not exceed 10% of 3 h. The results were identical both for pregnant and non-pregnant rats. The rate of sleep reduction during deprivation periods in our experimental conditions did not differ from that in the original system with the feedback. Thus the simplified "disk-over-water" method without feedback can be used in the studies involving relatively short sleep deprivation periods. PMID- 19445395 TI - [Cognitive advantages of the third age: a neural network model of brain aging]. AB - We consider a neural network model of age-related cognitive changes in aging brain based on Hopfield network with a sigmoid function of neuron activation. Age is included in the activation function as a parameter in the form of exponential rate denominator, which makes it possible to take into account the weakening of interneuronal links really observed in the aging brain. Analysis of properties of the Lyapunov function associated with the network shows that, with increasing parameter of age, its relief becomes smoother and the number of local minima (network attractors) decreases. As a result, the network gets less frequently stuck in the nearest local minima of the Lyapunov function and reaches a global minimum corresponding to the most effective solution of the cognitive task. It is reasonable to assume that similar changes really occur in the aging brain. Phenomenologically, these changes can be manifested as emergence in aged people of a cognitive quality such as wisdom i.e. ability to find optimal decisions in difficult controversial situations, to distract from secondary aspects and to see the problem as a whole. PMID- 19445396 TI - Healthcare reform: new report sets the stage for changes to come. PMID- 19445397 TI - Reading between the lines: building collaboration with ED clinicians can increase revenue. AB - Steps hospitals can take to enhance their ED billing, coding, and compliance include: Auditing records regularly to ensure ED nurses understand which procedures require specialized documentation. Determining whether assessment criteria would pass a compliance review. Ensuring ED documentation guidelines can be easily used by staff. Maintaining dated copies of revisions to these guidelines. PMID- 19445398 TI - Physician business deals: surveying the new landscape. AB - Strong hospitals and health systems should be on the lookout for opportunities today to acquire physician businesses at depressed fair market values. In some instances, an outright purchase of physicians' interest in a physician-hospital joint venture may be preferable; in others, the hospital may benefit more from simply increasing its interest in the venture. A critical part of the strategy should be taking steps to ensure the physicians remain engaged, including addressing physicians' income goals and need for control. PMID- 19445399 TI - Ensuring affordability of your hospital's strategies. AB - In light of the economic downturn, hospitals must carefully reassess: Capital capacity and position. Feasibilityand impact of improved operating performance. Strategic position and viability of strategic plans. PMID- 19445400 TI - Financial meltdown: key legal issues for healthcare organizations. AB - The economic downturn can lead to many types of legal issues, including: The need to negotiate forbearance agreements. Failure to pay vendors in a timely manner. Difficulty fulfilling charity care policies. The need for salary freezes or staff reductions. Healthcare financial leaders are advised to be familiar with debt/bond documents, track compliance, retain expert counsel, and keep management informed of key issues. PMID- 19445401 TI - The next wave of mergers and acquisitions. What's your organization's position? AB - Review your organization's strategic and financial plan given the current economic erosion and challenges. If your organization can and should be a consolidator, identify the likely and desired opportunities. If your organization cannot or should not go it alone, start to look for a partner. PMID- 19445402 TI - The new wisdom: collaborate with the competition. AB - Potential benefits for hospitals of collaborating with their competition include: Improved quality. Elimination of administrative redundancy. Improved ability to attract talent. Greater access to resources for small and rural hospitals. Greater purchasing power through economies of scale. PMID- 19445403 TI - Anesthesia subsidies: a strategic approach for financial executives. AB - Healthcare financial executives should employ a systematic approach to anesthesia contract negotiations that: Establishes costs and considers alternative options to reduce anesthesia expense. Defines expected value. Aligns compensation Defines performance parameters. Establishes tracking metrics. PMID- 19445404 TI - Finance needs to sit at the head table. PMID- 19445405 TI - Is your organization ready for stimulus? PMID- 19445406 TI - Somewhere to hide. PMID- 19445407 TI - U.S. providers challenged to reduce cost of HAIs. PMID- 19445408 TI - Maternal and infant health. PMID- 19445409 TI - The 25th anniversary of the Surgeon General's Workshop on Breastfeeding and Human Lactation: the status of breastfeeding today. PMID- 19445410 TI - The value and evolving role of the U.S. Poison Control Center System. PMID- 19445411 TI - Emerging disease syndromic surveillance for Hurricane Katrina evacuees seeking shelter in Houston's Astrodome and Reliant Park Complex. AB - Transmission of infectious diseases became an immediate public health concern when approximately 27,000 New Orleans-area residents evacuated to Houston's Astrodome and Reliant Park Complex following Hurricane Katrina. This article presents a surveillance system that was rapidly developed and implemented for daily tracking of various symptoms in the evacuee population in the Astrodome "megashelter." This system successfully confirmed an outbreak of acute gastroenteritis and became a critical tool in monitoring the course of this outbreak. PMID- 19445412 TI - Public health systems and services research: dataset development, dissemination, and use. AB - Public health systems and services research (PHSSR) is defined as "a field of study that examines the organization, financing, and delivery of public health services within communities and the impact of those services." PHSSR is a relatively young field and suffers from a paucity of research resources. In this article, we describe the development and utility of a data resource, housed on the Health Services and Sciences Research Resources website maintained by the National Library of Medicine, which provides easy access to instruments, indices, and datasets that are relevant to PHSSR researchers. We also investigate efforts to promote the use and dissemination of these data resources, including the awarding of research grants and the organization of a PHSSR conference. PMID- 19445413 TI - Assessment of a commercial searchable population directory as a means of selecting controls for case-control studies. AB - We explored the feasibility of using SalesGenie, a commercially available database, as a potential alternative to traditional methods of selecting controls for population-based case-control studies. An attractive feature of this particular database is that it permits a search within specific age ranges, geographic locations, and household income. Information on 1,068 cases reported to the California Cancer Registry between 2001 and 2005 was entered manually into the SalesGenie Web-based search engine. The frequency of Registry-to-SalesGenie matches was then compared with the frequency of matching the registry data to the California Department of Motor Vehicles (DMV) records. Our findings indicate that the SalesGenie database is currently less comprehensive than DMV records. Nevertheless, Web-based population data sources may provide a potential alternative for population-based studies when used in conjunction with other methods, particularly in states where DMV records are not accessible to researchers. PMID- 19445414 TI - Multivitamin use in pregnant and nonpregnant women: results from the Behavioral Risk Factor Surveillance System. AB - OBJECTIVE: Relatively few studies have investigated characteristics associated with multivitamin use in pregnant women in the U.S. We examined multivitamin use among pregnant and nonpregnant women of childbearing age, in relation to socioeconomic factors, demographic data, health behaviors, and health status. METHODS: This investigation used 2004 data from the Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional study of noninstitutionalized adults aged 18 years or older. Analyses were limited to women 18 to 44 years of age in states and territories where questions about multivitamin use were asked. RESULTS: Overall, 78% of pregnant women reported multivitamin use, compared with 47% of women who were not pregnant. Using logistic regression, two factors were found to be significantly associated with multivitamin use in pregnant women: income and marital status. Among nonpregnant women, the significant predictors were age, income, physical activity, education level, desire for a child in the near future, race/ethnicity, body mass index, and cigarette smoking status. CONCLUSION: We found differences in the reported use of multivitamins between pregnant and nonpregnant women of childbearing age as well as predictors of use. PMID- 19445415 TI - The challenge of multisite epidemiologic studies in diverse populations: design and implementation of a 22-site study of tuberculosis in foreign-born people. AB - OBJECTIVES: We designed a population-based study of the epidemiology of tuberculosis among foreign-born people in the U.S. and Canada. Challenges included standardizing recruitment and data entry at 22 sites, enrolling individuals who did not speak English and may be undocumented, and obtaining clearance from 36 institutional review boards (IRBs). METHODS: We used stratified sampling to recruit patients through the Tuberculosis Epidemiologic Studies Consortium, a research consortium funded by the Centers for Disease Control and Prevention. Because recruitment sites were overseen by more than 30 local IRBs, we developed a simple process to designate a central IRB. We translated instruments into 10 main languages, arranged for fast translation of consent "short forms" into other languages, used one telephone interpretation service at all sites, and provided extensive interviewer training including mock interviews with simulated patients. RESULTS: We interviewed 1,696 participants in 19 states and provinces. Participants from 99 countries were interviewed in 40 languages. Twenty-three percent did not speak English at all; 64% needed an interpreter. More than 20% of participants reported they were undocumented. Participants' age, gender, and birthplaces were broadly similar to the target populations. One-third of local IRBs used the central IRB. CONCLUSIONS: Special confidentiality protections, substantial resources for translation and interpretation, and a centralized IRB made possible the recruitment of a representative sample of foreign-born people. The approaches may be applicable to studies of other diseases in multinational populations in the U.S. and Canada. PMID- 19445416 TI - HIV testing and referral to care in U.S. hospitals prior to 2006: results from a national survey. AB - OBJECTIVES: We sought to provide a benchmark for human immunodeficiency virus (HIV) testing availability and practices in U.S. hospitals prior to the Centers for Disease Control and Prevention's (CDC's) 2006 revised recommendations. METHODS: We conducted a survey of nonfederal general hospitals in the U.S. in 2004. Chi-square tests detected significant associations with hospital characteristics. Questionnaires were completed electronically via a secure Internet site or on paper. Nonresponse analysis was conducted and data were weighted to adjust for nonresponse. RESULTS: HIV testing (on the basis of clinical symptoms or behavioral risk factors) was available in more than half of hospital inpatient units (62%), employee health departments (58%), and emergency departments (57%). Twenty-three percent offered routine screening (testing for people in a defined population regardless of clinical symptoms or behavioral risk), most commonly in labor and delivery. Teaching status, region, size, and type of metropolitan area were associated with the availability of HIV testing and routine screening (p<0.01). Hospitals used a variety of methods to link patients to care: referral to a hospital-based clinic (36%); on-site, same-day evaluation (35%); and referral to an unaffiliated HIV or community clinic (42%). CONCLUSIONS: Hospitals offered HIV testing on the basis of clinical suspicion or risk, but were far from meeting CDC's current recommendation to routinely test all patients aged 13 to 64. Hospital size, teaching status, and geographic location were associated with HIV testing availability and testing practices. Our understanding of current practice identifies opportunities for public health action at the practitioner, organization, and systems levels. PMID- 19445417 TI - ATV and bicycle deaths and associated costs in the United States, 2000-2005. AB - OBJECTIVE: We determined the rate and costs of recent U.S. all-terrain vehicle (ATV) and bicycle deaths. METHODS: Fatalities were identified from the National Center for Health Statistics Multiple Cause-of-Death public-access file. ATV and bicycle deaths were defined by International Classification of Diseases, 10th Revision codes V86.0-V86.9 and V10-V19, respectively. Lifetime costs were estimated using standard methods such as those used by the National Highway Traffic Safety Administration. RESULTS: From 2000 through 2005, 5,204 people died from ATV crashes and 4,924 from bicycle mishaps. A mean of 694 adults and 174 children died annually from ATV injuries, while 666 adults and 155 children died from bicycle injuries. Death rates increased among adult ATV and bike riders and child ATV riders. Males had higher fatality rates for both ATVs and bicycles. Among children, total costs increased 15% for ATV deaths and decreased 23% for bicycle deaths. In adults, ATV costs increased 45% and bike costs increased 39%. CONCLUSIONS: Bicycle- and ATV-related deaths and associated costs are high and, for the most part, increasing. Promotion of proven prevention strategies, including helmet use, is indicated. However, enforcement of helmet laws is problematic, which may contribute to observed trends. PMID- 19445418 TI - Risk factors for mumps at a university with a large mumps outbreak. AB - OBJECTIVES: Routine measles-mumps-rubella (MMR) vaccine use has greatly decreased the incidence of mumps in the U.S. However, a resurgence of mumps occurred in 2006. We investigated the large outbreak at a university and assessed risk factors for disease. METHODS: We described the outbreak and conducted a case control study. We interviewed case students (identified from student health service and health department records) and control students (selected from a randomly ordered administrative list) and assessed their vaccination status. We compared case students with > or = 2 MMR doses and control students with > or = 2 MMR doses in univariate and multivariate analyses. RESULTS: The mean age of the 174 case students was 20.9 years; 65% were women. Ninety-seven case students and 147 control students were enrolled in the study. Two-dose MMR coverage was 99% among case and control students with complete records. Only 33% of case students reported exposure to someone with mumps. Case students were more likely than control students to be aged 18 to 19 years (vs. aged 22 years, adjusted odds ratio [AOR] = 5.55; 95% confidence interval [CI] 2.09, 14.74), to report exposure to mumps (AOR=2.31, 95% CI 1.13, 4.73), and to have worked/volunteered on campus (AOR=2.91, 95% CI 1.33, 6.33). Also, women in dormitories had increased odds of mumps compared with men in dormitories. CONCLUSION: High two-dose MMR coverage was not sufficient to prevent the outbreak. Further study is needed to better understand the effects of dormitory residency and gender on mumps transmission. Clinicians should be vigilant for mumps in young adults presenting with parotitis regardless of immunization history. PMID- 19445420 TI - Do obese adults have a higher risk of asthma attack when exposed to indoor mold? A study based on the 2005 Behavioral Risk Factor Surveillance System. AB - OBJECTIVE: Some studies show an association between asthma and obesity, but it is unknown whether exposure to mold will increase the risk of asthma attacks among obese people. This study examined whether obese adults have a higher risk of asthma attacks than non-obese adults when exposed to indoor mold. METHODS: We used data from the 2005 Behavioral Risk Factor Surveillance System to conduct a cross-sectional analysis among 9,668 respondents who reported exposure to indoor mold. RESULTS: With exposure to indoor mold, weighted prevalence of asthma attacks among obese respondents was 11.4% (95% confidence interval [CI] 6.0, 20.6], which was 2.3 times as high as among the exposed non-obese respondents (5.0%, 95% CI 2.8, 8.8). This ratio was almost the same as the ratio of 2.0:1 between the obese respondents (5.7%, 95% CI 4.6, 7.2) and the non-obese respondents (2.8%, 95% CI 2.3, 3.9) when neither group had exposure to mold. The odds ratio of asthma attack among obese people was 3.10 (95% CI 1.10, 8.67) for those with exposure to mold and 2.21 (95% CI 1.54, 3.17) for those without exposure to mold after adjusting for age, sex, race/ethnicity, and smoking status. CONCLUSION: Our study suggests that obese adults who have been exposed to indoor mold may not necessarily have a higher risk of asthma attack than obese adults who have not been exposed, even though obesity and exposure to indoor mold are both major risk factors for asthma attack. Medical professionals should not only incorporate weight-control or weight-reduction measures as the components of asthma treatment plans, but also advise asthma patients to avoid exposure to indoor mold. PMID- 19445419 TI - Community-associated methicillin-resistant Staphylococcus aureus: trends in case and isolate characteristics from six years of prospective surveillance. AB - OBJECTIVES: In 2000, the Minnesota Department of Health (MDH) implemented active, sentinel site surveillance for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Data from 2000-2005 were analyzed to determine trends in case characteristics, pulsed-field types (PFTs), and antimicrobial susceptibilities including inducible clindamycin resistance (ICR). METHODS: Active sentinel site surveillance was initiated in 2000 at 12 hospital laboratories that served inpatients and outpatients. Patient medical records were reviewed to determine if they met the epidemiologic case criteria for CA-MRSA; isolates were obtained from patients meeting these criteria. The MDH Public Health Laboratory performed pulsed-field gel electrophoresis subtyping and antimicrobial susceptibility testing, including ICR. RESULTS: The proportion of MRSA cases classified as CA increased from 11% to 33% (p<0.01). The proportion of cases with skin or soft tissue infections also increased compared with other infection types from 75% to 87% (p<0.01). During the surveillance period, USA300 replaced USA400 as the dominant PFT. With the change in dominant PFT, the proportion of isolates susceptible to erythromycin (45% to 13%, p<0.01) and ciprofloxacin (80% to 59%, p<0.01) decreased. The proportion of erythromycin resistant/clindamycin-susceptible isolates with ICR (93% to 14%, p<0.01) decreased. The proportion of susceptible isolates also changed within the USA300 PFT; the proportion of isolates susceptible to erythromycin (33% vs. 3%) and the proportion susceptible to ciprofloxacin (67% to 62%) decreased significantly. CONCLUSION: CA-MRSA increased dramatically from 2000 to 2005. Changes in the predominant PFT have impacted susceptibility profiles of CA-MRSA, including ICR. Continued surveillance is needed to monitor the changing epidemiology of CA-MRSA and to inform clinical decisions. PMID- 19445421 TI - Use of insurance claims data to determine prevalence and confirm a cluster of sarcoidosis cases in Vermont. AB - OBJECTIVES: In 2006, the Vermont Department of Health was asked to respond to a potential cluster of sarcoidosis cases related to a Vermont office building. Sarcoidosis prevalence has not been formally described for the United States. A range of < 1-40/100,000 is commonly reported; however, we have not identified primary sources supporting this conclusion. Because of the wide prevalence range and lack of a local estimate, confirming existence of a cluster was difficult. METHODS: We ascertained the prevalence of sarcoidosis cases in Vermont by using insurance claims data to determine whether or not a cluster of sarcoidosis cases was related to the office building. We calculated county and state annual prevalence proportions for sarcoidosis for 2004 and 2005 and annual building prevalences for 1992-2006. RESULTS: The pooled sarcoidosis case prevalence for Vermont was 66.1/100,000. The pooled building annual prevalence (1,128/100,000) was statistically different from the county in which the building is located (odds ratio = 15.5, 95% confidence interval 3.0, 50.3). CONCLUSIONS: We reported the first statewide sarcoidosis prevalence in the United States. This prevalence exceeded previous limited and unsubstantiated U.S. reports. Even with Vermont's elevated sarcoidosis prevalence, the presence of a cluster in this building was apparent. PMID- 19445422 TI - Children with orofacial clefts: health-care use and costs among a privately insured population. AB - OBJECTIVES: Orofacial clefts are common birth defects that often require multiple surgeries and medical treatments during childhood. We used healthcare insurance claims data to estimate health-care expenditures for infants and children < or = 10 years of age with an orofacial cleft. METHODS: The data were derived from the 2000-2004 MarketScan Commercial Claims and Encounters databases, which include person-specific information on health-care use, expenditures, and enrollment for approximately 50 large employers, health plans, and government and public organizations. Health insurance claims data from 821,619 children < or = 10 years of age enrolled in employer-sponsored plans during 2004 were analyzed. Expenditures for inpatient admissions, outpatient services, and prescription drug claims were calculated for children with and those without an orofacial cleft. RESULTS: The difference in annual mean costs (i.e., incremental costs) between children aged 0 through 10 years with an orofacial cleft and those without an orofacial cleft was $13,405. The mean and median costs for children < or = 10 years of age with an orofacial cleft were eight times higher than for children of the same age without an orofacial cleft. Mean costs for infants with a cleft and another major, unrelated defect were 25 times higher than those for an infant without a cleft, and five times higher than for infants with an isolated cleft. CONCLUSION: These findings document substantially elevated medical care costs for privately insured children with an orofacial cleft. Additional study of the economic burden associated with this condition should include a broader range of economic costs. PMID- 19445423 TI - Perinatal hepatitis B prevention: adapting Public Health Services to meet the changing needs of a diverse community. PMID- 19445424 TI - Major components and themes of local public health laws in select U.S. jurisdictions. PMID- 19445425 TI - Border Health 2012: binational collaboration to develop an outreach environmental educational program. PMID- 19445426 TI - OpenEpi: a web-based epidemiologic and statistical calculator for public health. PMID- 19445427 TI - Adults with disabilities are aging. PMID- 19445428 TI - A prescription for personnel management. PMID- 19445429 TI - Stem cell research: regenerating the skeleton and craniofacial complex. PMID- 19445430 TI - Where are the next generations of health promotion leaders and what are you doing to help them grow? PMID- 19445431 TI - Understanding screen-related sedentary behavior and its contributing factors among school-aged children: a social-ecologic exploration. AB - PURPOSE: To explore the factors that contribute to children's screen-related sedentary (S-RS) behaviors. SETTINGS: Elementary schools. SUBJECTS: A random sample of children in grades five and six and their parents. MEASURES: The outcome measure was children's S-RS activity level measured by a self administered questionnaire. A full spectrum of potential contributing factors for children's S-RS behaviors was obtained through surveys. Multilevel linear regression methods were used to determine the associations between these factors and children's screen time (hours per day) and results were expressed as regression coefficients (g). RESULTS: Of 955 child-parent pairs in 14 participating schools, 508 pairs (53%) completed the surveys. At an intrapersonal level, protective factors included being a girl (g = -.71); belonging to a sports team inside (g = -.56) or outside (g = -.49) of school; having a negative attitude toward S-RS activities (g = -.13); and having a positive attitude toward physical activity (g = .48). At the interpersonal and social levels, parental leisure S-RS behaviors (g = .32) were positively associated, whereas strict parental rules on computer use (g = -.27) and family income (g = -.32) were inversely correlated with S-RS behavior. At the environmental level, the presence of TVs in children's bedrooms (g = .44) and owning videogame devices (g = .58) increased the risk of S-RS behaviors, whereas after school programs (g = - .86) and schools' participation in the Turn Off the Screen Week campaign (g = -.91) decreased the risk. CONCLUSIONS: Public health interventions should target multilevel factors, including increasing children's awareness, promoting parental involvement in healthy lifestyle pursuits, and creating less screenogenic environments. PMID- 19445432 TI - Safety of strength training in premenopausal women: musculoskeletal injuries from a two-year randomized trial. AB - PURPOSE: The health benefits of strength training must be weighed against risks, including injuries. A prior study observed 4.2 injuries that limited usual activities for a day per 1000 strength training sessions among men and women. The analysis herein explores the incidence rates of musculoskeletal injuries from strength training in women. DESIGN: Randomized controlled trial. SETTING; Free living community. SUBJECTS: A total of 163 injury-free, overweight, sedentary, premenopausal women aged 25 to 44 years. INTERVENTION: Two years of strength training (n = 81) or standard care (n = 82). The intervention followed published guidelines (U.S. Department of Health and Human Services) with hypothesized injury prevention strategies. MEASURES: An injury survey was administered at years 1 and 2. Injury was defined as physical activity or strength training associated injuries that limited daily activities for 1 week or more. Denominators for rate calculation were accelerometer-measured physical activity and strength training attendance (strength training only). The between-group probability of injuries was assessed using generalized estimating equations. RESULTS: Injury incidence rates were higher in strength training compared with standard care. In strength training, the injury rates were 3.6 per 1000 strength training sessions (95% confidence interval: 2.5-4.8 per 1000) for physical activity-related injuries, and 2.6 per 1000 (95% confidence interval: 1.5-3.6 per 1000) for strength training-related injuries. CONCLUSIONS: Injury rates varied by definition and denominator. Strength training had lower injury rates than previously reported, providing preliminary support for the prevention strategies. The finding of strength training injuries underscores the need for balancing the benefits against the potential risks of this exercise modality. PMID- 19445433 TI - School performance, lack of facilities, and safety concerns: barriers to parents' support of their children's physical activity. AB - PURPOSE: To identify barriers to parents' support of their children's physical activity (PA) and to develop a survey to assess such barriers. METHODS: Eighty two parents (40 white; 36 African-American; 6 other) of elementary school-aged children participated in small-group interviews. Parents reported barriers to supporting their children's PA and suggested possible solutions. This information was used to develop the Barriers to Activity Support Scale (BASS), which was completed by 75 of the 82 parents along with a survey that assessed the parents' support for their children's PA. RESULTS: Parents reported community-based, interpersonal, and intrapersonal barriers to supporting their children's PA. Top barriers included the importance of children's school performance, a lack of facilities, and concerns about safety. Parents who reported greater barriers reported lower support for their children's PA. DISCUSSION: Results provide preliminary evidence for the reliability and validity of the BASS and highlight the need to address barriers during the development of family-based PA programs. PMID- 19445434 TI - A brief intervention designed to increase breast cancer self-screening. AB - PURPOSE: To assess the efficacy of an intervention designed to increase appropriate use of breast self-examination (BSE). METHODS: Two-armed randomized clinical trial of cancer-control interventions in women that compared a BSE intervention program to a dietary intervention, which served as the control group. The study was conducted at a large health maintenance organization in Portland, Oregon. Participants were 616 female members of the health maintenance organization who were aged 40 to 70 years. The intervention consisted of a 30- to 45-minute individual counseling session that featured BSE instruction, training and practice with silicone models, identification of barriers to BSE, and problem solving. This intervention was followed by two brief follow-up telephone calls. The study outcome measure was self-reported BSE practice, which included duration, frequency, and specific elements of exam. RESULTS: The study had a 90% response rate. At the 1-year follow-up, chi2 analyses showed that significantly more individuals in the BSE intervention (59%) reported adequate BSE performance compared with those in the control group (12.2%; p < .001). CONCLUSIONS: This brief intervention was successful in encouraging women to perform adequate BSEs. Although the role of the BSE in patient care remains controversial, these results show that even brief intervention programs can be effective at encouraging self screening for cancer. This intervention could easily be modified to target other screening practices (e.g., skin or testicular cancer screening) that are associated with reduced cancer morbidity and mortality. PMID- 19445435 TI - Process evaluation results from the Eating for a Healthy Life study. AB - PURPOSE: Conduct a process evaluation of a low-fat, high-fruit/vegetable dietary intervention in religious organizations (ROs). The purpose of this process evaluation was to explore differences in healthy eating activities between the intervention and delayed control ROs and among the intervention ROs to identify the intervention activities most associated with dietary change. METHODS: Process data were collected via phone surveys and participation logs. A 12-month follow up phone survey was conducted with an RO representative from intervention and delayed control ROs. The survey asked about healthy eating activities. Eating for a Healthy Life staff maintained participation logs of intervention RO participation in intervention activities: advisory board meetings, volunteer activities, healthy eating sessions, social events, dietary change mailings, print advertisements, and motivational messages. We used a stepwise regression model to determine which intervention activities were associated with changes in fat- and fiber-related dietary behaviors. RESULTS: RO member participation in advisory board meetings, social activities, and healthy eating sessions were associated with healthier fat- and fiber-related dietary behaviors. Greater RO attendance at advisory board meetings and greater numbers of healthy eating sessions at the RO were associated with decreased fat-related dietary behaviors (p < or = .05). Member participation in social activities was associated with more favorable fat, fruit, and vegetable intake. CONCLUSION: We successfully delivered an increased number of healthy activities at the intervention ROs and improved dietary-related behaviors. PMID- 19445436 TI - Treatment for tobacco dependence for rural, lower-income smokers: outcomes, predictors, and measurement considerations. AB - PURPOSE: Outcomes from a statewide program that delivered evidence-based, intensive treatment for tobacco dependence to a rural population of lower socioeconomic status (SES) were evaluated. Factors that predicted success and measurement considerations were examined. DESIGN AND ANALYSES: Data were collected at intake, at all treatment sessions, and at 3- and 12-months posttreatment. Abstinence rates were calculated using complete-case analysis and intention-to-treat analysis, and they were estimated for all participants. Logistic regression was used to evaluate the predictive significance of demographic and clinical factors. SETTING: Twenty health care sites across Arkansas. PARTICIPANTS: A total of 2,350 predominantly rural, lower SES, Arkansas residents. INTERVENTION: Evidence-based, six-session, multi-component cognitive behavioral therapy with relapse prevention. RESULTS: The estimated percent abstinent was 26.47% at 3-months and 21.73% at 12-months posttreatment; 51.02% of patients completed treatment and demonstrated markedly higher quit rates. Although numerous factors predicted outcomes at different points, self-efficacy and dependence levels at intake were robust predictors across time and methods of calculating outcomes. Sex, partner smoking status, and educational level were significant predictors of long-term abstinence. CONCLUSIONS: This study demonstrates that intensive, evidence-based treatment for tobacco dependence can be successfully delivered in a statewide program and can yield long-term outcomes that approximate those seen in more controlled settings. Overall sample estimates may be more appropriate for the assessment of outcomes in this context. PMID- 19445437 TI - Risk perception and its association with cardiac risk and health behaviors among urban minority adults: the Bronx Coronary Risk Perception study. AB - PURPOSE: Examine the relationship among risk perceptions, health behaviors, and a measure for actual risk of coronary heart disease (CHD). DESIGN: Cross-sectional survey. SETTING/SUBJECTS: Adults from three outpatient medical clinics with at least one CHD risk factor. MEASURES: Perceived risk using the new Coronary Risk, Individual Perception (CRIP) scale, an index of CHD risk, and summary scores for self-reported diet and exercise. ANALYSIS: Bivariate associations using Spearman rank and Kruskal-Wallis; multiple regression models for outcomes (health behaviors). RESULTS: The 16-item CRIP scale had acceptable internal consistency (alpha = 0.76; interitem total correlation = 0.34 +/- 0.17). The response rate was 80.3%, and the mean age of 256 respondents was 56.6 (+/- 9.9) years; 70% were women, 63% Hispanic, and 27% black. CRIP scores were inversely associated with low fat/high fiber intake (r = - 0.17; p = .007) and exercise (r = -0.19; p = .003). Among respondents with three or more CHD risk factors (n = 132), 44% perceived themselves to be at low risk for CHD. In multivariable models, men with high CRIP scores had higher fat intake than women (p = .02), but men exercised more (p = .04). CONCLUSIONS: In this study, gender moderated the relationship between risk perception and health behaviors, and many respondents underestimated their risk of CHD. Behavioral intervention research aimed at reducing cardiometabolic risk in minority populations should resolve differences between perceived and actual risk of CHD to foster lifestyle changes and examine temporal relationships between risk perception and health behaviors. PMID- 19445438 TI - The role of incentive design, incentive value, communications strategy, and worksite culture on health risk assessment participation. AB - PURPOSE: To examine the impact of financial incentives, communications strategy, and worksite culture on health risk assessment (HRA) participation rates. DESIGN: A cross-sectional study design was used to examine factors that influence employee participation, including incentive value, incentive design, communications strategy, and worksite culture. SETTING: Large private-sector and public-sector employers. PARTICIPANTS: Thirty-six employers (n = 559,988 employees) that provided financial incentives to promote employee HRA participation. INTERVENTION: Organizations implemented the HRA as part of a more comprehensive worksite health promotion strategy that included follow-up interventions and a variety of other components. The primary outcome of interest was employee HRA participation. MEASURES: Information on program design and structure, as well as on HRA eligibility and participation, was collected for each organization via standard client report and semistructured interviews with account managers. General linear regression models were used to examine the extent to which factors influence HRA participation independently and when controlled for other factors. RESULTS: Incentive value (r2 = .433; p < .000), benefits-integrated incentive design (r2 = .184; p = .009), culture (r2 = .113; p = .045), and communications strategy (r = .300; p = .001) had positive bivariate associations with HRA participation rates. When all factors were included in the model, incentive value (p = .001) and communications strategy (p = .023) were significantly associated with HRA participation. Variance accounted for by all factors combined was R12 = .584. CONCLUSION: This study suggests that incentive value, incentive type, supportive worksite culture, and comprehensive communications strategy may all play a role in increasing HRA participation. PMID- 19445440 TI - Bringing wellness to the small employer. AB - Historically the predominant models of programming have evolved from mid to large size employer settings. Yet the majority of employees in any given community work for organizations that employ fewer than 500 employees. These small employers also constitute a disproportionate majority of all employers. Wellness practitioners need to develop programming models and strategies that are designed specifically for these small employer organizations. This article establishes a perspective for bringing wellness to the small employer based on recent research and considering the implications of the differences between small and large employers from a programming perspective. Finally, several anticipated aspects of future programming are described along with summary conclusions. PMID- 19445439 TI - Impact of obesity on work productivity and role disability in individuals with and at risk for diabetes mellitus. AB - PURPOSE: Evaluate work absence, work productivity, and disruption of work, social, and family life among individuals of varying body mass index (BMI) with or at risk for diabetes mellitus. DESIGN: Cross-sectional analysis of survey data. SETTING: Community-based U.S. population. SUBJECTS: Respondents (n = 15,132; n = 7338 working adults) participating in the U.S. Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) study were stratified by combinations of BMI (i.e., > or = 30 kg/m2 [obese], 25 to 29.9 kg/ m2 [overweight], and < 25 kg/m2 [normal weight]) and diabetes (i.e., type 2 diabetes mellitus [T2DM], type 1 diabetes mellitus [T1DM], and high risk [HR] or low risk [LR] of T2DM). MEASURES: Work impairment was measured using the Work Productivity and Activity Impairment Questionnaire: General Health. Disruption in life was measured using the Sheehan Disability Scale. HR was defined as 3 to 5 of the following factors: abdominal obesity, BMI > or = 28 kg/m2, reported diagnosis of "cholesterol problems,"reported diagnosis of "hypertension, "or history of coronary heart disease or stroke. LR was defined as < or = 2 of these factors. RESULTS: Percentage of work impairment and proportion with severe disruption of work, family, and social life increased systematically from normal weight to obese (p < .001). Obese individuals had the greatest impairment at work (11%-15% of work time), greatest impairment of daily activities (20 %-34% of time), and greatest overall impairment (11%-15% of time) in the LR, HR, and T2DM groups. Obesity and T2DM were independent predictors of overall work impairment and life disruption (p < .001). Between 5% and 7% of total variance was explained in the regression models with BMI category, diabetes/risk group, age, gender, race, income, and household size as variables. CONCLUSION; Greatest impairment of work and daily activities was evident among obese individuals for all groups. PMID- 19445441 TI - Allergic bronchopulmonary aspergillosis: Indian perspective. PMID- 19445442 TI - Computed tomography in blunt chest trauma. AB - OBJECTIVE: To assess the role of multidetector spiral CT in patients with blunt chest trauma. METHODS: Forty-two patients (38 males and four females), age range from 6 to 80 years, of blunt chest trauma were evaluated with multidetector computed tomogram (MDCT) after initial radiographs and the results were tabulated. RESULTS: The most common mode of injury was motor vehicle accidents (64%). On computed tomography (CT), major injuries were haemothorax (83.33%), consolidation (66.6%), rib fractures (61.90%), pneumothorax (54.76%), diaphragmatic injury (30.95%), lung contusions (28.57%), spinal injury (16.66%), lacerations (9.52%), tracheo-bronchial injury (4.76%), mediastinal haematoma (4.76%), thoracic-aortic injury (4.76%) and oesophageal injury (2.38%). Operative intervention was performed in 11 (26.19%) patients. Of these, diaphragmatic rent repair was done in seven patients (63.63%), exploratory laparotomy alone was done in two (18.18%) and resection and anastomosis and polytetrafluoroethylene graft in one patient each. Three patients each with chest wall injury, thoracic vascular injury and diaphragmatic injury died; while only one patient with lung injury died. CONCLUSION: Multidetector computed tomogram is the modality of choice for rapid assessment of emergency chest trauma patients. PMID- 19445443 TI - Effect of tripod position on objective parameters of respiratory function in stable chronic obstructive pulmonary disease. AB - OBJECTIVE: To examine changes in respiratory dynamics in patients with chronic obstructive pulmonary disease (COPD) sitting leaning forward with hands supported on the knees (tripod position), a posture frequently assumed by patients in respiratory distress. METHODS: Spirometry, maximal inspiratory and expiratory pressures (MIP and MEP) generated at the mouth, and diaphragmatic excursion during tidal and vital capacity maneuver breathing measured by B-mode ultrasonography were studied in 13 patients with stable COPD in sitting, supine and tripod positions. RESULTS: Mean +/- SD age of patients was 52.2 +/- 6.8 years. Median disease duration was three years. There was no statistically significant difference in spirometry for sitting, supine and tripod positions (FEV1: 1.11 +/- 0.4L, 1.14 +/- 0.5L and 1.11 +/- 0.4L; p = 0.99), respectively, (FEV1/FVC: 49.2 +/- 11.0, 53.7 +/- 8.5 and 48.5 +/- 11.3, p = 0.37), mouth pressures (MIP: 102.9 +/- 28.9, 90.6 +/- 29.1 and 99.2 +/- 32.9 cm H2O, p = 0.61 and MEP: 100.8 +/- 29.9, 100.4 +/- 34.4 and 90.6 +/- 32.6 cm H2O, p = 0.74) and diaphragmatic movements during tidal (16.1 +/- 5.9, 20.1 +/- 6.8 and 16.6 +/- 6.2 mm, p = 0.22) and forced breathing (33.9 +/- 11.0, 43.1 +/- 19.6 and 37.4 +/- 17.1 mm, p = 0.35). CONCLUSION: Commonly measured indices of respiratory function were not different in the tripod compared to sitting and supine positions. PMID- 19445444 TI - Assessment of pulmonary function in amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by diffuse and progressive death of motor neurons and deteriorating pulmonary functions. At diagnosis most patients with ALS usually do not have any respiratory complaints. However, sub-clinical pulmonary dysfunction is known. OBJECTIVE: To study pulmonary dysfunction in patients who clinically and electro-physiologically fulfil El escorial criteria of probable and definite ALS. METHODS: We performed a standard battery of pulmonary function tests (PFTs) including spirometry, maximum voluntary ventilation (MVV) and maximum inspiratory and expiratory pressure (MEP, MIP) on 63 patients fulfilling the El escorial criteria for probable and definite ALS. Results were compared between the El escorial groups, bulbar- and limb-onset ALS and with age- and sex-matched healthy volunteers, taken as controls. RESULTS: Only 11% of the patients had respiratory complaints at diagnosis. There was no statistical difference in pulmonary parameters between bulbar- and limb-onset ALS. The pulmonary dysfunction was restrictive. Both definite and probable ALS patients had significant reduction in all the measured pulmonary function parameters. The reduction in definite ALS patients was greater in forced vital capacity percent (FVC%) predicted, peak expiratory flow rate (PEFR) percent predicted and MIP. The proportion of patients with severe and very severe dysfunction was higher in the definite ALS group as compared to probable ALS group. CONCLUSIONS: Significant pulmonary dysfunction of restrictive type was noted in ALS patients. Both types of ALS, bulbar- and limb-onset, had similar levels of dysfunction. PMID- 19445445 TI - Pulmonary manifestations of primary Sjogren's syndrome. AB - Sjogren's syndrome (SS) is a complex autoimmune exocrinopathy with multifactorial pathogenesis and multisystem manifestation. It is called primary Sjogren's syndrome (PSS) when the manifestations are seen without any other co-existent rheumatic diseases. The incidence of respiratory system involvement varies widely in the reported medical literature, partly due to lack of a universal agreement over the diagnostic criteria of the disease and the type of study methods employed. Respiratory system manifestations are protean; upper airway symptoms are very common and so is the complaint of dry cough. The PSS patients may develop interstitial lung diseases (ILDs) such as usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), lymphocytic interstitial pneumonia (LIP), bronchiolitis obliterans and organising pneumonia (BOOP), etc. They may also develop the whole spectrum of lymphoproliferative disorders of the lung ranging from LIP to follicular bronchiolitis, nodular lymphoid hyperplasia and low-grade lymphomas. Therapeutic options include symptomatic and supportive measures and corticosteroids as the mainstay of the treatment for ILDs occurring in these patients. In recent years, rituximab (anti-CD20) has emerged as a promising treatment for this disease, though data from controlled trials are still lacking. Pulmonary involvement may be a source of significant morbidity in these patients, though only rarely, it is the cause of death. PMID- 19445446 TI - Radiation dose escalation by percutaneous interstitial brachytherapy in locally advanced non-small cell lung cancer. AB - Management of locally advanced non-small cell lung cancer is associated with a poor overall survival using concurrent chemoradiotherapy. Therefore, newer approaches to treatment which enable dose escalation are warranted. Interstitial brachytherapy in lung is a new emerging concept with many distinct advantages. We report here a case of locally advanced non-small cell lung cancer with residual disease after conventional treatment. The patient was successfully treated using percutaneous interstitial brachytherapy and is disease-free at 18-month follow up. PMID- 19445447 TI - Endobronchial non-Hodgkin's lymphoma presenting as mass lesion. AB - A 40-year-old male presented with clinical and radiological manifestations of right lung atelectasis and post-obstructive pneumonia. Flexible bronchoscopy revealed gross narrowing of the right upper lobe bronchus and a smooth, white endobronchial mass completely occluding the right lower lobe bronchus. Endobronchial biopsy from the mass lesion yielded low grade B-cell non-Hodgkin's lymphoma. This is one of the rarest presentation of non-Hodgkin's lymphoma. PMID- 19445448 TI - Giant cystic thymoma with haemorrhage and necrosis: an unusual case. AB - Extreme degree of cystic, haemorrhagic and necrotic changes in a thymoma is rare. A 22-year-old male presented with cough, grade 2 dyspnoea, and occasional chest pain for the past six months. Radiological investigations revealed a large cystic lesion in the anterior mediastinum. A benign cystic tumour was suspected. Surgical resection of the tumour was done. Grossly, the almost entirely cystic and haemorrhagic dumb-bell shaped encapsulated tumour showed a subcapsular residual nodule. Histopathological examination was suggestive diagnosis of benign thymoma (World Health Organization [WHO] Type A, medullary type) associated with the rare features of cells with dendritic processes containing melanin pigment seen singly scattered throughout the tumour. PMID- 19445449 TI - Use of non-invasive ventilation in a pregnant woman with acute respiratory distress syndrome due to pneumonia. AB - Utility of non-invasive ventilation (NIV) in patients with acute respiratory distress syndrome (ARDS) is not proven. We report a case of a 28-year-old primigravida female with ARDS due to community-acquired severe pneumonia in whom non-invasive ventilation was instituted in an attempt to improve oxygenation and avoid intubation. This lead to an improvement in arterial oxygenation and reduction in respiratory rate of the patient and gradual disappearance of fetal distress. PMID- 19445450 TI - Recurrent haemoptysis following sildenafil administration. AB - Sildenafil is widely used in the treatment of male erectile disorder and is generally well-tolerated. Its adverse effects are reported to be mild and include flushing, headache, dyspepsia and visual disturbances. We document a case of recurrent haemoptysis observed soon after self administration of sildenafil in a 38-year-old male with no other causative factors. The episodes of haemoptysis stopped following stoppage of sildenafil. PMID- 19445451 TI - Explicit orientation dependence in empirical potentials and its significance to side-chain modeling. AB - Protein structure modeling and prediction have important applications throughout the biological sciences, from the design of pharmaceuticals to the elucidation of enzyme mechanisms. At the core of most protein modeling is an energy function, the minimum of which represents the free energy "cost" for forming a correct protein structure. The most commonly used energy functions are knowledge-based statistical potential functions; that is, they are empirically derived from statistical analysis of a set of high-resolution protein structures. When that kind of potential function is constructed, the anisotropic orientation dependence between the interacting groups is a critical component for accurately representing key molecular interactions, such as those involved in protein side chain packing. In the literature, however, many potential functions are limited in their ability to describe orientation dependence. In all-atom potentials, they typically ignore heterogeneous chemical-bond connectivity. In coarse-grained potentials, such as (semi)-residue-based potentials, the simplified representation of residues often reduces the sensitivity of the potential to side chain orientation. Recently, in an effort to maximally capture the orientation dependence in side-chain interactions, a new type of all-atom statistical potential was developed: OPUS-PSP (potential derived from side-chain packing). The key feature of this potential is its explicit description of orientation dependence in molecular interactions, which is achieved with a basis set of 19 rigid-body blocks extracted from the chemical structures of 20 amino acid residues. This basis set is specifically designed to maximally capture the essential elements of orientation dependence in molecular packing interactions. The potential is constructed from the orientation-specific packing statistics of pairs of those blocks in a nonredundant structural database. On decoy set tests, OPUS-PSP significantly outperforms most of the existing knowledge-based potentials in terms of both its ability to recognize native structures and its consistency in achieving high Z scores across decoy sets. The application of OPUS PSP to conformational modeling of side chains has led to another method, called OPUS-Rota. In terms of combined speed and accuracy, OPUS-Rota outperforms all of the other methods in modeling side-chain conformation. In this Account, we briefly outline the basic scheme of the OPUS-PSP potential and its application to side-chain modeling via OPUS-Rota. Future perspectives on the modeling of orientation dependence are also discussed. The computer programs for OPUS-PSP and OPUS-Rota can be downloaded at http://sigler.bioch.bcm.tmc.edu/MaLab . They are free for academic users. PMID- 19445452 TI - Characterization of membrane-protein interactions for the leucine transporter from Aquifex aeolicus by molecular dynamics calculations. AB - Multinanosecond molecular dynamics (MD) simulations have been employed to characterize the interaction of an integral membrane protein (IMP), the leucine transmitter from Aquifex aeolicus (Yamashita et al., Nature 2005, 437, 215-223), with hydrated lipid bilayer membranes in their physiologically relevant liquid crystalline phases. Analysis of the MD trajectories for dimyristoyl phosphatidylcholine (DMPC), 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), and 1-palmitoyl-2-oleoyl phosphatidylethanolamine (POPE) focused on the contacts between aromatic and basic side chains of the IMP with the lipid head groups and water. Structural fluctuations of the IMP were investigated as well as the contact dynamics of neighboring lipids. In characterizing the IMP-membrane systems, the behaviors of the protein's cytoplasmic and periplasmic parts are considered separately. All three lipid membranes show a rather similar overall level of association with the IMP. However, for DMPC there is a better matching of the membrane core to the hydrophobic transmembrane portion of the IMP. The closed cytoplasmic end of the IMP exhibits a higher degree of association with lipids than the more open periplasmic end, an observation which correlates with the more compact structure and a slower dynamics of surrounding lipids. PMID- 19445454 TI - Evaluation of a cationic poly(beta-hydroxyalkanoate) as a plasmid DNA delivery system. AB - Poly(beta-hydroxyalkanoates) (PHAs) are biodegradable polymers produced by a wide range of bacteria. The structures of these polymers may be tuned by controlling the available carbon source composition, but the range of functional groups accessible in this manner is limited to those that the organism is able to metabolize. Much effort has been made to chemically modify the side chains of these polymers to achieve new materials with new applications. We have previously reported the synthesis of the first cationic PHA, poly(beta-hydroxyoctanoate)-co (beta-hydroxy-11-(bis(2-hydroxyethyl)-amino)-10-hydroxyundecanoate) (PHON). Here, we report the use of this polymer as a plasmid DNA delivery system. PHON was found to bind and condense the DNA into positively charged particles smaller than 200 nm. In this manner, PHON was shown to protect plasmid DNA from nuclease degradation for up to 30 min. In addition, treatment of mammalian cells in vitro with PHON/DNA complexes resulted in luciferase expression as the result of the delivery of the encoded gene. PMID- 19445453 TI - Structure-activity relationships comparing N-(6-methylpyridin-yl)-substituted aryl amides to 2-methyl-6-(substituted-arylethynyl)pyridines or 2-methyl-4 (substituted-arylethynyl)thiazoles as novel metabotropic glutamate receptor subtype 5 antagonists. AB - The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20-23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range = 2-5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders. PMID- 19445455 TI - Considerations for the construction of the solvation correlation function and implications for the interpretation of dielectric relaxation in proteins. AB - The dielectric response of proteins is conveniently measured by monitoring the time-dependent Stokes shift of an associated chromophore. The interpretation of these experiments depends critically upon the construction of the solvation correlation function, C(t), which describes the time-dependence of the Stokes shift and hence the dielectric response of the medium to a change in charge distribution. We provide an analysis of various methods of constructing this function and review selected examples from the literature. The naturally occurring amino acid, tryptophan, has been frequently used as a probe of solvation dynamics in proteins. Its nonexponential fluorescence decay has stimulated the generation of an alternative method of constructing C(t). In order to evaluate this method, we have studied a system mimicking tryptophan. The system is comprised of two coumarins (C153 and C152) having different fluorescence lifetimes but similar solvation times. The coumarins are combined in different proportions in methanol to make binary probe mixtures. We use fluorescence upconversion spectroscopy to obtain wavelength-resolved kinetics of the individual coumarins in methanol as well as the binary mixtures of 75:25, 50:50, and 25:75 of C153:C152. The solvation correlation functions are constructed for these systems using different methods and are compared. PMID- 19445456 TI - Nazarov cyclization initiated by peracid oxidation: the total synthesis of (+/-) rocaglamide. AB - The total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization are described. Generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization. The synthesis is efficient, highly diastereoselective, and strategically distinct from previous syntheses of rocaglamide. PMID- 19445458 TI - Intensely colored mixed-valence iron(II) iron(III) formate analogue of Prussian Blue exhibits neel N-type ferrimagnetism. AB - The reaction of colorless iron(II) formate or the mixed-valence cluster Fe(3)O(MeCOO)(6)(H(2)O)(3) with formic acid in dimethylformamide exposed to air at 110 degrees C affords black crystals of the mixed-valence (Me(2)NH(2))[Fe(II)Fe(III)(HCOO)(6)] three-dimensional (3D) structure in which the cations occupy half of the channels. The structure consists of alternating layers of Fe(II)O(6) [Fe(1)-O(1), 2.119(1) A] and Fe(III)O(6) [Fe(2)-O(2), 2.0049(9) A] octahedra bridged by anti-anti-bonded formates to afford an open framework 3D structure. The structure is very similar to those of (Me(2)NH(2))[Fe(II)(HCOO)(3)] and [Fe(III)(HCOO)(3)].HCOOH, both of which are colorless. The black crystals appear dark-purple (lambda(max) approximately 520 nm) when powdered. The room-temperature Mossbauer spectrum confirms the 1:1 ratio of Fe(II) (delta = 1.03 mm/s, DeltaE(Q) = 1.16 mm/s) and Fe(III) (delta = 0.62 mm/s, DeltaE (Q) = 0.49 mm/s). Magnetic ordering that includes negative magnetization at low fields occurs at low temperature. The only molecular-based magnetic materials in which this phenomenon has been observed are the 2D polyiron(II,III) oxalates A[Fe(II)Fe(III)(C(2)O(4))(3)] (A = R(4)N(+) cation). PMID- 19445459 TI - Elucidation of the phosphate binding mode of DING proteins revealed by subangstrom X-ray crystallography. AB - PfluDING is a bacterial protein isolated from Pseudomonas fluorescens that belongs to the DING protein family, which is ubiquitous in eukaryotes and extends to prokaryotes. DING proteins and PfluDING have very similar topologies to phosphate Solute Binding Proteins (SBPs). The three-dimensional structure of PfluDING was obtained at subangstrom resolution (0.88 and 0.98 A) at two different pH's (4.5 and 8.5), allowing us to discuss the hydrogen bond network that sequesters the phosphate ion in the binding site. From this high resolution data, we experimentally elucidated the molecular basis of phosphate binding in phosphate SBPs. The phosphate ion is tightly bound to the protein via 12 hydrogen bonds between phosphate oxygen atoms and OH and NH groups of the protein. The proton on one oxygen atom of the phosphate dianion forms a 2.5 A low barrier hydrogen bond with an aspartate, with the energy released by forming this strong bond ensuring the specificity for the dianion even at pH 4.5. In particular, contrary to previous theories on phosphate SBPs, accurate electrostatic potential calculations show that the binding cleft is positively charged. PfluDING structures reveal that only dibasic phosphate binds to the protein at both acidic and basic phosphate, suggesting that the protein binding site environment stabilizes the HPO(4)(2-) form of phosphate. PMID- 19445460 TI - Progress in the perturbation approach in fluid and fluid-related theories. PMID- 19445461 TI - Relative stereochemistry determination and synthesis of the major chlorosulfolipid from Ochromonas danica. AB - The relative stereochemistry of the major chlorosulfolipid of the chrysophyte alga Ochromonas danica, to which we have given the name "danicalipin A", is reported. The first synthesis of this lipid, via several stereospecific electrophilic additions to alkenes, serves to corroborate the stereochemical assignment made by NMR spectroscopy. The synthesis strategy described should be applicable to other chlorosulfolipids and should provide access to sufficient material for studies of the lipid's properties and function in membranes. PMID- 19445463 TI - Molecular dynamics of water-mediated interactions of a linear benzimidazole biphenyl diamidine with the DNA minor groove. AB - DB921 has a benzimidazole-biphenyl system with terminal amidines that gives the compound a linear conformation with a radius of curvature that does not match the DNA minor groove shape. Surprisingly, the compound binds in the groove with an unusually high equilibrium constant [Miao, Y.; Lee, M. P. H.; Parkinson, G. N.; Batista-Parra, A.; Ismail, M. A.; Neidle, S.; Boykin, D. W.; Wilson, W. D. Biochemistry 2005, 44, 14701-14708]. X-ray crystallographic analysis of DB921 bound to -AATT- in d(CGCGAATTCGCG)(2) showed that the benzimidazole is in position to directly interact with bases at the floor of the groove, while the phenylamidine of DB921 forms indirect contacts with the bases through an interfacial water. The DB921-water pair forms a curved, flexible module with a high K(a) (or a low K(d)) value of binding. To better understand the dynamics of the DB921-DNA complex and how water can be used in the design of compounds to recognize DNA, a 100 ns molecular dynamics simulation of the complex was conducted. In addition to the X-ray conformation, some significantly variant, dynamic conformations, which had additional interfacial water molecules between DB921 and DNA, appeared in the MD simulation. The benzimidazole contacts remained relatively constant through the entire simulation. The biphenylamidine end of the bound molecule, however, undergoes much larger changes in orientation relative to the floor of the groove as well as variations in the type of water interactions. The results provide an understanding of how water couples the linear DB921 compound to the minor groove for tight binding, without a large unfavorable contribution to the entropy of binding. PMID- 19445462 TI - Photoinduced charge transfer and electrochemical properties of triphenylamine I(h)-Sc3N@C80 donor-acceptor conjugates. AB - Two isomeric [5,6]-pyrrolidine-I(h)-Sc(3)N@C(80) electron donor-acceptor conjugates containing triphenylamine (TPA) as the donor system were synthesized. Electrochemical and photophysical studies of the novel conjugates were made and compared with those of their C(60) analogues, in order to determine (i) the effect of the linkage position (N-substituted versus 2-substituted pyrrolidine) of the donor system in the formation of photoinduced charge separated states, (ii) the thermal stability toward the retro-cycloaddition reaction, and (iii) the effect of changing C(60) for I(h)-Sc(3)N@C(80) as the electron acceptor. It was found that when the donor is connected to the pyrrolidine nitrogen atom, the resulting dyad produces a significantly longer lived radical pair than the corresponding 2-substituted isomer for both the C(60) and I(h)-Sc(3)N@C(80) dyads. In addition to that, the N-substituted TPA-I(h)-Sc(3)N@C(80) dyad has much better thermal stability than the 2-substituted one. Finally, the I(h) Sc(3)N@C(80) dyads have considerably longer lived charge separated states than their C(60) analogues, thus approving the advantage of using I(h)-Sc(3)N@C(80) instead of C(60) as the acceptor for the construction of fullerene based donor acceptor conjugates. These findings are important for the design and future application of I(h)-Sc(3)N@C(80) dyads as materials for the construction of plastic organic solar cells. PMID- 19445464 TI - Functional expression and characterization of keratinase from Pseudomonas aeruginosa in Pichia pastoris. AB - Recombinant keratinase (rK) from Pseudomonas aeruginosa was secreted by Pichia pastoris SMD1168H with a final yield of 580 mg/L (1.03 kU/mL) after 72 h of induction. The rK was purified after nickel affinity chromatography and was stable at pH 6.0-9.0 and 10-60 degrees C. It was nonglycosylated protein with a molecular mass of 33 kDa and had an optimal pH and temperature at 8.0 and 60 degrees C, respectively. Ba(2+), Ca(2+), Mg(2+), Mn(2+), Zn(2+), dithiothreitol, glutathione, and beta-mercaptoethanol activated, while Cu(2+), Fe(2+), Hg(2+), Fe(3+), ethylene glycol tetraacetic acid, ethylene diamine tetraacetic acid, and p-chloromercuribenzoate inhibited its activity. rK could hydrolyze broad substrates and cleave hydrophobic and aromatic amino acids at P(1) position, behaving as those from the wild type strain and E. coli transformant. PMID- 19445465 TI - Amino acid-based synthesis of trifluoromethylalkene dipeptide isosteres by alcohol-assisted nucleophilic trifluoromethylation and organozinc-copper-mediated S(N)2' alkylation. AB - A novel synthetic approach to Xaa-Yaa-type (Z)-trifluoromethylalkene dipeptide isostere (CF(3)-ADI) has been developed. Starting from readily available l phenylalanine and l-alanine, several CF(3)-ADIs were obtained through nucleophilic trifluoromethylation of gamma-keto esters and S(N)2' alkylation of trifluoromethylated mesylates. The influence of a trifluoromethyl group on the diastereoselectivity of the S(N)2' reaction is also discussed. PMID- 19445466 TI - A versatile route to (E)- and (Z)-2-hydroxy-3,4-unsaturated disubstituted sulfilimines and their haloamidation reaction. AB - Alpha-chloro ynones have been reduced using Noyori's Ru catalyst to furnish alpha chloro propargylic alcohols with excellent enantioselectivity. These have been used as a common precursor for the preparation of (E)- and (Z)-2-hydroxy-3,4 unsaturated disubstituted sulfilimines. The latter serve as precursors for the highly regio- and stereoselective preparation of bromo carbamates. PMID- 19445467 TI - Monodentate non-C(2)-symmetric chiral N-heterocyclic carbene complexes for enantioselective synthesis. Cu-catalyzed conjugate additions of aryl- and alkenylsilylfluorides to cyclic enones. AB - A new class of enantioselective conjugate addition (ECA) reactions that involve aryl- or alkenylsilyl fluoride reagents and are catalyzed by chiral non-C(2) symmetric Cu-based N-heterocyclic carbene (NHC) complexes are disclosed. Transformations have been designed based on the principle that a catalytically active chiral NHC-Cu-aryl or NHC-Cu-alkenyl complex can be accessed from reaction of a Cu-halide precursor with in situ-generated aryl- or alkenyltetrafluorosilicate. Reactions proceed in the presence of 1.5 equiv of the aryl- or alkenylsilane reagents and 1.5 equiv of tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF). Desired products are isolated in 63-97% yield and 73.5:26.5-98.5:1.5 enantiomeric ratio (47%-97% ee). A major focus of the present studies is the design, evaluation, and development of new chiral imidazolinium salts and their derived NHC-Cu complexes as catalysts that promote reactions of various carbosilanes to a range of electrophilic substrates. Toward this end, nearly 20 new chiral monodentate imidazolinium salts, most of which are non-C(2)-symmetric, have been prepared and fully characterized and their ability to serve as catalysts in the ECA reactions has been investigated. PMID- 19445469 TI - Product profile of PEN3: the last unexamined oxidosqualene cyclase in Arabidopsis thaliana. AB - The triterpene product profile is reported for At5g36150 (PEN3), the last unexamined oxidosqualene cyclase in the reference plant Arabidopsis thaliana. PEN3 makes tirucalla-7,24-dien-3beta-ol ( approximately 85%) and several minor products. Also discussed are the unexpectedly facile convergent evolution of another Arabidopsis tirucalladienol synthase (LUP5), mechanistic origins of the 20S configuration, and active-site remodeling necessary to accommodate the 17alpha side chain. This work marks the first completed functional characterization of all triterpene synthases in a higher plant. PMID- 19445470 TI - Polarized light emitting diode by long-range nanorod self-assembling on a water surface. AB - We demonstrate a straightforward strategy to fabricate a multilayer inorganic/organic polarized light-emitting diode device based on highly ordered arrays of rod-shaped nanocrystals as the active species. We have developed a simple and effective method that allows colloidal CdSe/CdS core/shell nanorods to be laterally aligned in smectic or nematic phases on the surface of water. A floating film of such ordered nanorods has been collected by a poly(dimethylsiloxane) (PDMS) stamp pad and transferred by contact printing onto previously evaporated organic layers. Thanks to the lateral nanorod alignment the as-prepared film exhibited strong polarized photoluminescence and it has been used as emissive layer in the polarized electroluminescent device. PMID- 19445471 TI - Cobalt complex as building blocks: synthesis, characterization, and catalytic applications of {Cd2+-Co3+-Cd2+} and {Hg2+-Co3+-Hg2+} heterobimetallic complexes. AB - The present work demonstrates the utilization of the Co(3+) complex of pyridine amide ligand as building blocks for the assembly of heterobimetallic complexes. These Co(3+)-centered building blocks orient the tethered pyridine groups to a preorganized cleft that successively coordinates to the Cd(2+) and Hg(2+) ions in the periphery. Both {Cd(2+)-Co(3+)-Cd(2+)} and {Hg(2+)-Co(3+)-Hg(2+)} heterobimetallic complexes have been thoroughly characterized, including crystal structures depicting interesting weak interactions in the solid state. The {Cd(2+)-Co(3+)-Cd(2+)} and {Hg(2+)-Co(3+)-Hg(2+)} heterobimetallic complexes have been further used for the catalytic cyanosilylation of imines and ring-opening reactions of oxiranes and thiiranes. The results suggest peripheral metal selective catalytic reactions. PMID- 19445472 TI - Identification and characteristics of iron-chelating peptides from soybean protein hydrolysates using IMAC-Fe3+. AB - The iron-chelating peptides from soybean protein hydrolysates (SPH) were investigated using immobilized metal affinity chromatography (IMAC). The results demonstrated that SPH could absorb on the IMAC-Fe(3+) column, while the capability of the binding iron was different in SPH (10-30 kDa), SPH (3-10 kDa), and SPH (1-3 kDa). The highest binding amount on the column occurred with SPH (10 30 kDa). With the IMAC method, the iron-chelating peptides were shown to be formed at pH lower than 5.5, and they were not affected by NaCL with the concentration between 0.1 mol/L and 1 mol/L, while the iron-chelating peptides could be partially disrupted by 0.02 mol/L Na(2)HPO(4) at pH 8.0. Furthermore, the iron-chelating peptides were identified with reversed phase (RP)-HPLC, SDS PAGE, and MALDI-TOF MS/MS. The binding characteristics of the SPH on IMAC-Fe(3+) and the sequences of the iron-chelating peptides revealed that binding sites between SPH and iron might be the carboxyl groups of Glu and Asp residues. PMID- 19445473 TI - Theoretical study of the reaction between HF molecules and hydroxyl layers of Mg(OH)2. AB - The reaction of HF molecules with brucite, Mg(OH)(2), leading to the formation of Mg(OH)(2-x)F(x), was theoretically studied by ab initio density functional theory (DFT) with periodic boundary conditions. We proposed as mechanism for this reaction four elementary steps: adsorption of the HF molecule, OH(-) liberation from brucite as a water molecule, desorption of the newly formed H(2)O, and rearrangement of the F(-) anion into a hydroxyl position. For the Mg(OH)(2-x)F(x) formation, with x = 1/9, the final product, outcome from an initially adsorbed HF molecule, we computed the Helmholtz free energy variation DeltaF = -23 kcal/mol. The calculated frequency for the most intense infrared band, a Mg-F stretching mode, was 342 cm(-1). Two transition states, corresponding to the hydroxyl reacting with a proton forming a water molecule and migration of a fluoride anion into a hydroxyl vacancy, were computed. The calculated reaction barriers indicate that the reaction between Mg(OH)(2) layers and HF molecules is slow and irreversible. PMID- 19445474 TI - DFT studies of the ring-opening mechanism of SB-3CT, a potent inhibitor of matrix metalloproteinase 2. AB - SB-3CT is a 2-[(arylsulfonyl)methyl]thiirane that achieves potent inhibition, by a thiirane-opening mechanism, of the MMP2 and MMP9 zinc metalloproteases. The deprotonation mechanism for thiirane opening of SB-3CT and for the opening of its oxirane analogue, both relevant to the inhibition of MMP2, was investigated computationally using the acetate anion as the Bronsted base and in methanol and acetonitrile as solvents. The activation barriers for the reaction show a significant stereoelectronic effect. The lowest energy paths have the breaking C H bond gauche to both sulfone oxygens and with this C-H bond anti to the breaking C-S bond of the thiirane. The calculated primary isotope effect agrees with experimental data. PMID- 19445475 TI - Excited-state energy flow in phenylene-linked multiporphyrin arrays. AB - The dynamics and pathways for excited-state energy transfer in three dyads and five triads composed of combinations of zinc, magnesium, and free base porphyrins (denoted Zn, Mg, Fb) connected by p-phenylene linkers have been investigated. The processes in the triads include energy transfer between adjacent nonequivalent porphyrins, between adjacent equivalent porphyrins, and between nonadjacent nonequivalent porphyrins using the intervening porphyrin as a superexchange mediator. In the case of the triad ZnZnFbPhi, excitation of the zinc porphyrin (to yield Zn) ultimately leads to production of the excited free base porphyrin (Fb) via the three processes with the derived rate constants as follows: (2.8 ps)(-1) for ZnZn Fb --> ZnZnFb, (4 ps)(-1) for Zn ZnFb left arrow over right arrow ZnZn Fb, and (14 ps)(-1) for Zn ZnFb --> ZnZnFb. These results and those obtained for the other four triads show that energy transfer between nonadjacent sites is significant and is only 5-7-fold slower than between adjacent sites. This same scaling was found previously for arrays joined via diphenylethyne linkers. Simulations of the energy-transfer properties of fictive dodecameric arrays based on the data reported herein show that nonadjacent transfer steps make a significant contribution to the observed performance of such larger molecular architectures. Collectively, these results indicate that energy transfer between nonadjacent sites has important implications for the design of multichromophore arrays for molecular-photonic and solar-energy applications. PMID- 19445476 TI - Tumor imaging and therapy using radiolabeled somatostatin analogues. AB - Molecular imaging plays an essential role in balancing the clinical benefits and risks of radionuclide-based cancer therapy. To effectively treat individual patients, careful assessment of biodistribution, dosimetry, and toxicity is essential. In this Account, we describe advances that combine features of molecular imaging and radionuclide therapy to provide new avenues toward individualized cancer treatment. Selective receptor-targeting radiopeptides have emerged as an important class of radiopharmaceuticals for molecular imaging and therapy of tumors that overexpress peptide receptors on the cell membrane. After such peptides labeled with gamma-emitting radionuclides bind to their receptors, they allow clinicians to visualize receptor-expressing tumors non-invasively. Peptides labeled with beta-particle emitters could also eradicate receptor expressing tumors. The somatostatin receptors, which are overexpressed in a majority of neuroendocrine tumors, represent the first and best example of targets for radiopeptide-based imaging and radionuclide therapy. The somatostatin analogue (111)In-octreotide permits the localization and staging of neuroendocrine tumors that express the appropriate somatostatin receptors. Newer modified somatostatin analogues, including Tyr(3)-octreotide and Tyr(3) octreotate, are successfully being used for tumor imaging and radionuclide therapy. Because there are few effective therapies for patients with inoperable or metastasized neuroendocrine tumors, this therapy is a promising novel treatment option for these patients. Peptide receptor imaging and radionuclide therapy can be combined in a single probe, called a "theranostic". To select patients who are likely to benefit from this type of intervention, we first use a peptide analogue labeled with a diagnostic radionuclide to obtain a scan. Selected patients will be treated using the same or a similar peptide analogue labeled with a therapeutic radionuclide. The development of such theranostics could greatly advance the development of personalized treatments. Apart from patient selection for radionuclide therapy, other imaging applications of targeted radiopeptides include localization of primary tumors, detection of metastatic disease (staging/restaging), dosimetry (prediction of response and radiotoxicity), monitoring effects of surgery, radio(nuclide)therapy or chemotherapy, and detection of progression of disease or relapse (follow up). For further evaluation of tumor receptor expression and to increase the value of cancer targeting using radiopeptides, researchers have introduced and evaluated different radiolabeled analogues of other peptide families, such as cholecystokinin (CCK), gastrin, bombesin, substance P, vasoactive intestinal peptide (VIP), and neuropeptide (NP)-Y analogues. We expect improvements in the development of new peptide analogues: such advances could reduce side effects and allow for the use of combination therapy (for example, combining radiopeptide analogues with chemotherapeutics). PMID- 19445478 TI - Quantification in comprehensive two-dimensional liquid chromatography. AB - This correspondence corrects the description in a recent paper by Mondello et al., "Quantification in Comprehensive Two-Dimensional Liquid Chromatography" [Mondello, L.; Herrero, M.; Kumm, T.; Dugo, P.; Cortes, H.; Dugo, G. Anal. Chem., 2008, 80, 5418-5424], of previous research on peak integration. This correspondence also shows that the peak integration method proposed in that paper is equivalent to, but is less efficient than, simply summing the data values. PMID- 19445479 TI - Mixed frequency-/time-domain coherent multidimensional spectroscopy: research tool or potential analytical method? AB - Coherent multidimensional spectroscopy (CMDS) is now the optical analogue of nuclear magnetic resonance (NMR). Just as NMR heteronuclear multiple-quantum coherence (HMQC) methods rely on multiple quantum coherences, achieving widespread application requires that CMDS also excites multiple quantum coherences over a wide range of quantum state energies. This Account focuses on frequency-domain CMDS because these methods tune the excitation frequencies to resonance with the desired quantum states and can form multiple quantum coherences between states with very different energies. CMDS methods use multiple excitation pulses to excite multiple quantum states within their dephasing time, so their quantum mechanical phase is maintained. Coherences formed from pairs of the excited states emit coherent beams of light. The temporal ordering of the excitation pulses defines a sequence of coherences that can result in zero, single, double, or higher order coherences as required for multiple quantum coherence CMDS. Defining the temporal ordering and the excitation frequencies and spectrally resolving the output frequency also defines a particular temporal pathway for the coherences, just as an NMR pulse sequence defines an NMR method. Two dimensional contour plots through this multidimensional parameter space allow visualization of the state energies and dynamics. This Account uses nickel and rhodium chelates as models for understanding mixed frequency-/time-domain CMDS. Mixed frequency-/time-domain methods use excitation pulse widths that are comparable to the dephasing times, so multidimensional spectra are obtained by scanning the excitation frequencies, while the coherence and population dynamics are obtained by scanning the time delays. Changing the time delays changes the peaks in the 2D excitation spectra depending upon whether the pulse sequence excites zero, single, or double quantum coherences. In addition, peaks split as a result of the frequency-domain manifestation of quantum beating. Similarly, changing the excitation and monochromator frequencies changes the dependence on the excitation delay times depending upon whether the frequencies match the resonances involved in the different time-ordered pathways. Contour plots that change a time delay and frequency visualize the temporal changes of specific spectral features. Frequency-domain methods are resonant with specific states, so the sequence of coherences and populations is defined. Coherence transfer, however, can cause output beams at unexpected frequencies. Coherence transfer occurs when the thermal bath induces a coherence between two states (a and g) to evolve to a new coherence (b and g). Since the two coherences have different frequencies and since there are different time orderings for the occurrence of coherence transfer, the delay time dependence develops modulations that depend on the coherences' frequency difference. Higher order coherences can also be generated by raising the excitation intensities. New features appear in the 2D spectra and dynamic Stark splittings occur. These effects will form the basis for the higher order multiple quantum coherence methods and also provide a method for probing molecular potential energy surfaces. PMID- 19445477 TI - Lipid droplets: their role in nanoparticle-induced oxidative stress. AB - Lipid droplets are cytoplasmic organelles found in almost all cells under physiological or pathological conditions. Certain nanoparticles can induce lipid droplet formation under oxidative stress conditions. Small metallic nanoparticles such as cadmium telluride (CdTe) nanoparticles, particularly those with incompletely protected surfaces, induce oxidative stress and may inflict damages to several intracellular organelles. The objective of this study was to assess formation of lipid droplets in cells treated with CdTe nanoparticles and relate their status to cell function (mitochondrial activity and cell viability). Multicolor labeling of cellular organelles (lipid droplets and lysosomes) showed that lipid droplets formed in pheochromocytoma (PC12) cells following nanoparticle or oleic acid treatment. Some lipid droplets were found closely apposed to lysosomes suggesting possible communication between these organelles during severe oxidative stress. Combination of microscopy of living cells with cell viability assays showed that oleic acid-induced lipid droplets not only serve as intracellular lipid storage sites but also play a protective role in starving stressed cells. Results from these studies suggest that oleic acid induced LD in PC12 cells are dynamic and adaptive organelles, which provide energy to starving cells and facilitate their rescue under starvation and exposure to metallic nanoparticles. PMID- 19445480 TI - Roles of aquaporin-4 isoforms and amino acids in square array assembly. AB - Aquaporin-4 (AQP4) is a water channel found at high concentrations around blood vessels in the brain and is organized into elaborate assemblies called square arrays. The natural functions of AQP4 and the square arrays remain unknown, but under pathophysiological conditions, AQP4 has been shown to influence brain edema, synapse function, and cellular migration. AQP4 was recently found to have six isoforms, where AQP4a (also known as M1), AQP4c (also known as M23), and AQP4e are functional water transport channels. Furthermore, by two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis of the internal composition of square arrays, three distinct isoforms were visualized. Here we combine these advances in technique with mutational analysis to test a series of current hypotheses about AQP4 functional structure. We find that the square array destabilizing N-terminus of AQP4a is partly functional through the C13 and C17 amino acids, and not through R8 and R9. We find a discrepancy between our data and the proposed tetramer-tetramer binding site based on the in vitro AQP4 two dimensional crystal structure. On the other hand, we find that isoforms AQP4a and AQP4e, while not being able to form square arrays alone, are able to interact with AQP4c and be incorporated into higher-order structures. Our results with the novel BN-PAGE analysis technique point toward a model in which the presence of accessory isoforms (AQP4a and AQP4e) regulates the square array assembly process of the main isoform, AQP4c. PMID- 19445481 TI - Confocal images of circulating tumor cells obtained using a methodology and technology that removes normal cells. AB - A completely negative enrichment technology was used to detect circulating tumor cells, CTCs, in the peripheral blood of head and neck cancer patients. Of 32 blood samples, 63% contained CTCs and the number of CTCs identified per mL of blood collected ranged from 0 to 214. The final purity ranged from 1 CTC in 9 total cells to 1 CTC in 20,000 total cells, the final purity being both a function of the number of CTCs and the performance of the specific enrichment. Consistent with previous reports, CTC were positively identified if: (1) they contained a nucleus based on DAPI stain, (2) stained positive for cytokeratins, and (3) have a high nuclei to cytoplasmic ratio. In addition, for a blood sample to be considered positive for CTCs, the enriched sample must be positive for epithelial growth factor receptor, EGFR, as measured by RT-PCR. While most of the blood samples were obtained during surgery, a number were taken prior to and during surgery. In all of the pre- and postsurgery paired samples, significant numbers of CTCs were detected. A number of these enriched samples were observed under confocal microscope in addition to the microscopic observations under traditional wide-field fluorescent microscope. As expected, the FITC stained cytokeratins appeared in the cytoplasm and the average size of these positively stained cells, on the cytospin, was in the range of 8-12 mum. Future studies will involve the investigation if cancer stem cell and mesenchymal markers are present on these CTCs and correlations of patient outcome to the number and type of CTC present. PMID- 19445482 TI - Cell uptake and in vitro toxicity of magnetic nanoparticles suitable for drug delivery. AB - Magnetic targeting is useful for intravascular or intracavitary drug delivery, including tumor chemotherapy or intraocular antiangiogenic therapy. For all such in vivo applications, the magnetic drug carrier must be biocompatible and nontoxic. In this work, we investigated the toxic properties of magnetic nanoparticles coated with polyethylenoxide (PEO) triblock copolymers. Such coatings prevent the aggregation of magnetic nanoparticles and guarantee consistent magnetic and nonmagnetic flow properties. It was found that the PEO tail block length inversely correlates with toxicity. The nanoparticles with the shortest 0.75 kDa PEO tails were the most toxic, while particles coated with the 15 kDa PEO tail block copolymers were the least toxic. Toxicity responses of the tested prostate cancer cell lines (PC3 and C4-2), human umbilical vein endothelial cells (HUVECs), and human retinal pigment epithelial cells (HRPEs) were similar. Furthermore, all cell types took up the coated magnetic nanoparticles. It is concluded that magnetite nanoparticles coated with triblock copolymers containing PEO tail lengths of above 2 kDa are biocompatible and appropriate for in vivo application. PMID- 19445483 TI - Multiplex charge-transfer interactions between quantum dots and peptide-bridged ruthenium complexes. AB - Simultaneous detection of multiple independent fluorescent signals or signal multiplexing has the potential to significantly improve bioassay throughput and to allow visualization of concurrent cellular events. Applications based on signal multiplexing, however, remain hard to achieve in practice due to difficulties in both implementing hardware and the photophysical liabilities associated with available organic dye and protein fluorophores. Here, we used charge-transfer interactions between luminescent semiconductor quantum dots (QDs) and proximal redox complexes to demonstrate controlled quenching of QD photoemission in a multiplexed format. In particular, we show that, because of the ability of the Ru complex to effectively interact with CdSe-ZnS QDs emitting over a broad window of the optical spectrum, higher orders of multiplexed quenching can be achieved in a relatively facile manner. Polyhistidine-appended peptides were site-specifically labeled with a redox-active ruthenium (Ru) phenanthroline complex and self-assembled onto QDs, resulting in controlled quenching of the QD emission. Different QD colors either alone or coupled to Ru phen-peptide were then mixed together and optically interrogated. Composite spectra collected from mixtures ranging from four up to eight distinct QD colors were deconvoluted, and the individual QD photoluminescence (PL) loss due to charge transfer was quantified. The current multiplexing modality provides a simpler format for exploiting the narrow, size-tunable QD emissions than that offered by resonance energy transfer; for the latter, higher orders of multiplexing are limited by spectral overlap requirements. PMID- 19445484 TI - Surfactant mobility in nanoporous glass films. AB - Polymer molecules when physically confined at nanometer length scales diffuse nonclassically and very differently depending on their molecular weight and the nature of the confinement. Long polymers that exhibit "snakelike" reptation based mobility in melts may diffuse faster in confined nanometer sized cylinders with pore diameter d approximately 15 nm, and short polymers subject to Rouse dynamics have shown signatures of reptation and slower diffusion when confined in nanoporous glass with d approximately 4 nm. However, the mobility of short polymers with radii of gyration similar to a smaller pore diameter (d < or = 2.1 nm) but with extended lengths well larger than the pore diameter has not as yet been studied. In this work, we demonstrate that those short molecules including nonionic surfactants can readily diffuse in strongly hydrophobic nanoporous glasses film with d < or = 2.1 nm. The diffusivity was found sensitive to molecular weight, hydrophilic-lipophilic balance, and molecular structure of surfactants. Remarkably, analysis of the measured diffusion coefficients reveals that short-chain surfactants exhibit signature of reptation based diffusion in the nanoscopic pore confinements. Such reptation mobility in agreement with theoretical predictions is not even observed in reptating polymer melts due to fluctuations of the entanglement pathway. The fixed pathways in the interconnected nanoporous films provide ideal nanoscale environments to explore mobility of confined molecules, and the results have implications for a number of technologies where nanoporous materials are in contact with surfactant molecules. PMID- 19445486 TI - Hydrofluoric acid etched stainless steel wire for solid-phase microextraction. AB - Stainless steel wire has been widely used as the substrate of solid-phase microextraction (SPME) fibers to overcome the shortcomings of conventional silica fibers such as fragility, by many researchers. However, in previous reports various sorbent coatings are always required in conjunction with the stainless steel wire for SPME. In this work, we report the bare stainless steel wire for SPME without the need for any additional coatings taking advantage of its high mechanical and thermal stability. To evaluate the performance of stainless steel wire for SPME, polycyclic aromatic hydrocarbons (PAHs), benzene, toluene, ethylbenzene, chlorobenzene, n-propylbenzene, aniline, phenol, n-hexane, n octane, n-decane, n-undecane, n-dodecane, chloroform, trichloroethylene, n octanol, and butanol were tested as analytes. Although the stainless steel wire had almost no extraction capability toward the tested analytes before etching, it did exhibit high affinity to the tested PAHs after etching with hydrofluoric acid. The etched stainless steel wire gave a much bigger enhancement factor (2541 3981) for the PAHs than the other analytes studied (< or = 515). Etching with hydrofluoric acid produced a porous and flower-like structure with Fe(2)O(3), FeF(3), Cr(2)O(3), and CrF(2) on the surface of the stainless steel wire, giving high affinity to the PAHs due to cation-pi interaction. On the basis of the high selectivity of the etched stainless steel wire for PAHs, a new SPME method was developed for gas chromatography with flame ionization detection to determine PAHs with the detection limits of 0.24-0.63 microg L(-1). The precision for six replicate extractions using one SPME fiber ranged from 2.9% to 5.3%. The fiber-to fiber reproducibility for three parallel prepared fibers was 4.3-8.8%. One etched stainless steel wire can stand over 250 cycles of SPME without significant loss of extraction efficiency. The developed etched stainless steel wire is very stable, highly selective, and reproducible for the SPME of PAHs. PMID- 19445485 TI - Solid-phase synthetic strategy and bioevaluation of a labeled delta-opioid receptor ligand Dmt-Tic-Lys for in vivo imaging. AB - A general solid-phase synthetic strategy is developed to prepare fluorescent and/or lanthanide-labeled derivatives of the delta-opioid receptor (deltaOR) ligand H-Dmt-Tic-Lys(R)-OH. The high delta-OR affinity (K(i) = 3 nM) and desirable in vivo characteristics of the Cy5 derivative 1 suggest its usefulness for structure-function studies and receptor localization and as a high-contrast noninvasive molecular marker for live imaging ex vivo or in vivo. PMID- 19445487 TI - Titanium(IV) halide mediated coupling of alkoxides and alkynes: an efficient and stereoselective route to trisubstituted (E)-alkenyl halides. AB - Alkoxide C-O bond cleavage occurs readily at room temperature in the presence of titanium(IV) halide. Capture of the resultant carbocation by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity. PMID- 19445488 TI - Tandem alkylation-Michael addition to vinylogous carbonates for the stereoselective construction of 2,3,3,6-tetrasubstituted tetrahydropyrans. AB - A stereoselective method for the synthesis of substituted tetrahydropyran derivatives employing a tandem S(N)2-Michael addition sequence to vinylogous carbonates is developed. The method is extended to the synthesis of bicyclic ether motifs present in polyether ladder toxins. PMID- 19445489 TI - Recognition preference of rhodamine-thiospirolactams for mercury(II) in aqueous solution. AB - This work presents the design, syntheses, photophysical properties and Hg(2+) binding of the red-emitting rhodamine derivatives RS1, RS2, and RS3 with different coordination ability and different spatial effects that derived from rhodamine thiohydrazone chromophores and respective carboxaldehydes (benzaldehyde, pyridine-2-carboxaldehyde, ferrocenecarboxaldehyde). Chemosensors RS2 and RS3 afford turn-on fluorescence enhancement and display high brightness in water with the EC(50) for Hg(2+) of 0.5 ppb. The fluorescence intensities are nearly proportional to the amount of Hg(2+) at ppb level, when employing 100 nM probes in water. The fluorescence responses of these two chemosensors are Hg(II) specific, and the probes are selective for Hg(II) over alkali, alkaline earth metals, divalent first-row transition metal ions, and Group 12 congeners Zn(II) and Cd(II), as well as heavy metals Pb(II) and Ag(I). X-ray crystal structure analyses exhibit the thioether derivative of the spirolactone in these compounds. Hg(II)-specific binding in water would make the opening of the spirolactam ring and consequently causes the appearance of strong absorption at visible range, and the obvious and characteristic color change from colorless to pink. Compared to the thioamides, the improved selectivity for Hg(2+) is attributed to the poorer coordination affinity of the thioether over other interference metal ions. PMID- 19445490 TI - Regiospecific syntheses of 6alpha-(1R-Hydroxyoctyl)penicillanic acid and 6beta (1R-hydroxyoctyl)penicillanic acid as mechanistic probes of class D beta lactamases. AB - The unique hydrophobic surface patches in class D beta-lactamases presented an opportunity for designing two compounds, 6alpha-(1R-hydroxyoctyl)penicillanic acid and 6beta-(1R-hydroxyoctyl)penicillanic acid, as mechanistic probes of these enzymes. In a sequence of three synthetic steps from benzhydryl 6,6 dibromopenicillanate, the targeted compounds were prepared in a stereospecific manner. PMID- 19445491 TI - Biomimetically inspired short access to the 2-aminoimidazole-fused tetracyclic core of (+/-)-dibromoagelaspongin. AB - A six-step synthesis of the tetracyclic core of the natural compound (+/-) dibromoagelaspongin, isolated from Agelas sp. Sponge, was achieved from the commercially available 5-aminopentan-1-ol, 2-trichloroacetylpyrrole, and 2 aminopyrimidine. Following a biomimetic inspired approach, successive oxidative reactions including the final DMDO biomimetic oxidation gave the interesting triaminomethane-fused core. PMID- 19445492 TI - Absorption of inhaled NO(2). AB - Nitrogen dioxide (NO(2)), a sparingly water-soluble pi-radical gas, is a criteria air pollutant that induces adverse health effects. How is inhaled NO(2)(g) incorporated into the fluid microfilms lining respiratory airways remains an open issue because its exceedingly small uptake coefficient (gamma approximately 10( 7)-10(-8)) limits physical dissolution on neat water. Here, we investigate whether the biological antioxidants present in these fluids enhance NO(2)(g) dissolution by monitoring the surface of aqueous ascorbate, urate, and glutathione microdroplets exposed to NO(2)(g) for approximately 1 ms via online thermospray ionization mass spectrometry. We found that antioxidants catalyze the hydrolytic disproportionation of NO(2)(g), 2NO(2)(g) + H(2)O(l) = NO(3)(-)(aq) + H(+)(aq) + HONO, but are not consumed in the process. Because this function will be largely performed by chloride, the major anion in airway lining fluids, we infer that inhaled NO(2)(g) delivers H(+), HONO, and NO(3)(-) as primary transducers of toxic action without antioxidant participation. PMID- 19445493 TI - Infrared spectroscopy of the microhydrated nitrate ions NO(3)(-)(H2O)(1-6). AB - We present infrared photodissociation spectra of the microhydrated nitrate ions NO(3)(-)(H(2)O)(1-6), measured from 600 to 1800 cm(-1). The assignment of the spectra is aided by comparison with calculated B3LYP/aug-cc-pVDZ harmonic frequencies, as well as with higher-level calculations. The IR spectra are dominated by the antisymmetric stretching mode of NO(3)(-), which is doubly degenerate in the bare ion but splits into its two components for most microhydrated ions studied here due to asymmetric solvation of the nitrate core. However, for NO(3)(-)(H(2)O)(3), the spectrum reveals no lifting of this degeneracy, indicating an ion with a highly symmetric solvation shell. The first three water molecules bind in a bidentate fashion to the terminal oxygen atoms of the nitrate ion, keeping the planar symmetry. The onset of extensive water-water hydrogen bonding is observed starting with four water molecules and persists in the larger clusters. PMID- 19445494 TI - Nanostructured polymers prepared using a self-assembled nanofibrillar scaffold as a reverse template. AB - We describe the preparation of nanostructured polymeric materials by polymerizing a monomer within a scaffold composed of self-assembled nanofibrils. 1,3:2,4 Dibenzylidene sorbitol (DBS) is an inexpensive sugar derivative that can form nanofibrillar networks in a variety of organic solvents at relatively low concentrations. Here, we induce DBS nanofibrils in styrene and then thermally initiate the free-radical polymerization of the monomer. The polymerization proceeds without any evidence of macroscopic phase separation, ultimately yielding a transparent solid of polystyrene. Within this material, intact DBS nanofibrils (diameter 10-100 nm) are preserved, as shown by atomic force microscopy (AFM). The DBS fibrils can also be subsequently extracted from the polymer, leaving behind a network of nanoscale pores. The porosity of the resulting polymer has been characterized by the BET technique. PMID- 19445495 TI - The Heisenberg-Weyl algebra on the circle and a related quantum mechanical model for hindered rotation. AB - We discuss a periodic variant of the Heisenberg-Weyl algebra, associated with the group of translations and modulations on the circle. Our study of uncertainty minimizers leads to a periodic version of canonical coherent states. Unlike the canonical, Cartesian case, there are states for which the uncertainty product associated with the generators of the algebra vanishes. Next, we explore the supersymmetric (SUSY) quantum mechanical setting for the uncertainty-minimizing states and interpret them as leading to a family of "hindered rotors". Finally, we present a standard quantum mechanical treatment of one of these hindered rotor systems, including numerically generated eigenstates and energies. PMID- 19445496 TI - Characterizing radiation-induced oxidation of DNA by way of the monohydrated guanine-cytosine radical cation. AB - The interaction of one water molecule with the guanine-cytosine radical cation has been studied with ab initio and density functional methods in order to help elucidate the nature of oxidized aqueous DNA. The theoretical spin density of [GC]*(+) reveals that the radical center is localized on guanine. The adiabatic ionization potential lowers from 7.63 to 6.71 eV in concurrence with the formation of the Watson-Crick base pair and hydration by one water molecule. A natural bond orbital analysis of partial charges shows that approximately 80% of the positive charge persists on guanine upon hydration and formation of the Watson-Crick base pair with cytosine. Hydration energies were computed with second-order Z-averaged perturbation theory (ZAPT2) using the aug-cc-pVDZ basis set at 11 stationary points on the B3LYP/DZP++ potential energy surface. The hydration energy at the global minimum is 14.2 kcal mol(-1). The lowest energy structures correspond to hydration near the glycosidic bond sites. Structural changes in the Watson-Crick base pair are predominantly seen for monohydration in the groove regions of double-helix DNA. PMID- 19445497 TI - Investigations of enzyme-catalyzed reactions based on physicochemical descriptors applied to hydrolases. AB - The EC number system for the classification of enzymes uses different criteria such as reaction pattern, the nature of the substrate, the type of transferred groups or the type of acceptor group. These criteria are used with different emphasis for the various enzyme classes and thus do not contribute much to an understanding of the mechanisms of enzyme catalyzed reactions. To explore the reasons for bonds being broken in enzyme catalyzed metabolic reactions, we calculated physicochemical effects for the bonds reacting in the substrate of these enzymatic reactions. These descriptors allow the definition of similarities within these reactions and thus can serve as a method for the classification of enzyme reactions. To foster an understanding of the investigations performed here, we compare the similarities found on the basis of the physicochemical effects with the EC number classification. To allow a reasonable comparison we selected enzymatic reactions where the EC number system is largely built on criteria based on the reaction mechanism. This is true for hydrolysis reactions, falling into the domain of the EC class 3 (EC 3.b.c.d). The comparison is made by a Kohonen neural network based on an unsupervised learning algorithm. For these hydrolysis reactions, the similarity analysis on physicochemical effects produces results that are, by and large, similar to the EC number. However, this similarity analysis reveals finer details of the enzymatic reactions and thus can provide a better basis for the mechanistic comparison of enzymes. PMID- 19445498 TI - Identifying novel molecular structures for advanced melanoma by ligand-based virtual screening. AB - We recently discovered a new class of thiazole analogs that are highly potent against melanoma cells. To expand the structure-activity relationship study and to explore potential new molecular scaffolds, we performed extensive ligand-based virtual screening against a compound library containing 342,910 small molecules. Two different approaches of virtual screening were carried out using the structure of our lead molecule: (1) connectivity-based search using Scitegic Pipeline Pilot from Accelerys and (2) molecular shape similarity search using Schrodinger software. Using a testing compound library, both approaches can rank similar compounds very high and rank dissimilar compounds very low, thus validating our screening methods. Structures identified from these searches were analyzed, and selected compounds were tested in vitro to assess their activity against melanoma cancer cell lines. Several molecules showed good anticancer activity. While none of the identified compounds showed better activity than our lead compound, they provided important insight into structural modifications for our lead compound and also provided novel platforms on which we can optimize new classes of anticancer compounds. One of the newly synthesized analogs based on this virtual screening has improved potency and selectivity against melanoma. PMID- 19445499 TI - Docking ligands into flexible and solvated macromolecules. 4. Are popular scoring functions accurate for this class of proteins? AB - In our previous report, we investigated the impact of protein flexibility and the presence of water molecules on the pose-prediction accuracy of major docking programs. To complete these investigations, we report herein a study of the impact of these two aspects on the accuracy of scoring functions. To this effect, we developed two sets of protein/ligand complexes made up of ligands cross-docked or cocrystallized with a large variety of proteins, featuring bridging water molecules and demonstrating protein flexibility. Efforts were made to reduce the correlation between the molecular weights of the selected ligands and their binding affinities, a major bias in some previously reported benchmark sets. Using these sets, 18 available scoring functions have been assessed for their accuracy to predict binding affinities and to rank-order compounds by their affinity to cocrystallized proteins. This study confirmed the good and similar accuracy of Xscore, GlideScore, DrugScore(CSD), GoldScore, PLP1, ChemScore, RankScore, and the eHiTS scoring function. Our next investigations demonstrated that most of the assessed scoring functions were much less accurate when the correct protein conformation was not provided. This study also revealed that considering the water molecules for scoring does not greatly affect the accuracy. Finally, this work sheds light on the high correlation between scoring functions and the poor increase in accuracy one can expect from consensus scoring. PMID- 19445500 TI - Hybrid calix[4]arenes via ionic hydrogenation and transition-metal-mediated processes. AB - We report the first application of ionic hydrogenation for the synthesis of upper rim urea- or carbamate-derived hybrid calix[4]arenes. Subsequent metal-mediated transformations using 4-iodophenylurea calixarenes afforded structurally unique 1,3-di(biaryl)-, 1,3-di(biarylalkyne)-, or 1,3-(biaryl)(biarylalkyne)-derived hybrid calixarenes. PMID- 19445501 TI - Studies in acyl C-H activation via aryl and alkyl to acyl "through space" migration of palladium. AB - Examples of the 1,4-migration of a palladium moiety in aryl- and alkylpalladium intermediates to the acyl position of an aldehyde or formamide have been observed. The resulting acylpalladium intermediate can undergo ester or carbamate formation by reaction with an alcohol; decarbonylation, followed by beta hydride elimination to an alkene; reaction with an organomercurial to form an ester; or alkene insertion. Deuterium-labeling studies have been used to confirm the palladium migration mechanism. PMID- 19445502 TI - SERS not to be taken for granted in the presence of oxygen. AB - Oxidation of the Ag nanoparticle surface has a dramatic effect on the adsorption, orientation, and SERS detection limit of nitroaromatic molecules in aqueous solutions. Ultrasensitive SERS detection of p-nitrophenol can be achieved when oxidation of surface-immobilized Ag nanoparticles is inhibited by replacing the oxygen dissolved in water with argon gas. The presence of silver oxide at the nanoparticle surface hinders charge transfer between the aromatic ring and the underlying Ag metal surface and drastically decreases the overall detection sensitivity. PMID- 19445503 TI - Broad-spectrum antimicrobial peptides by rational combinatorial design and high throughput screening: the importance of interfacial activity. AB - We recently described 10 peptides selected from a 16,384-member combinatorial library based on their ability to permeabilize synthetic lipid vesicles in vitro. These peptides did not share a common sequence motif, length, or net charge; nonetheless, they shared a mechanism of action that is similar to the natural membrane permeabilizing antimicrobial peptides (AMP). To characterize the selected peptides and to compare the activity of AMPs in vivo and in vitro, we report on the biological activity of the same selected peptides in bacteria, fungi, and mammalian cells. Each of the peptides has sterilizing activity against all classes of microbes tested, at 2-8 microM peptide, with only slight hemolytic or cytotoxicity against mammalian cells. Similar to many natural AMPs, bacteria are killed within a few minutes of peptide addition, and the lethal step in vivo is membrane permeabilization. Single D-amino acid substitutions eliminated or diminished the secondary structure of the peptides, and yet, they retained activity against some microbes. Thus, secondary structure and biological activity are not coupled, consistent with the hypothesis that AMPs do not form pores of well-defined structure in membranes but rather destabilize membranes by partitioning into membrane interfaces and disturbing the organization of the lipids, a property that we have called "interfacial activity". The observation that broad-spectrum activity, but not all antimicrobial activity, is lost by small changes to the peptides suggests that the in vitro screen is specifically selecting for the rare peptides that have broad-spectrum activity. We put forth the hypothesis that methods focusing on screening peptide libraries in vitro for members with the appropriate interfacial activity can enable the design, selection, and discovery of novel, potent, and broad-spectrum membrane-active antibiotics. PMID- 19445505 TI - Synthesis and immunological characterization of toll-like receptor 7 agonistic conjugates. AB - Activation of toll-like receptors (TLRs) on cells of the innate immune system initiates, amplifies, and directs the antigen-specific acquired immune response. Ligands that stimulate TLRs, therefore, represent potential immune adjuvants. In this study, a potent TLR7 agonist was conjugated to phospholipids, poly(ethylene glycol) (PEG), or phospholipid-PEG via a versatile benzoic acid functional group. Compared to the unmodified TLR7 agonist, each conjugate displayed a distinctive immunological profile in vitro and in vivo. In mouse macrophages and human peripheral blood mononuclear cells, the phospholipid TLR7 agonist conjugate was at least 100-fold more potent than the free TLR7 ligands, while the potency of PEG-phospholipid conjugate was similar to that of the unmodified TLR7 agonist. When administered systemically in mice, the phospholipid and phospholipid-PEG TLR7 conjugates induced prolonged increases in the levels of proinflammatory cytokines in serum, compared to the unmodified TLR7 activator. When the conjugates were used as adjuvants during vaccination, only the phospholipid TLR7 agonist conjugates induced both Th1 and Th2 antigen-specific immune responses. These data show that the immunostimulatory activity of a TLR7 ligand can be amplified and focused by conjugation, thus broadening the potential therapeutic application of these agents. PMID- 19445504 TI - Facile preparation of a new gadofullerene-based magnetic resonance imaging contrast agent with high 1H relaxivity. AB - A new magnetic resonance imaging (MRI) contrast agent based on the trimetallic nitride templated (TNT) metallofullerene Gd(3)N@C(80) was synthesized by a facile method in high yield. The observed longitudinal and transverse relaxivities r(1) and r(2) for water hydrogens in the presence of the water-soluble gadofullerene 2 Gd(3)N@C(80)(OH)(approximately 26)(CH(2)CH(2)COOM)(approximately 16) (M = Na or H) are 207 and 282 mM(-1) s(-1) (per C(80) cage) at 2.4 T, respectively; these values are 50 times larger than those of Gd(3+) poly(aminocarboxylate) complexes, such as commercial Omniscan and Magnevist. This high (1)H relaxivity for this new hydroxylated and carboxylated gadofullerene derivative provides high signal enhancement at significantly lower Gd concentration as demonstrated by in vitro and in vivo MRI studies. Dynamic light scattering data reveal a unimodal size distribution with an average hydrodynamic radius of ca. 78 nm in pure water (pH = 7), which is significantly different from other hydroxylated or carboxylated fullerene and metallofullerene derivatives reported to date. Agarose gel infusion results indicate that the gadofullerene 2 displayed diffusion properties different from those of commercial Omniscan and those of PEG5000 modified Gd(3)N@C(80). The reactive carboxyl functionality present on this highly efficient contrast agent may also serve as a precursor for biomarker tissue targeting purposes. PMID- 19445506 TI - Paramagnetic ions enable tuning of nuclear relaxation rates and provide long range structural restraints in solid-state NMR of proteins. AB - Magic-angle-spinning solid-state nuclear magnetic resonance (SSNMR) studies of natively diamagnetic uniformly (13)C,(15)N-enriched proteins, intentionally modified with side chains containing paramagnetic ions, are presented, with the aim of using the concomitant nuclear paramagnetic relaxation enhancements (PREs) as a source of long-range structural information. The paramagnetic ions are incorporated at selected sites in the protein as EDTA-metal complexes by introducing a solvent-exposed cysteine residue using site-directed mutagenesis, followed by modification with a thiol-specific reagent, N-[S-(2 pyridylthio)cysteaminyl]EDTA-metal. Here, this approach is demonstrated for the K28C and T53C mutants of B1 immunoglobulin-binding domain of protein G (GB1), modified with EDTA-Mn(2+) and EDTA-Cu(2+) side chains. It is shown that incorporation of paramagnetic moieties, exhibiting different relaxation times and spin quantum numbers, facilitates the convenient modulation of longitudinal (R(1)) and transverse (R(2), R(1rho)) relaxation rates of the protein (1)H, (13)C, and (15)N nuclei. Specifically, the EDTA-Mn(2+) side chain generates large distance-dependent transverse relaxation enhancements, analogous to those observed previously in the presence of nitroxide spin labels, while this phenomenon is significantly attenuated for the Cu(2+) center. Both Mn(2+) and Cu(2+) ions cause considerable longitudinal nuclear PREs. The combination of negligible transverse and substantial longitudinal relaxation enhancements obtained with the EDTA-Cu(2+) side chain is especially advantageous, because it enables structural restraints for most sites in the protein to be readily accessed via quantitative, site-resolved measurements of nuclear R(1) rate constants by multidimensional SSNMR methods. This is demonstrated here for backbone amide (15)N nuclei, using methods based on 2D (15)N-(13)C chemical shift correlation spectroscopy. The measured longitudinal PREs are found to be highly correlated with the proximity of the Cu(2+) ion to (15)N spins, with significant effects observed for nuclei up to approximately 20 A away, thereby providing important information about protein structure on length scales that are inaccessible to traditional SSNMR techniques. PMID- 19445507 TI - Asymmetric [4 + 3] cycloadditions between vinylcarbenoids and dienes: application to the total synthesis of the natural product (-)-5-epi-vibsanin E. AB - The total synthesis of (-)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4). PMID- 19445509 TI - Synthesis of unique ultrathin lamellar mesostructured CoSe2-amine (protonated) nanobelts in a binary solution. AB - Unique ultrathin CoSe(2)-DETA (protonated) mesostructured nanobelts with multiple stacked layers which are highly parallel to the axial direction have been first prepared in a binary solution composed of organic amine and water under mild solvothermal conditions. This synthesis strategy may open new avenues toward the syntheses of other new mesostructured nanomaterials, which may bring new nontrivial functionalities. PMID- 19445508 TI - Electrostatically mediated liposome fusion and lipid exchange with a nanoparticle supported bilayer for control of surface charge, drug containment, and delivery. AB - The loading and containment of cargo within nanoparticles and their efficient delivery to cells represent a primary challenge in nanomedicine. We report lipid exchange between free and mesoporous silica nanoparticle-supported lipid bilayers as an effective means of containing cargo, controlling charge, and directing delivery to mammalian cells. The delivery of a membrane-impermeable dye (calcein) and a chemotherapeutic drug (doxorubicin) are demonstrated. Exchanged lipid bilayers minimized premature drug release, and an overall positive charge on the supported lipid bilayer effected enhanced delivery. PMID- 19445510 TI - Tailoring structure-property relationships in dithienosilole-benzothiadiazole donor-acceptor copolymers. AB - Four new DTS-BTD copolymers (P1-P4) differing by the concentration of electron donating and -withdrawing substituents along the backbone have been synthesized and characterized by 2D-WAXS and in bottom-contact FETs. While all copolymers can self-assemble into lamellar superstructures, only P2 and P4 show a propensity to pi-stack. P4 exhibits a hole mobility as high as 0.02 cm(2) V(-1) s(-1) in excellent agreement with the close pi-stacking and lamellar distances found by structural analysis (0.36 and 1.84 nm, respectively) and absorbs homogenously across the entire visible spectrum as solar cell applications require. PMID- 19445511 TI - Controlling the number and positions of oligonucleotides on gold nanoparticle surfaces. AB - We describe a new method to immobilize a given number of oligonucleotides (ODNs) on gold nanoparticles (AuNPs) in a specific arrangement directed by a geometrical template made of DNA. The basic strategy is as follows. First, a set of thiolated ODNs for immobilization and a nonthiolated template are hybridized to make a DNA nanostructure. Next, the DNA nanostructure is reacted with AuNPs via the thiol groups to form a complex of the AuNP and the DNA nanostructure. Finally, the intended AuNP/ODN conjugate is obtained by removing the template from the complex. The above strategy enables us to make various formats of AuNP/ODN conjugates simply by changing the design of the DNA nanostructure. We demonstrate proof-of-concept experiments using a linear design of the DNA nanostructure. PMID- 19445512 TI - Asymmetric synthesis of diphosphine ligands containing phosphorus and carbon stereogenic centers by means of a chiral palladium complex promoted hydrophosphination reaction. AB - An organopalladium complex containing ortho-metalated (R)-(1-(dimethylamino) ethyl)naphthalene as the chiral auxiliary has been used to promote the asymmetric hydrophosphination reaction between diphenylphosphine and phenyldi[(Z)-prop-1 enyl]phosphine in high regio- and stereoselectivity under mild conditions. The hydrophosphination reaction generated only two diastereomers in a ratio of 1:1. The two hydrophosphination products contained both phosphorus and carbon stereogenic centers and were subsequently isolated by fractional crystallization. Their absolute stereochemistries were analyzed by X-ray crystallography. The naphthylamine auxiliary could be removed chemoselectively from the template products by treatment with concentrated hydrochloric acid to form the corresponding optically pure neutral dichloro complexes. Subsequently, the dichloro complexes underwent ligand displacement with aqueous cyanide to generate the optically pure diphosphine ligands in high yields. PMID- 19445513 TI - Fluorinated isatin derivatives. Part 2. New N-substituted 5-pyrrolidinylsulfonyl isatins as potential tools for molecular imaging of caspases in apoptosis. AB - Caspases are responsible for the execution of the cell death program and are potentially suitable targets for the specific imaging of apoptosis in vivo. A series of N-1-substituted analogues of the small molecule nonpeptide caspase inhibitor (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (1), which may be useful for the development of caspase-targeted radioligands, were synthesized and their inhibition potencies were evaluated in vitro. Two of the most powerful techniques to introduce fluorine into organic compounds, viz, bromofluorination of olefins and fluorohydrin synthesis by ring-opening of epoxides, were used. Most of the target compounds are potent inhibitors of the two effector caspases-3 and -7. Furthermore, the (18)F-radiolabeled model compound (S)-1-[4-(1 [(18)F]fluoro-2-hydroxyethyl)benzyl]-5-[1-(2-methoxymethyl pyrrolidinyl)sulfonyl]isatin ([(18)F]37), a putative tracer for the noninvasive imaging of apoptosis by positron emission tomography (PET) was synthesized by nucleophilic epoxide ring-opening of its precursor 36. The radiochemistry utilized in the (18)F-fluorination reverted to carrier-added [(18)F]Et(3)N.3HF, a new fluorine-18 source for radiolabeling. PMID- 19445515 TI - Physicochemical determinants of human renal clearance. AB - Kidney plays an important role in the elimination of drugs, especially with low or negligible hepatic clearance. An analysis of the interrelation of physicochemical properties and the human renal clearance for a data set of 391 drugs or compounds tested in humans is presented. The data set indicated that lipophilicity shows a negative relationship while polar descriptors show a positive relationship with renal clearance. Analysis of net secreted and net reabsorbed subsets revealed that hydrophilic ionized compounds are probable compounds to show net secretion and a possible drug-drug interaction due to their likely interaction with uptake transporters and inherent low passive reabsorption. The physicochemical space and renal clearance were also statistically analyzed by therapeutic area. In conclusion, ionization state, lipophilicity, and polar descriptors are found to be the physicochemical determinants of renal clearance. These fundamental properties can be valuable in early prediction of human renal clearance and can aid the chemist in structural modifications to optimize drug disposition. PMID- 19445514 TI - Discovery of the development candidate N-tert-butyl nodulisporamide: a safe and efficacious once monthly oral agent for the control of fleas and ticks on companion animals. AB - Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds. PMID- 19445516 TI - Design and implementation of an ribonucleic acid (RNA) directed fragment library. AB - The design of RNA binding ligands is complicated by issues of specificity, target flexibility, and the tractability of known RNA inhibitors toward chemical derivitization. To address these difficulties, an RNA-directed fragment compound library is presented. We began with an analysis of 120 small molecules with reported RNA-binding activity. Calculated physical and chemical properties for the RNA ligands are comparable to those of ligands for established protein drug targets. To ensure that our library contained RNA-binding functionalities that might not be detected by the above comparisons, 114 fragment compounds were purchased on the basis of similarity to substructures of RNA ligands. Five "hits" were identified for the decoding site from the bacterial ribosome by NMR. These included fragments derived from A-site binding ligands but also compounds not previously identified as A-site binders. Hits generated in this manner can be used to probe the interaction surface of RNA and its conformational plasticity, facilitating structure-based optimization. PMID- 19445517 TI - Antibacterial diterpenes from Plectranthus ernstii. AB - Three new diterpenoids including two pimaranes (1 and 2) and a labdane (3) were isolated from the whole herb of Plectranthus ernstii. The structures of these compounds were determined as rel-15(zeta),16-epoxy-7alpha-hydroxypimar-8,14-ene (1) and rel-15(zeta),16-epoxy-7-oxopimar-8,14-ene (2), and compound 3 was elucidated as 1R,11S-dihydroxy-8R,13R-epoxylabd-14-ene on the basis of single crystal X-ray structural analysis. Compound 1 exhibited moderate antistaphylococcal activity against a range of multidrug-resistant (MDR) and methicillin-resistant (MRSA) strains of Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 32 microg/mL. All three diterpenes exhibited antimycobacterial activity against three strains of rapidly growing mycobacteria with MIC values ranging from 8 to 128 microg/mL. PMID- 19445519 TI - Individualization of nano-sized plant cellulose fibrils by direct surface carboxylation using TEMPO catalyst under neutral conditions. AB - A new catalytic oxidation using 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) and NaClO is applied to hardwood cellulose in water at 60 degrees C and pH 6.8 with NaClO(2) used as a primary oxidant. The oxidized celluloses with carboxylate content of approximately 0.8 mmol/g were convertible to highly crystalline and individual fibrils 5 nm in width and at least 2 MUm in length by disintegration in water. The oxidized celluloses had no aldehyde groups, and high degrees of polymerization of more than 900. Solid-state (13)C NMR and X-ray analyses revealed that the C6 carboxylate groups formed are selectively present on the crystalline fibril surfaces at high densities. Films prepared from the dispersions were transparent and flexible, and exhibited a high tensile strength of 312 MPa even at a low density of 1.47 g/cm(3). PMID- 19445518 TI - Structure and function of Vps15 in the endosomal G protein signaling pathway. AB - G protein-coupled receptors mediate cellular responses to a wide variety of stimuli, including taste, light, and neurotransmitters. In the yeast Saccharomyces cerevisiae, activation of the pheromone pathway triggers events leading to mating. The view had long been held that the G protein-mediated signal occurs principally at the plasma membrane. Recently, it has been shown that the G protein alpha subunit Gpa1 can promote signaling at endosomes and requires two components of the sole phosphatidylinositol-3-kinase in yeast, Vps15 and Vps34. Vps15 contains multiple WD repeats and also binds to Gpa1 preferentially in the GDP-bound state; these observations led us to hypothesize that Vps15 may function as a G protein beta subunit at the endosome. Here we show an X-ray crystal structure of the Vps15 WD domain that reveals a seven-bladed propeller resembling that of typical Gbeta subunits. We show further that the WD domain is sufficient to bind Gpa1 as well as to Atg14, a potential Ggamma protein that exists in a complex with Vps15. The Vps15 kinase domain together with the intermediate domain (linking the kinase and WD domains) also contributes to Gpa1 binding and is necessary for Vps15 to sustain G protein signaling. These findings reveal that the Vps15 Gbeta-like domain serves as a scaffold to assemble Gpa1 and Atg14, whereas the kinase and intermediate domains are required for proper signaling at the endosome. PMID- 19445520 TI - Ruthenium-catalyzed oxidation of alcohols into amides. AB - The synthesis of secondary amides from primary alcohols and amines has been developed using commercially available [Ru(p-cymene)Cl(2)](2) with bis(diphenylphosphino)butane (dppb) as the catalyst. PMID- 19445521 TI - Dynamics of adsorbed hydrocarbon in nanoporous zeolite framework. AB - We report quasielastic neutron scattering (QENS) and molecular dynamics (MD) simulation study of the dynamics of propylene molecules adsorbed in Na-ZSM5 zeolite. MD simulation studies suggest that rotational motion is almost an order of magnitude faster than translational motion. Therefore, spectrometers having different energy resolutions were used to determine the translational and rotational contributions. Translational motion, being slower, was distinctly observed in a narrower window spectrometer while both contribute to the wider one. Diffusion of propylene in the channels of Na-ZSM5 zeolite was found to follow jump diffusion model. Dynamical parameters corresponding to translational diffusion obtained from experiment are found to be consistent with MD simulation. Variation of elastic incoherent structure factor (EISF) suggests that rotational motion of propylene is isotropic. Although at short times the rotational motion was found to be anisotropic, as indicated in the MD simulation depicting restricted channel framework, but at long time it results in isotropic rotational motion. PMID- 19445522 TI - Tetra-n-butylammonium borohydride semiclathrate: a hybrid material for hydrogen storage. AB - In this study, we demonstrate that tetra-n-butylammonium borohydride [(n C(4)H(9))(4)NBH(4)] can be used to form a hybrid hydrogen storage material. Powder X-ray diffraction measurements verify the formation of tetra-n butylammonium borohydride semiclathrate, while Raman spectroscopic and direct gas release measurements confirm the storage of molecular hydrogen within the vacant cavities. Subsequent to clathrate decomposition and the release of physically bound H(2), additional hydrogen was produced from the hybrid system via a hydrolysis reaction between the water host molecules and the incorporated BH(4)( ) anions. The additional hydrogen produced from the hydrolysis reaction resulted in a 170% increase in the gravimetric hydrogen storage capacity, or 27% greater storage than fully occupied THF + H(2) hydrate. The decomposition temperature of tetra-n-butylammonium borohydride semiclathrate was measured at 5.7 degrees C, which is higher than that for pure THF hydrate (4.4 degrees C). The present results reveal that the BH(4)(-) anion is capable of stabilizing tetraalkylammonium hydrates. PMID- 19445523 TI - Benzylic oxidation of gemfibrozil-1-O-beta-glucuronide by P450 2C8 leads to heme alkylation and irreversible inhibition. AB - Gemfibrozil-1-O-beta-glucuronide (GEM-1-O-gluc), a major metabolite of the antihyperlipidemic drug gemfibrozil, is a mechanism-based inhibitor of P450 2C8 in vitro, and this irreversible inactivation may lead to clinical drug-drug interactions between gemfibrozil and other P450 2C8 substrates. In light of this in vitro finding and the observation that the glucuronide conjugate does not contain any obvious structural alerts, the current study was conducted to determine the potential site of GEM-1-O-gluc bioactivation and the subsequent mechanism of P450 2C8 inhibition (i.e., modification of apoprotein or heme). LC/MS analysis of a reaction mixture containing recombinant P450 2C8 and GEM-1-O gluc revealed that the substrate was covalently linked to the heme prosthetic heme group during catalysis. A combination of mass spectrometry and deuterium isotope effects revealed that a benzylic carbon on the 2',5'-dimethylphenoxy group of GEM-1-O-gluc was covalently bound to the heme of P450 2C8. The regiospecificity of substrate addition to the heme group was not confirmed experimentally, but computational modeling experiments indicated that the gamma meso position was the most likely site of modification. The metabolite profile, which consisted of two benzyl alcohol metabolites and a 4'-hydroxy-GEM-1-O-gluc metabolite, indicated that oxidation of GEM-1-O-gluc was limited to the 2',5' dimethylphenoxy group. These results are consistent with an inactivation mechanism wherein GEM-1-O-gluc is oxidized to a benzyl radical intermediate, which evades oxygen rebound, and adds to the gamma-meso position of heme. Mechanism-based inhibition of P450 2C8 can be rationalized by the formation of the GEM-1-O-gluc-heme adduct and the consequential restriction of additional substrate access to the catalytic iron center. PMID- 19445525 TI - Electronic properties of 4-substituted naphthalimides. AB - This paper describes a study of excited-state properties of naphthalimide (NI) and four 4-substituted derivatives: 4-chloronaphthalimide (Cl-NI), 4 methylthionaphthalimide (MeS-NI), 4-nitronaphthalimide (O(2)N-NI), and 4-(N,N dimethylaminonaphthalimide (Me(2)N-NI). Steady-state absorption and fluorescence spectra were collected in solvents of varying polarity to determine the excited state character of NI derivatives. Furthermore, the excited-state dynamics were studied using femtosecond transient absorption spectroscopy. The experimental findings were compared to calculated data obtained using time-dependent density functional (TD-DFT) methods. We found that light absorption by all NI derivatives leads to the production of the second excited state (S(2)), which was found to have a n,pi* character. Within approximately 40 ps, the S(2) state undergoes internal conversion to produce the S(1) state. The S(1) state is relatively long lived (approximately 4 ns) and has charge-transfer character in NI derivatives with electron-withdrawing and electron-donating groups (MeS-NI, O(2)N-NI, and Me(2)N-NI). In the case of NI and Cl-NI, the S(1) state has a pi,pi* character and undergoes intersystem crossing to produce the T(1) state within 400 ps. PMID- 19445524 TI - Rapid in situ generation of two patterned chemoselective surface chemistries from a single hydroxy-terminated surface using controlled microfluidic oxidation. AB - In this work, we develop a new, rapid and inexpensive method to generate spatially controlled aldehyde and carboxylic acid surface groups by microfluidic oxidation of 11-hydroxyundecylphosphonic acid self-assembled monolayers (SAMs) on indium tin oxide (ITO) surfaces. SAMs are activated and patterned using a reversibly sealable, elastomeric polydimethylsiloxane cassette, fabricated with preformed micropatterns by soft lithography. By flowing the mild oxidant pyridinium chlorochromate through the microchannels, only selected areas of the SAM are chemically altered. This microfluidic oxidation strategy allows for ligand immobilization by two chemistries originating from a single SAM composition. ITO is robust, conductive, and transparent, making it an ideal platform for studying interfacial interactions. We display spatial control over the immobilization of a variety of ligands on ITO and characterize the resulting oxime and amide linkages by electrochemistry, X-ray photoelectron spectroscopy, contact angle, fluorescence microscopy, and atomic force microscopy. This general method may be used with many other materials to rapidly generate patterned and tailored surfaces for studies ranging from molecular electronics to biospecific cell-based assays and biomolecular microarrays. PMID- 19445526 TI - Theoretical determination of the redox potentials of NRH:quinone oxidoreductase 2 using quantum mechanical/molecular mechanical simulations. AB - NRH:quinone oxidoreductase 2 (NQO2) is a flavoenzyme that catalyzes a one-step two-electron reduction of quinones. During this enzyme catalysis, the 7,8 dimethyl isoalloxazine (flavin) ring of the enzyme-bound cofactor, flavin adenine dinucleotide (FAD), shuttles between reduced and oxidized states as the enzyme passes through multiple cycles of binding/release of alternate substrates. These redox changes in NQO2, however, lead to unequal charge separation between the flavin ring and the active site, which must be stabilized by reorganization of the surrounding protein matrix. In this study, we have used a combined quantum mechanical/molecular mechanical method to simulate the electron and proton addition reactions of the flavin-bound NQO2. We have computed the redox potentials and pK(a)'s of the enzyme-bound flavin. The present work demonstrates that upon reduction, the NQO2 active site stabilizes the flavin anionic hydroquinone state. Simulation data has also allowed quantitative estimation of the electrostatic contributions of active site residues. Their significance in oscillatory redox transition of this flavoenzyme is discussed. PMID- 19445527 TI - Comparative proteomic analysis of differentially expressed proteins in shoots of Salicornia europaea under different salinity. AB - Soil salinity is a major abiotic stress that limits agriculture productivity worldwide. Salicornia europaea is a succulent annual euhalophyte and one of the most salt tolerant plant species. The elucidation of its salt tolerance mechanism is of significance for generating salt-tolerant crops. In this study, we provided high resolution of proteome reference maps of S. europaea shoot and obtained evidence on the salt tolerance mechanism by analyzing the proteomic responses of this plant to high salinity. Our results demonstrated significant variations existed in 196 out of 1880 protein spots detected on CBB stained 2-DE gels. Of these, 111 proteins were identified by mass spectrometry. Among them, the majority was energy production and conversion related proteins, followed by photosynthesis and carbohydrate metabolism associated enzymes. Analysis of protein expression patters revealed that energy production and ion homeostasis associated proteins played important roles for this plant salt tolerance ability. Hierarchical clustering results revealed many proteins were involved in S. europaea salt tolerance mechanism as a dynamic network. Finally, based on our proteomic results, we brought forward a possible schematic representation of mechanism associated with the systematic salt tolerance phenotype in S. europaea. PMID- 19445528 TI - NMR-based metabolic profiling identifies biomarkers of liver regeneration following partial hepatectomy in the rat. AB - Tissue injury and repair are often overlapping consequences of disease or toxic exposure, but are not often considered as distinct processes in molecular studies. To establish the systemic metabolic response to liver regeneration, the partial hepatectomy (PH) model has been studied in the rat by an integrated metabonomics strategy, utilizing (1)H NMR spectroscopy of urine, liver and serum. Male Sprague-Dawley rats were subjected to either surgical removal of approximately two-thirds of the liver, sham operated (SO) surgery, or no treatment (n = 10/group) and samples collected over a 7 day period. A number of urinary metabolic perturbations were observed in PH rats compared with SO and control animals, including elevated levels of taurine, hypotaurine, creatine, guanidinoacetic acid, betaine, dimethylglycine and bile acids. Serum betaine and creatine were also elevated after PH, while levels of triglyceride were reduced. In the liver, triglycerides, cholesterol, alanine and betaine were elevated after PH, while choline and its derivatives were reduced. Upon examining the dynamic pattern of urinary response (the 'metabolic trajectory'), several metabolites could be categorized into groups likely to reflect perturbations to different processes such as dietary intake or hepatic 1-carbon metabolism. Several of the urinary perturbations observed during the regenerative phase of the PH model have also been observed after exposure to liver toxins, indicating that hepatic regeneration may make a contribution to the systemic alterations in metabolism associated with hepatotoxicity. The observed changes in 1-carbon and lipid metabolism are consistent with the proposed role of these pathways in the activation of a regenerative response and provide further evidence regarding the utility of urinary NMR profiles in the detection of liver-specific pathology. Biofluid (1)H NMR-based metabolic profiling provides new insight into the role of metabolism of liver regeneration, and suggests putative biomarkers for the noninvasive monitoring of the regeneration process. PMID- 19445531 TI - Genomic consequences of cytochrome P450 2C9 overexpression in human hepatoma cells. AB - Cytochrome P450 2C9 (P450 2C9) is one of the most important P450 isoforms in the human liver, as it metabolizes numerous exogenous and endogenous substrates. Moreover, it is inducible by several compounds, such as rifampicin, phenobarbital, and NSAIDs (nonsteroidal anti-inflammatories). The aim of this study was to investigate the global cellular consequences of P450 2C9 overexpression at the transcriptional level using an untargeted approach: pangenomic microarrays. Recombinant adenovirus was used to express P450 2C9 instead of an inducer to prevent a per se effect of inducer or its metabolites. P450 2C9 overexpression induced endoplasmic reticulum (ER) stress and regulated genes implicated in the unfolded protein response (UPR) as heat shock protein (HSP) (we studied particurlarly HSPA5 and HSPB1) and in the endoplasmic reticulum associated degradation (ERAD) system as Sec61 and ubiquitin and proteasome pathways. UPR and ERAD are two mechanisms of adaptative response to ER stress. Moreover, activation of Akt was observed in HepG2 cells that overexpress P450 2C9 and might participate in the cellular adaptive response to stress, thus leading to the activation of cell survival pathways. UPR and ERAD should be caused by accumulation of native and misfolded P450 2C9 protein. Our results indicated that P450 2C9 overexpression did not lead to toxicity but induced an ER stress due to protein overexpression rather than mono-oxygenase activity. The ER stress triggered activation of the adaptative response and of pathways leading to cell survival. PMID- 19445532 TI - Substrate specificity and scope of MvdD, a GRASP-like ligase from the microviridin biosynthetic gene cluster. AB - The cyanobacterial protease inhibitor microviridin K is ribosomally biosynthesized as a prepeptide (MvdE) and subsequently modified posttranslationally by double lactonization followed by lactamization. Two proteins belonging to the GRASP superfamily of ligases catalyze these ring closures. We here show that one of these ligases (MvdD) forms the lactones in a specific order, the larger ring being formed first, and that the ring size requirement for both lactonizations is stringent. However, for the first cyclization MvdD accepts alanine substitution in all C-terminal positions of the microviridin prepeptide that are not directly involved in the cross-linking, whereas the second lactonization is dependent on the presence of specific residues in MvdE. This suggests that MvdD possesses some, albeit limited, substrate tolerance that might be useful for the modification of peptides and proteins not belonging to the microviridin group of metabolites. PMID- 19445533 TI - Evaluation of photocrosslinked Lutrol hydrogel for tissue printing applications. AB - Application of hydrogels in tissue engineering and innovative strategies such as organ printing, which is based on layered 3D deposition of cell-laden hydrogels, requires design of novel hydrogel matrices. Hydrogel demands for 3D printing include: 1) preservation of the printed shape after the deposition; 2) maintaining cell viability and cell function and 3) easy handling of the printed construct. In this study we analyze the applicability of a novel, photosensitive hydrogel (Lutrol) for printing of 3D structured bone grafts. We benefit from the fast temperature-responsive gelation ability of thermosensitive Lutrol-F127, ensuring organized 3D extrusion, and the additional stability provided by covalent photocrosslinking allows handling of the printed scaffolds. We studied the cytotoxicity of the hydrogel and osteogenic differentiation of embedded osteogenic progenitor cells. After photopolymerization of the modified Lutrol hydrogel, cells remain viable for up to three weeks and retain the ability to differentiate. Encapsulation of cells does not compromise the mechanical properties of the formed gels and multilayered porous Lutrol structures were successfully printed. PMID- 19445534 TI - Placement of MammoSite brachytherapy catheter under computed-tomography scan guidance. AB - Placement of the MammoSite breast brachytherapy catheter is most commonly performed either intraoperatively or under ultrasound-guided technique. Below, we present a case report of an alternate approach utilizing CT-scan guidance. This is the first reported case of a balloon brachytherapy catheter placement with this technique. PMID- 19445535 TI - Technical aspects of the integration of three-dimensional treatment planning dose parameters (GEC-ESTRO Working Group) into pre-implant planning for LDR gynecological interstitial brachytherapy. AB - This study investigates the technical feasibility of pre-implant image-based treatment planning for LDR GYN interstitial brachytherapy(IB) based on the GEC ESTRO guidelines. Initially, a virtual plan is generated based on the prescription dose and GEC-ESTRO defined OAR dose constraints with a pre-implant CT. After the actual implant, a regular diagnostic CT was obtained and fused with our pre-implant scan/initial treatment plan in our planning software. The Flexi needle position changes, and treatment plan modifications were made if needed. Dose values were normalized to equivalent doses in 2 Gy fractions (LQED 2 Gy) derived from the linear-quadratic model with alpha/beta of 3 for late responding tissues and alpha/beta of 10 for early responding tissues. D(90) to the CTV, which was gross tumor (GTV) at the time of brachytherapy with a margin to count for microscopic disease, was 84.7 +/- 4.9% of the prescribed dose. The OAR doses were evaluated by D(2cc) (EBRT+IB). Mean D(2cc) values (LQED(2Gy)) for the rectum, bladder, sigmoid, and small bowel were the following: 63.7 +/- 8.4 Gy, 61.2 +/- 6.9 Gy, 48.0 +/- 3.5 Gy, and 49.9 +/- 4.2 Gy. This study confirms the feasibility of applying the GEC-ESTRO recommended dose parameters in pre-implant CT-based treatment planning in GYN IB. In the process, this pre-implant technique also demonstrates a good approximation of the target volume dose coverage, and doses to the OARs. PMID- 19445536 TI - Assessing four-dimensional radiotherapy planning and respiratory motion-induced dose difference based on biologically effective uniform dose. AB - Four-dimensional (4D) radiotherapy is considered as a feasible and ideal solution to accommodate intra-fractional respiratory motion during conformal radiation therapy. With explicit inclusion of the temporal changes in anatomy during the imaging, planning, and delivery of radiotherapy, 4D treatment planning in principle provides better dose conformity. However, the clinical benefits of developing 4D treatment plans in terms of tumor control rate and normal tissue complication probability as compared to other treatment plans based on CT images of a fixed respiratory phase remains mostly unproven. The aim of our study is to comprehensively evaluate 4D treatment planning for nine lung tumor cases with both physical and biological measures using biologically effective uniform dose (D =) together with complication-free tumor control probability, P+. Based on the examined lung cancer patients and PTV margin applied, we found similar but not identical curves of DVH, and slightly different mean doses in tumor (up to 1.5%) and normal tissue in all cases when comparing 4D, P0%, and P50% plans. When it comes to biological evaluations, we did not observe definitively PTV size dependence in P+ among these nine lung cancer patients with various sizes of PTV. Moreover, it is not necessary that 4D plans would have better target coverage or higher P+ as compared to a fixed phase IMRT plan. However, on the contrary to significant deviations in P+ (up to 14.7%) observed if delivering the IMRT plan made at end-inhalation incorrectly at end-exhalation phase, we estimated the overall P+, PB, and PI for 4D composite plans that have accounted for intra fractional respiratory motion. PMID- 19445537 TI - Biochemical control and toxicity after intensity-modulated radiation therapy for prostate cancer. AB - Intensity modulated radiation therapy (IMRT) has achieved widespread use for prostate cancer; however, in relation to this use, outcomes studies are still relatively sparse. We report a single-institutional experience in outcomes analysis with the use of IMRT for the primary management of prostate cancer. One hundred thirty consecutive patients with adenocarcinoma of the prostate were treated at a single institution using IMRT with curative intent. Thirty-six (28%) patients were classified as low-risk, 69 (53%) as intermediate-risk, and 25 (19%) as high-risk. The median dose prescription was 76 Gy to the planning target volume. Sixty-five (50%) patients received androgen deprivation therapy (ADT) for a median 4 months, starting 2 months prior to IMRT. Biochemical failure was defined as PSA < post-treatment nadir+2. Gastrointestinal (GI) and Genitourinary (GU) toxicity were defined by RTOG criteria. Median follow-up was 53 months. By NCCN risk category, 4-year biochemical control was 97%, 94%, and 87% for low, intermediate, and high-risk patients, respectively. Among disease factors, multivariable analysis demonstrated the strongest association between biochemical control and Gleason score < or =6 (p=0.0371). Therapy was well tolerated with no Grade 4 toxicity and limited grade 3 GI or GU toxicity. Acute Grade 3+ GI and GU toxicity rates were 0% and 2%, and maximal late Grade 3+ GI and GU toxicity rates were 5% and 6%, respectively. Late rectal toxicity was associated with higher volumes of RT to the rectum. By last follow-up late Grade 3+ toxicity was 2% for both GI and GU systems. In conclusion, patients treated with IMRT for prostate cancer have excellent rates of biochemical control and low rates of severe toxicity of treatment. PMID- 19445538 TI - Percutaneous tumor ablation: microencapsulated echo-guided interstitial chemotherapy combined with cryosurgery increases necrosis in prostate cancer. AB - This study aimed at confirming the increased growth inhibition (GI) of human prostate tumors produced by a intentionally palliative combination treatment of cryochemotherapy, i.e., partial cryoablation (CA) followed by intratumor partial chemotherapy with injection of microencapsulated 5-fluorouracil (MCC/5FU) at the ice ball (IB) periphery. We report the local effectiveness of cryochemotherapy compared to chemotherapy only with using multiple injections of MCC/5FU spaced out to maximize cumulative effect of sustained release of 5-fluorouracil (5FU) during a 21-day period. Prostate bioluminescent tumor cells - DU145 Luc+ - were implanted sub-cutaneously and bilaterally in each flank of nude mice. Tumors were treated with: (i) cryoablation alone (CA), causing necrosis in approximately 45% of the tumor volume; (ii) cryo-chemotherapy (CA+MCC/5FU), a combined regimen consisting of partial CA followed immediately and on day 14 by ultrasound assisted, intra-tumor injections (40 mul) of MCC/5FU( 0.81 ng/mm3 of tumor) containing Ethiodol (IPO) an imaging contrast agent, on two opposite sides of the unfrozen part of tumor; (iii) intratumor chemotherapy (MCC/5FU), consisting of three successive intra-tumor injections of microencapsulated 5FU on two opposite sides on Day 0, 4, and 11, and (iv) control series (MM), consisting of a single injection of echogenic microcapsules (mucaps) containing IPO but no 5FU. Tumor growth and viability were followed during a 21-day period with using biometric measurements, bioluminescent imaging (BLI) and ultrasonography (US), and then animals were sacrificed. CA, spared 54.4% of the tumor volume and the IB kill ratio was 0.4 +/-0.9. The maximum tumor volume reduction observed by Day 3 was short-lived as re-growth became significant by Day 6. CA+ MCC/5FU spared 55.6% of the tumor volume and the IB kill ratio was 0.54 +/- 0.12. The viable tumor cells, as measured by BLI remained at preoperative levels. After 11 days CA+ MCC/5FU limited the growth of the partially ablated tumors to only 10.6% of the growth of CA treated tumors (p=0.04). By Day 18 the CA+MCC/5FU had inhibited tumor growth by 78% compared to the CA treated tumors (p=0.05) and after 21 days the growth was inhibited by 71% (p=0.04) compared to more than 650% growth in the MM group and 600% growth in the CA treated group. The two injections of MCC/5FU produced a visible focal necrosis in 55% of the tumors. MCC/5FU proved effective by themselves and reduced the growth of prostate tumor volumes by 51% (p=0.025) compared to MM controls during the 21 days. Focal necrosis was macroscopically visible at the site of 66% of the tumors injected only with MCC/5FU. The BLI clearly showed zones of reduced tumor cell viability at the injection sites. The mean number of bioluminescent (viable) tumor cells, remained below preoperative levels for the first 6 days and then increased at a rate approximately 20% that of the growth of control tumor cells. The chemoablative effects of intentionally limited doses of MCC/5FU injected within the IB margin augment the effects of incomplete cryoablation in this prostate tumor model, with dramatic tumor GI and directionally increased necrosis dimensions compared to CA alone, confirming the results of a previous study. Our results indicate the potential advantages of our combination cryochemotherapy that utilizes different mechanisms to kill tumor cells and retard tumor growth in the region surrounding the IB where tumor cells escape the lethal effects of cryosurgery. The study suggests that cryochemotherapy may become a more predictable technique that could be indicated as an adjuvant or an alternative to palliative therapy of hormone refractory prostate cancer (HRPC). PMID- 19445539 TI - Complications of high intensity focused ultrasound for patients with hepatocellular carcinoma. AB - High intensity focused ultrasound (HIFU) is a noninvasive treatment modality that induces complete coagulative necrosis of a deep tumor through the intact skin. This study was conducted to analyze and evaluate the complications of HIFU for the treatments of hepatocellular carcinoma. A total of 59 patients with hepatocellular carcinoma, with a total of 72 lessions were enrolled in this study. Tumor size ranged from 2.5 to 14.0 cm in diameter, with a mean diameter of 7.6 cm. All patients had accepted HIFU treatment, and the median number of HIFU sessions was 1.32 per patient. RESULTS: The common complications from HIFU therapy were skin burns of various grades (eight cases of grade 1 skin burns, 48 of grade 2, three cases of 3), and pain in the treatment regions (15 cases of mild pain, 37 cases of moderate pain, 7 cased of severe pain). Other systemic complications were relatively rare and included fever (5 cases), hypertension (8 cases), supraventricular tachycardia (3 cases), mild impairment of hepatic function (48 cases), and mild mpairment of renal function (2 cases). Local damage consisted of acute cholecystitis (2 cases), hematuria (6 cases ), cholangiectasis (5 cases), light pericardial effusion (2 cases), impairment of peripheral nerves (10 cases), pleural effusion in the right thorax (3 cases), and impairment of vertebral column (1 case). No gastric or intestinal tract perforation, big vessel rupture, or hepatic rupture occurred. CONCLUSIONS: HIFU is a minimally invasive treatment for patients with hepatocellular carcinoma; however, there are some systemic and local complications that should be taken into consideration in evaluating HIFU for therapeutic use. PMID- 19445540 TI - SELDI-TOF-MS-based serum proteomic screening in combination with CT scan distinguishes renal cell carcinoma from benign renal tumors and healthy persons. AB - In order to identify the proteomic differences between renal cell carcinoma (RCC) and benign renal tumors, we analyzed 168 serum samples from 65 RCC patients, 34 patients with benign renal tumors, and 69 healthy persons using the IMAC-Cu2+ ProteinChip system by surface enhanced laser desorption/ionization mass spectrometry technology. Two decision trees were generated by Biomarker Pattern software to distinguish between RCC versus healthy and RCC versus patients with benign tumors, respectively. Although the sensitivity and specificity of the RCC vs. healthy decision tree were 97.6% and 95.7%, respectively, it could not be used to distinguish RCC from benign renal tumors. The sensitivity of a blind test process using RCC, benign tumors and healthy persons were 92%. The specificity of the test process was 35.3% for benign tumors and 95.5% for healthy persons. The sensitivity and specificity of the RCC-Benign tumors decision tree were 85.7% and 95.5%, respectively. The blind test process using RCC, benign tumors and healthy persons also showed significant results. The sensitivity was 90.0%. The specificity was 95.7% for healthy persons and 90.0% for benign tumors. Combining these data with the results of CT scanning, the sensitivity can be improved over the use of either CT and decision tree analysis and the specificity may reach 100%. Two peaks with molecular masses of 3887.11 Da and 11079.8 Da were detected that are potentially useful for the diagnosis or screening of RCC. It was found that these two peaks can be used, not only to distinguish the RCC vs. healthy cases, but also to distinguish RCC from benign renal tumors. In combination with CT scanning, the sensitivity and specificity of the diagnosis of renal tumors can be improved. However, the decision tree constructed for RCC and healthy persons may not present good specificity for use in distinguishing malignant from benign renal tumors. PMID- 19445541 TI - The correlation between GPR30 and clinicopathologic variables in breast carcinomas. AB - The G-protein-coupled-receptor 30 (GPR30) is a new membrane estrogen receptor. The aim of the present study was to determine the correlations among GPR30, ERalpha, PR, C-erbB-2, p53, TNM stage, and pathologic grade in breast carcinomas. Two hundred forty-one biopsy specimens were evaluated with immunohistochemical assays, and then correlations were analyzed. Low negative correlations of GPR30 with ERalpha (r = -0.144, P<0.05) and PR (r = -0.214, P<0.01) were observed. Associations of GPR30 with C-erbB-2, p53, TNM stage, and pathologic grade were not confirmed. These findings indicated that GPR30 might be an independent prognostic factor in breast carcinomas. PMID- 19445543 TI - Simulating sharp gradients for short-term, Ca(2+) transients and long-term chemotaxis in cancer cells. AB - Rapid progress in the elucidation of candidate genes and proteins that play a role in disease processes such as cancer has been possible with widespread use of genomics and proteomics in the last ten years. It is becoming important to adapt the knowledge gained from mass analytical techniques to visual techniques that enable spatial-temporal discernment of molecular events. This is significant, particularly for the study of pathways that regulate dynamic processes such as cell migration or early events associated with differentiation such as Ca(2+) signaling. This paper describes the use of techniques that create sharp growth factor gradients suitable for local activation of cell surface receptors. The methods involve retardation of the direct flow to create steep gradients at the surface plane where cells are grown. These methods are shown to be suitable for rapid biological assays such as Ca(2+) transients that occur within 1 min of receptor activation, demonstrating that the speed and level of Ca(2+) transients are related to gradient strength. A microfabricated chamber is also determined to be suitable for longer-term analyses such as cancer cell chemotaxis. PMID- 19445542 TI - Effect of siRNA targeting HIF-1alpha combined L-ascorbate on biological behavior of hypoxic MiaPaCa2 cells. AB - The aim of the study was to observe the effect of small interference RNA (siRNA) targeting hypoxia-inducible factor 1alpha (HIF-1alpha) combined L-ascorbate on proliferation, migration, and apoptosis of hypoxic MiaPaCa2 human pancreatic cancer cells. A cassette encoding siRNA targeting HIF-1alpha mediated by recombinant adeno-associated virus (rAAV) was constructed, giving rAAV-siHIF. rAAV-siHIF and L-ascorbate, which were used alone or in combination, were delivered to exponentially growing MiaPaCa2 cells under hypoxic conditions. Then, we observed the expression of HIF-1alpha mRNA and protein, the proliferation, apoptosis, and migration of MiaPaCa2 cells by real-time PCR, Western blot, MTT, TUNEL, and Transwell assay, respectively. Under hypoxic conditions, rAAV-siHIF inhibited the expression of HIF-1alpha mRNA in MiaPaCa2 cells but L-ascorbate did not. However, rAAV-siHIF and L-ascorbate both inhibited the expression of HIF 1alpha protein and the proliferation and migration of MiaPaCa2 cells and induced MiaPaCa2 cell apoptosis. The effect in the combined group was more efficient than that seen when rAAV-siHIF or L-ascorbate was used separately. rAAV-siHIF and L ascorbate both affect biological behavior of hypoxic MiaPaCa2 cells through modulating HIF-1alpha protein expression and rAAV-siHIF and L-ascorbate have synergy under hypoxic conditions. PMID- 19445544 TI - The Dutch Medicines for Children Research Network: a new resource for clinical trials. AB - In Europe, several national networks have been established to undertake clinical research of medicines for children. In the Netherlands, the Dutch Medicines for Children Research Network (MCRN) was launched in September 2008. The purpose of the Dutch MCRN is to improve the speed, quality, and coordination of clinical drug research in children, ultimately resulting in better patient care. PMID- 19445545 TI - Multimodal treatments versus pharmacotherapy alone in children with psychiatric disorders: implications of access, effectiveness, and contextual treatment. AB - Practice guidelines for the treatment of youth with mental health problems tend to endorse integrating psychopharmacologic treatment with psychosocial interventions, such as psychotherapy and parent skills training. However, poor access to pediatric mental health specialists and inadequate training of primary care physicians in psychosocial interventions make it difficult for families to receive this standard of care. Large pediatric randomized, multicenter trials, including the Multimodal Treatment Study of ADHD (attention deficit hyperactivity disorder) [MTA] and the Treatment for Adolescents with Depression Study (TADS), have begun to identify specific advantages of multimodal treatment compared with psychopharmacology alone. Advantages of combined treatment include improvement of both symptoms and family functioning. More research is needed to determine effective and appropriate multimodal interventions for complex and severe pediatric mental illness. Advantages of multimodal treatment must be balanced with the treatment burden on the family system. PMID- 19445546 TI - Pediatric generalized anxiety disorder: epidemiology, diagnosis, and management. AB - Pediatric generalized anxiety disorder (GAD) is characterized by excessive and uncontrollable worry about a variety of events and is accompanied by physical symptoms such as headaches, tension, restlessness, gastrointestinal distress, and heart palpitations. Symptoms impose marked distress and interfere with social, emotional, and educational functioning. GAD occurs in over 10% of children and adolescents, has an average age of onset of 8.5 years, and is more often reported in girls. Common co-occurring conditions include separation anxiety disorder and social phobia. Assessment involves a multi-informant, multi-method approach involving the child, parents, and school teachers. A clinical interview should be conducted to assess for the three primary ways anxiety presents: behaviors, thoughts, and somatic symptoms. Several semi-structured diagnostic interviews are available, and the Anxiety Disorders Interview Schedule is increasingly used. Rating scales completed by the patient, caregivers, and teachers provide useful information for diagnosis and symptom monitoring. Several scales are available to assess patients for the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) GAD diagnosis; however, instruments generally cannot distinguish children with GAD from children with similar anxiety disorders. Both cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) have demonstrated efficacy for the treatment of pediatric anxiety disorders including GAD. Evidence suggests that the combination of CBT plus sertraline offers additional benefit compared with either treatment alone. With pharmacotherapy, systematic tracking of treatment-emergent adverse events such as headaches, stomach aches, behavioral activation, worsening symptoms, and emerging suicidal thoughts is important. Recommended starting doses are fluvoxamine 25 mg/day, fluoxetine 10 mg/day, and sertraline 25 mg/day, though lower starting doses are possible. Dosing can be adjusted as often as weekly with the goal of achieving a high-quality response, while minimizing side effects. Long-term treatment with medication has not been well studied; however, to achieve optimal long-term outcome extended use of medication may be required. It is recommended to continue medication for approximately 1 year following remission in symptoms, and when discontinuing medication to choose a stress-free time of the year. If symptoms return, medication re-initiation should be considered seriously. PMID- 19445547 TI - Current pharmacological management of gastro-esophageal reflux in children: an evidence-based systematic review. AB - Gastro-esophageal reflux (GER) is a common phenomenon, characterized by the regurgitation of the gastric contents into the esophagus. Gastro-esophageal reflux disease (GERD) is the term applied when GER is associated with sequelae or faltering growth. The main aims of treatment are to alleviate symptoms, promote normal growth, and prevent complications. Medical treatments for children include (i) altering the viscosity of the feeds with alginates; (ii) altering the gastric pH with antacids, histamine H(2) receptor antagonists, and proton pump inhibitors; and (iii) altering the motility of the gut with prokinetics, such as metoclopramide and domperidone. Our aim was to systematically review the evidence base for the medical treatment of gastro-oesophageal reflux in children. We searched PubMed, AdisOnline, MEDLINE, and EMBASE, and then manually searched reviews from the past 5 years using the key words 'gastro-esophageal' (or 'gastroesophageal'), 'reflux', 'esophagitis', and 'child$' (or 'infant') and 'drug$' or 'therapy'. Articles included were in English and had an abstract. We used the levels of evidence adopted by the Centre for Evidence-Based Medicine in Oxford to assess the studies for all reported outcomes that were meaningful to clinicians making decisions about treatment. This included the impact of clinical symptoms, pH study profile, and esophageal appearance at endoscopy. Five hundred and eight articles were reviewed, of which 56 papers were original, relevant clinical trials. These were assessed further. Many of the studies considered had significant methodological flaws, although based on available evidence the following statements can be made. For infant GERD, ranitidine and omeprazole and probably lansoprazole are safe and effective medications, which promote symptomatic relief, and endoscopic and histological healing of esophagitis. Gaviscon(R) Infant sachets are safe and can improve symptoms of reflux. There is less evidence to support the use of domperidone or metoclopramide. More evidence is needed before other anti-reflux medications can be recommended. For older children, acid suppression is the mainstay of treatment. The largest evidence base supports the early use of H(2) receptor antagonists or proton pump inhibitors. PMID- 19445548 TI - Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. AB - Atomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. Atomoxetine is rapidly absorbed, and demonstrates dose proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. Atomoxetine did not differ significantly from or was noninferior to immediate release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR QOL) appeared to be positively affected by atomoxetine in both short- and long term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year. PMID- 19445549 TI - Management of acute and chronic pain in the Italian setting and a look toward the future. Foreword. PMID- 19445550 TI - Pain treatment with opioids : achieving the minimal effective and the minimal interacting dose. AB - Appropriate and successful management of pain with opioid analgesics is based on tailoring pharmacologic treatment to the individual and identifying the minimal effective dose at which pain is controlled with minimal adverse effects. Morphine and morphine-like-agonists exhibit similar pharmacodynamic profiles, but substantially different receptor affinities and pharmacokinetic properties, which dictate the dosage, route and regimen required to achieve analgesic effect. Opioids exhibit differences in drug elimination resulting in marked variations in the plasma half-life value. Although fentanyl is more potent than morphine, with a shorter duration of action than parenteral morphine, its oral bioavailability is poor and it is administered transdermally. Morphine, with a short half-life and a time to steady-state plasma concentrations of 10-12 hours is better suited than transdermal fentanyl for initial opioid therapy and for the treatment of unstable pain, which requires a fluctuating opioid dose. International guidelines recommend normal-release morphine for initial optimization of individual dose because its pharmacokinetics allow 'real-time' dose regimen changes and rapid identification of the dose required for pain control. Once an effective normal release morphine dosage is achieved, other administration routes, formulations and opioids can be considered as required. Despite guidelines advocating that transdermal fentanyl should only be used in patients who are shown to be tolerant to strong opioid therapy, in Italy and other European countries, controlled release or transdermal opioids are often used when starting opioid therapy. Opioids are associated with a wide range of adverse reactions, but these can be minimized with careful drug titration and maintenance. A major challenge with pain control is polypharmacy and the risk of pharmacokinetic or pharmacodynamic drug-drug interactions. Prevention and management of interactions rely on careful and timely adjustment of drug regimens involved, according to the severity of the effect. Dose titration is the key to successful therapy initiation with strong opioids in patients with moderate-to-severe pain. It is the only way to establish the optimal and minimal effective dose and provides the best protection against adverse effects. Committed physicians should adhere to guidelines on the appropriate use of opioids in all patients, particularly those with a high risk of adverse reactions. PMID- 19445551 TI - Standard therapy with opioids in chronic pain management : ORTIBER study. AB - OBJECTIVE: Moderate to severe pain is commonly experienced by cancer and non cancer patients. Although opioids are generally the most important drugs in chronic pain management, their use in Italy remains low. We designed a prospective open trial to assess the efficacy and safety of a standard therapy clinically available for a large range of patients. METHODS: A total of 172 consecutive patients (89 women and 83 men) with chronic pain (daily mean visual analogue scale (VAS) score > 4) that was not adequately managed by their existing pain regimen were enrolled to receive an immediate release (IR) dose of morphine: 30 mg/day (opioid-naive patients) or 60 mg/day (non-naive patients) for 5 days. After this period (start therapy), all patients were switched to slow release (SR) opioid therapy for 30 days (steady therapy). Each breakthrough pain (BTP) episode was treated with a single dose of IR morphine (20% of the daily dose) during all study periods. RESULTS: Daily VAS score was reduced from 7.4 +/- 1.3 at baseline to 3.8 +/- 1.5 (p < 0.0001) after 30 days of steady therapy in cancer and non-cancer patients. Fewer patients reported BTP events by study end (55% of patients with BTP at basal time had no BTP at last follow up), and the number of daily BTP events experienced by patients was reduced by therapy to 1-2 per day in 75% of patients reporting BTP. Further, the time delay to reach pain relief following administration of a rescue dose of IR morphine was 15 minutes or less in 52.1% of patients at study end. The standard therapy was well tolerated and fewer adverse effects were recorded at the end of the study period compared with baseline, with the exception of constipation, which showed a moderate increase (from 18.2% to 25.0%). CONCLUSION: Start therapy with IR morphine followed by conversion to SR opioid therapy could be implemented as a standard therapy to manage moderate to severe chronic pain in patients with cancer or non-cancer pain. ORamorph in TIBER study (ORTIBER). PMID- 19445552 TI - Premedication with sublingual morphine sulphate in abdominal surgery. AB - BACKGROUND: Treatment with analgesics before surgery may be effective in reducing post-operative pain. This approach is defined as "pre-emptive analgesia" and recent reviews show conflicting results. OBJECTIVES: The aim of this study was to investigate the efficacy of pre-emptive analgesia with sublingual morphine sulphate, compared with sublingual midazolam in patients undergoing elective abdominal surgery. METHODS: Prior to surgery, 29 patients were randomized and premedicated with sublingual morphine sulphate 0.5 mg/kg (Group A; n = 15) or with sublingual midazolam 0.03 mg/kg (Group B; n = 14). General anaesthesia was maintained with sevoflurane and fentanyl. Post-operatively, intravenous (IV) acetaminophen 0.02 mg/kg was given to all patients and a bolus of IV morphine 0.1 mg/kg was given to Group B patients. Post-operative pain was controlled by IV morphine via a patient-controlled analgesia (PCA) device. IV acetaminophen 0.02 mg/kg was also administered four times daily. Efficacy was assessed using static Visual Analogue Scale (sVAS) scores, dynamic VAS (dVAS) scores, number of PCA doses administered and number of failed doses registered from the PCA device at 4, 6, 24 and 48 hours after surgery. Results were statistically analysed using the Student t-test; a value of p < 0.05 was considered significant. RESULTS: Significantly lower sVAS and dVAS scores were observed in Group A patients than in Group B at all assessment periods (p < 0.05 for all time points). There were less PCA administered and failed doses in Group A, compared with Group B (all time points p < 0.05). There was no difference in the occurrence of common side effects between the two treatments. CONCLUSIONS: In patients undergoing elective abdominal surgery, premedication with sublingual morphine sulphate results in a better control of post-operative pain, compared to premedication with sublingual midazolam. The beneficial effect of pre-operative sublingual morphine sulphate was apparent in the immediate post-operative period and was sustained over the 48 hour assessment period. PMID- 19445553 TI - Adequacy assessment of oxycodone/paracetamol (acetaminophen) in multimodal chronic pain : a prospective observational study. AB - BACKGROUND: Multimodal pain is comprised of nociceptive/inflammatory and neuropathic components. Pharmacological pain therapies from different classes provide pain relief using different mechanistic actions; often a combination of such therapies provides more effective pain relief than monotherapy. To assess whether pain management is adequate requires a comprehensive pain scoring system. OBJECTIVE: To evaluate the adequacy of a low-dose combination of oxycodone and paracetamol (acetaminophen) in patients with multimodal, chronic, non-malignant pain using the Pain Management Index (PMI). METHODS: During this prospective, observational study, consecutive patients were classified according to the presence of prevalent osteoarticular pain (group A, n = 78) or prevalent neuropathic pain (group B, n = 72). Existing pain-relief medications were discontinued and both groups received oxycodone 5 mg and paracetamol 325 mg up to 8 hourly for a planned duration of >/= 6 weeks. Patients in group B who were receiving gabapentin continued this treatment up to a maximum daily dosage of 2400 mg during the observation period. Pain intensity was evaluated using a visual analogue scale (VAS from 0 to 10). Functional limitation for patients in group A was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The intensities of dynamic allodynia and hyperalgesia in patients in group B were evaluated by a VAS. Results from the WOMAC, dynamic allodynia, and hyperalgesia assessments were evaluated using the PMI. RESULTS: In group A, 64.3% of patients showed improvements in pain symptoms after 15 days of treatment in the WOMAC categories of "pain preventing sleep" and "walks with aid". The PMI showed that the oxycodone/paracetamol therapy was adequate in patients with osteoarticular pain. In group B, 83.3% of patients reported improvement in the category of "pain preventing sleep", and all patients rated the remaining four categories ("spontaneous pain", "burning pain", "painful paresthesia", and "pinprick") as either stable or improved after 15 days of treatment. Using the PMI, hyperalgesia resolved with oxycodone/paracetamol therapy. 37.1% and 58.3% of patients did not complete the study in group A and B, respectively. CONCLUSION: The PMI was an effective tool for assessment of pain management efficacy. Oxycodone/paracetamol improved pain symptoms in the majority of compliant patients. In patients with neuropathic pain, rescue therapy with oxycodone/paracetamol showed a lesser, but significant, improvement of pain symptoms. PMID- 19445554 TI - Pain biomarkers. AB - The value of biomarkers in aiding early diagnosis of disease and predicting response to pharmacologic interventions is well known. The idea that biomarkers may also be used to identify and quantify pain has been investigated in preclinical and clinical studies. Findings from a preclinical study show that inflammatory pain and neuropathic pain have different biomarkers. Further investigations provided mixed results, on the one hand, cystatin C levels in cerebrospinal fluid appear to be a predictive marker for postherpetic neuralgia in patients with varicella-zoster virus, and a pain marker in women experiencing labour pain, but is not correlated with pain duration or intensity. Investigations into potential biomarkers for chest pain showed that cardiac markers used to aid in diagnosis and prognosis of cardiac disease correlate with tissue damage rather than with pain. Further studies are needed to gain insights into biomarkers for pain to enhance pain management practices. PMID- 19445555 TI - SETAC and the green economy. PMID- 19445557 TI - Rural health in a time of cataclysm. AB - How can the academic discipline of rural health position itself to be relevant in a global environment dominated by financial crisis and climate change? This commentary by Rural and Remote Health Australasian regional editors looks beyond the present time of gloom to opportunities for this young academic discipline to flourish and increase in impact. Steps towards solutions for each of these major global challenges may well be made in the coming years by rural health research conducted in regional and remote Australia. PMID- 19445556 TI - Areca nut and betel quid chewing among South Asian immigrants to Western countries and its implications for oral cancer screening. AB - The South Asian community is the largest and one of the fastest growing minority groups in Canada, according to the 2006 census. These immigrants bring to Canada talents and skills that can promote Canada's economy and cultural diversity, but they also bring lifestyle habits that may lead to serious health issues. Chewing areca nut and betel quid (paan, with and without tobacco) is a known risk factor for oral cancer. This habit is common in the Indo-Canadian population, as evidenced by its sales in local Indian markets and restaurants. In this article, we present an overview of the sociocultural beliefs, knowledge and practices regarding betel quid/areca nut chewing, and discuss its implications for oral cancer screening among this immigrant population. PMID- 19445558 TI - Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis. AB - Bazedoxifene acetate (WAY-140424; TSE-424) is an oral, nonsteroidal, indole-based selective estrogen receptor modulator (SERM) being developed for the prevention and treatment of osteoporosis. Preclinical studies on bazedoxifene have demonstrated estrogen agonist effects on the skeleton and lipid metabolism but not on breast and uterine endometrium. In combination with estrogen, bazedoxifene antagonizes the stimulatory action of estrogens on proliferation of breast cancer cells and endometrium. Phase III clinical studies have shown favorable effects on the skeleton without stimulation of endometrium and breast. Bazedoxifene prevents bone loss in postmenopausal women without osteoporosis and reduces vertebral fractures in women with postmenopausal osteoporosis. In women at high risk of fracture with multiple risk factors, bazedoxifene reduces nonvertebral fracture risk in post-hoc analysis. Bazedoxifene in combination with conjugated estrogens represents a new form of therapeutic agents for the treatment of postmenopausal symptoms and prevention of postmenopausal osteoporosis. Clinical trials with bazedoxifene/conjugated estrogens have shown beneficial effects on bone mineral density and bone turnover markers with improvement in vasomotor symptoms and little or no stimulation of breast and endometrium. PMID- 19445559 TI - Pharmacotherapy of vasculitis. AB - The systemic vasculitides are characterized by inflammatory lesions in blood vessels. Therapeutic approaches should be based on the aetiology or pathophysiology of disease. Unfortunately, for many of these disorders neither is fully understood and empirical treatment based on clinical presentation and the pattern of organ involvement is used. This approach is effective in improving survival in the most serious forms. We undertook a systematic literature review to assess the evidence for using drug therapies in vasculitis. Glucocorticoids remain essential for many forms of vasculitis; indeed, in giant-cell arteritis, they may be the only therapy necessary. However, additional immunosuppressive agents are required for other forms of vasculitis: methotrexate in Takayasu's arteritis and non-renal small-vessel vasculitis and cyclophosphamide for classic Wegener's granulomatosis, microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome with poor prognostic features. Subsequent disease control is with low-dose glucocorticoid and azathioprine or methotrexate. Biologic therapy is being used in resistant cases. Patients experience significant short- to medium-term toxicity, especially infection and steroid side effects. Late sequelae due to high cumulative doses of cyclophosphamide include infertility and malignancy. Such risks are being reduced due to more judicious use of short courses of cyclophosphamide followed by substitution by safer agents. PMID- 19445560 TI - Treatment of steroid-naive ulcerative colitis. AB - The introduction of steroid therapy by Truelove and Witts in the 1950s revolutionized the treatment of ulcerative colitis. Corticosteroids are potent inhibitors of T-cell activation and proinflammatory cytokines and still represent the mainstay of therapy of patients with ulcerative colitis. About 15% of patients are resistant to steroids, and about a quarter of patients become dependent within 1 year of therapy. Steroid-related adverse events are numerous and occur frequently. So, new steroids with low systemic absorption and better safety profile have been studied, but they show an overall lower efficacy compared with traditional steroids. A new drug-delivery system based on the use of autologous erythrocytes loaded with dexamethasone 21-phosphate has been recently developed. Several studies have demonstrated its efficacy in steroid dependent patients leading to complete withdrawal of oral steroids and disappearance of the most steroid-related adverse events. In this review we elaborate on the role of steroids in the treatment of ulcerative colitis, focusing on the aspects related to the mechanisms of action and resistance to the steroids, and their secondary effects. Moreover, we analyse the alternatives to traditional systemic steroids such as the new steroids with low bioavailability and the steroids encapsulated into erythrocytes. PMID- 19445561 TI - Treatment strategies for myasthenia gravis. AB - Advances in the treatment of myasthenia gravis (MG) have reduced mortality rates due to the disease and improved patients' quality of life. Nowadays, attending neurologists can choose among different treatment strategies for MG patients. An exhaustive revision of published data on the efficacy of the different therapeutic options for MG indicates that there are insufficient evidence-based results. However, recommendations based on expert opinion can be provided. Thymectomy is indicated in all patients with a thymoma or for generalized acetylcholine receptor-seropositive patients aged 18 - 55 years. Steroids are the most widely used immunosuppressive drug for MG. They are recommended as the first line drug in all patients with generalized MG without response to thymectomy, or in those patients who do not fulfill criteria for the surgery. The selection of second-line drugs may vary between protocols. We recommend to start with azathioprine if insufficient remission is achieved with steroids, followed by ciclosporin, mycophenolate and others. We use rituximab or cyclophosphamide only in severely drug-resistant patients. Finally, we recommend intravenous immunoglobulins or plasma exchange in MG crisis, or for unstable patients before thymectomy or in clinical exacerbations. PMID- 19445562 TI - Medroxyprogesterone acetate in the management of cancer cachexia. AB - BACKGROUND: Medroxyprogesterone acetate (MPA) is a synthetic, orally active derivative of the natural steroid hormone progesterone, widely used in oncology both in the endocrine treatment of hormone-related cancers and as supportive therapy in the cachexia syndrome. OBJECTIVE: The anticachectic mechanisms of medroxyprogesterone, beyond its endocrine activity, are described to explain its therapeutic efficacy in the treatment of cachexia. METHODS: After reviewing its pathophysiology and preclinical studies, the main clinical trials on the use of medroxyprogesterone acetate in cancer cachexia, are reviewed. RESULTS/CONCLUSIONS: Progestagens, including MPA, are at present the only approved drugs in Europe for the clinical treatment of cancer-related anorexia/cachexia syndrome. Placebo-controlled trials on the effect of MPA on cachexia have generally reported an improvement of both anorexia and body weight as well as of quality-of-life parameters. However, the weight gain was due to increased body fat, while fat-free mass was not significantly influenced by MPA treatment. Moreover, very recently the combination of MPA with other new anticachectic agents has been suggested as a way of ameliorating their efficacy in the treatment of cachexia. PMID- 19445563 TI - Comparative review of anastrozole, letrozole and exemestane in the management of early breast cancer. AB - The hormonal therapy of patients with endocrine-sensitive early breast cancer has mainly consisted, for several decades, of the gold standard tamoxifen. The efficacy and favorable toxicity profiles of third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, in advanced disease led to their development in early breast cancer. Recent results consistently show the superiority of these agents over tamoxifen. Adjuvant trials evaluated AIs using four different therapeutic approaches: (1) Upfront strategy: randomization of newly diagnosed patients: tamoxifen for 5 years versus AI for 5 years. (2) Sequencial strategy: randomization of newly diagnosed patients: tamoxifen (2 - 3 years) followed by AI or the inverse for a total of 5 years versus upfront AI for 5 years. (3) Switch strategy: delayed randomization (or analysis) after 2 - 3 years of tamoxifen (patients free of disease): 2 - 3 years of tamoxifen versus 2 3 years of AI (total treatment 5 years). (4) Extended strategy: delayed randomization after 5 years of tamoxifen (patients free of disease): 2 - 5 years of AI versus placebo. Overall, AIs show evidence of superiority over tamoxifen in the adjuvant setting with proven improved efficacy and better toxicity profile. Despite some common characteristics, a body of evidence on AIs indicates some specific differences between the three agents in mechanism of action, pharmacokinetics, efficacy as well as toxicity profiles. Consequently, these hormonal agents may not be considered interchangeable in clinical practice. This review explores available results from AI trials and tries to define their present role in the adjuvant management of postmenopausal patients with breast cancer. PMID- 19445564 TI - Casopitant: a new warrior in the antiemetic crusade. AB - The effective treatment of emetic complications of cancer therapies has remained a challenging task for cancer patients and their cancer care providers. Despite striking advances in antiemetic interventions, the need for more personalized targeted treatments in those who fail to response to the currently available antiemetic agents are yet to be met. Casopitant, a potent selective inhibitor of neurokinin-1 receptors, is a product of the increasingly heightened interest in this particular subset of cancer patients. The current review examines the emerging data about the benefits and safety of casopitant for treatment of chemotherapy-induced acute and delayed emesis, as well as the postoperative nausea/vomiting. Although preclinical studies promoted the notion of a potential superiority of casopitant over the already approved aprepitant in enhancing food and fluid intake, the limited comparison in clinical settings have yet to affirm a demonstratable meaningful superiority. The prevailing view from the published prospective studies supports a single 100 or 150 mg dose schedule of casopitant, orally or intravenously, as an effective and safe prophylaxis for acute and delayed emesis. The relative inferior outcomes of "nausea" control, as compared to a more impressive "vomiting" prevention, are similarly shared by both casopitant and aprepitant. This repeated and disappointing observation has challenged the precision and accuracy of our current understandings about the exact fabric of the "emesis axis." The future efforts should be directed to identify more effective agents for managing nausea and anticipatory emesis equally in both genders. PMID- 19445565 TI - Treatment strategies for central nervous system infections. AB - Central nervous system (CNS) infections continue to be an important cause of mortality and morbidity. Current strategies for prevention and therapy of CNS infection are compromised by incomplete understanding of the microbial-host interactions that contribute to its pathogenesis and emergence of antimicrobial resistant microorganisms. Our development of successful strategies in prevention and treatment of bacterial meningitis requires multifactorial concepts and approaches, which include advances in vaccinology, epidemiology of meningitis, emergence of antimicrobial-resistant pathogens, knowledge of pharmacokinetics and pharmacodynamics of antimicrobial agents, as well as the pathogenesis of meningitis. Prevention of bacterial meningitis targeting microbes has been effective, such as vaccination. The introduction of the protein conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis has changed the epidemiology of bacterial meningitis. Antimicrobial chemoprophylaxis is efficacious in prevention against H. influenzae type b and N. meningitidis meningitis. Suspected bacterial meningitis is a medical emergency and requires empiric antimicrobial therapy without delay, but recognition of pathogens with increasing resistance to antimicrobial agents is an important factor in selection of empiric antimicrobial regimen. A more complete understanding of the microbial-host interactions that are involved in the pathogenesis of CNS infections and associated neurologic sequelae is likely to help in developing new strategies for prevention and therapy of CNS infection. PMID- 19445567 TI - Validation of the radiosurgery-based arteriovenous malformation score in a large linear accelerator radiosurgery experience. AB - OBJECT: The radiosurgery-based arteriovenous malformation (AVM) score (RBAS) is a grading system designed to predict patient outcomes after Gamma Knife surgery for AVMs. This study seeks to validate independently the predictive nature of the RBAS, not only after single treatment but for retreatment, and to assess the overall outcome regardless of number of radiosurgeries. METHODS: The authors analyzed 403 patients treated with linear accelerator (LINAC) radiosurgery for AVMs between May 1988 and June 2008. The AVM scores were determined by the following equation: AVM score = (0.1 x volume in cm(3)) + (0.02 x age in years) + (0.3 x location). The location values are as follows: frontal/temporal = 0, parietal/occipital/corpus callosum/cerebellar = 1, and basal ganglia/thalamus/brainstem = 2. RESULTS: Testing demonstrated that the RBAS correlated with excellent outcomes after single or repeat radiosurgery (p < 0.001 for both variables). One hundred sixty-two (49%) of 330 patients had excellent outcomes (obliteration without deficit) after a single treatment. Excellent outcomes were achieved in 74, 64, 50, and 11% of patients with AVM scores of < 1.0 (Group 1), between 1.0 and < 1.8 (Group 2), between 1.8 and < 2.5 (Group 3), and >or= 2.5 (Group 4), respectively. Fifty-one patients (70%) obtained radiosurgical cure and 46 (63%) achieved excellent outcomes after repeat radiosurgery. Of these, 100% achieved excellent outcomes in Group 1, 70% did so in Group 2, 47% in Group 3, and 14% in Group 4. The RBAS correlated with excellent outcomes after overall treatment (p < 0.001). Two hundred seventy-seven patients (69%) obtained AVM obliteration, and 62% achieved excellent outcomes. In Group 1, 87% achieved excellent outcomes, 75% did so in Group 2, 61% in Group 3, and 24% in Group 4. CONCLUSIONS: The RBAS is a good predictor of patient outcomes after LINAC radiosurgery. PMID- 19445568 TI - Influence of interleukin-6 on the development of peritumoral brain edema in meningiomas. AB - OBJECT: Peritumoral brain edema (PTBE) is associated with perioperative neurological deficits in patients with meningiomas. However, the pathogenesis of meningioma-associated edema remains unclear. In the present study, the authors investigated the expression of interleukin-6 (IL-6) and its relationship with PTBE in resected meningiomas. METHODS: Thirty-six benign meningiomas obtained in 36 patients were studied retrospectively. Edema volume was assessed on MR images, and an edema index (EI) was calculated. Interleukin-6 mRNA and protein expression were examined by real-time reverse transcriptase polymerase chain reaction and immunohistochemical staining. RESULTS: Peritumoral brain edema was found in 16 patients (44%). Neither age, sex, histological subtype, nor tumor location were related to PTBE. The level of IL-6 mRNA was 7.72 times greater in the edema group (EI > 0.2) than in the nonedema group (EI < 0.2; p = 0.011). On immunohistochemical analysis, IL-6 protein was found localized in the cytoplasm of the tumor cells, and was detected in 12 (75%) of 16 cases of edematous meningiomas, but in only 6 (30%) of 20 nonedematous cases. There was a significant correlation between the severity of PTBE and IL-6 expression (p = 0.004). CONCLUSIONS: The authors' results in this study indicate that IL-6 expression may contribute to the development of brain edema associated with meningiomas. PMID- 19445569 TI - Surgical outcome of phrenic nerve transfer to the anterior division of the upper trunk in treating brachial plexus avulsion. AB - OBJECT: The purpose of this investigation was to study the surgical results of phrenic nerve transfer to the anterior division of the upper trunk of the brachial plexus. METHODS: Between 2002 and 2005, 40 patients received a phrenic nerve transfer to the anterior division of the upper trunk of the brachial plexus to restore elbow flexion. These cases were followed postoperatively for > 2 years, and the efficacy of the surgery and related factors were evaluated. RESULTS: The overall effective rate of this procedure was 82.5% (Medical Research Council Grade >or= 3). The results show that for patients with surgical delay of > 1 year or prolongation of the latency of the preoperative phrenic nerve evoked potential > 20%, the recovery rates were 25 and 50%, respectively. CONCLUSIONS: Phrenic nerve transfer to the anterior division of the upper trunk of the brachial plexus is a simple procedure that causes minor surgical trauma and yields good recovery of elbow flexion. It is suitable in patients with a relatively intact structure at the division level of the brachial plexus. PMID- 19445571 TI - Unmet needs in the treatment of glioblastoma. PMID- 19445573 TI - Somatostatin analog octreotide LAR in gastro-entero-pancreatic tumors. AB - Neuroendocrine tumors (NETs) are considered to be rare but, during the last two decades, their incidence and prevalence has considerably increased in gastro entero-pancreatic (GEP) NETs. Most GEP-NETs express somatostatin receptors, which could be targets for treatment. The development of somatostatin analogs for treatment of functioning NETs was a revolution in the treatment of these patients and is still a cornerstone for managing hormone-related clinical symptoms. Furthermore, somatostatin analogs have also demonstrated an anti-tumor effect, with stabilization of tumor growth over long periods of time. The development of a long-acting formulation of octreotide long-acting release (LAR) significantly improved the quality of life for patients with functioning NETs in terms of necessitating only monthly injections. The side effects are few and easily manageable. In the future, somatostatin analogs will continue to be a major treatment option for functioning NETs, but will be combined with other biologicals, such as a-interferons, mTOR inhibitors and VEGF inhibitors. A new multireceptor somatostatin analog, SOM230 (pasireotide), as well as chimeric molecules, such as dopastatin (a combination of a somatostatin analogue plus a dopamine agonist), will come into the clinical management of GEP-NETs. PMID- 19445574 TI - Molecular-targeted therapy in malignant melanoma. AB - Malignant melanoma is a deadly disease in which standard treatment options have remained remarkably static over the past 30 years. Recent discoveries have expanded the understanding of the molecular processes critical to melanomagenesis. During this same time period, therapeutic agents have been developed that target these processes, leading to an explosion of preclinical research. Several agents that have shown promise in the preclinical setting have now entered clinical trials. To date, the success of these molecularly targeted approaches as single agents has been limited. Although more encouraging results have been seen when these agents have been used in combination with cytotoxic therapy, the specific contribution of the targeted agents to the observed anti tumor effects remains to be established in randomized controlled Phase III trials. This article presents a review of the limitations of current therapy, a description of key pathogenic mechanisms for which inhibitors exist and a summary of therapeutic trials of molecularly targeted agents in this disease. PMID- 19445575 TI - Role of radiation therapy in the treatment of melanoma. AB - Melanoma has been widely described as radioresistant but this should not be construed as meaning that melanoma is radioincurable. Many melanoma cell lines are as radiosensitive as other tumors commonly treated successfully with radiotherapy (RT). The use of RT requires careful planning resulting in the administration of a tumoricidal dose to the tumor cells with adequate sparing of normal tissues. RT has been used for primary therapy, postresection adjuvant therapy and palliation of symptomatic melanoma. Curative RT has been given for uveal melanoma yielding patient survival equivalent to enucleation. RT has been administered to patients with unresectable disease yielding relatively favorable results. As an adjuvant therapy postoperatively, RT has been used selectively to improve local disease control. Finally, RT is used successfully as a palliative maneuver for symptoms related to distant metastatic melanoma in patients with incurable disease. PMID- 19445576 TI - Current systemic therapy for metastatic melanoma. AB - Metastatic melanoma remains a lethal disease with a long-term remission rate of less than 10%. Despite many years of research, there has not been a new drug approved in this disease in over two decades. Single-agent chemotherapy is palliative in some patients and there is no advantage of combination chemotherapy or chemo-immunotherapy in randomized trials. High-dose bolus IL-2 produces some long-term remissions and is available for highly selected individuals at selected centers in the USA but is impractical for most patients. Research is ongoing in exploring novel immunotherapeutic and targeted approaches. The status of recently completed and ongoing trials is discussed in this review. PMID- 19445578 TI - Treatment options for recurrent glioblastoma: pitfalls and future trends. AB - Standard treatment with temozolomide and radiotherapy for patients with newly diagnosed glioblastoma has increased the median overall survival and, more importantly, the 2-year survival rate of patients. However, as yet, no investigations have been conducted to define effective strategies against recurrence, which occurs in most patients following combined radiotherapy/temozolomide treatment. Furthermore, in recent years, new issues have emerged regarding the evaluation of disease response, and also with the identification of patterns such as pseudoprogression, frequently indistinguishable from real disease progression. New therapeutic strategies, such as targeted therapies and anti-angiogenic treatments that appear promising with regard to improving the results at the time of recurrence are discussed. PMID- 19445579 TI - Stereotactic body radiation therapy for oligometastases. AB - The standard treatment for metastatic cancer is systemic therapy. However, in a subset of patients with limited extracranial metastases or oligometastases, local ablative therapy in combination with systemic therapy may improve treatment outcomes. Stereotactic body radiation therapy (SBRT) has emerged as a novel approach for local ablation of extracranial oligometastases. There is a good body of experience in the use of SBRT for the treatment of oligometastases in various sites including the lung, the liver and the spine with promising results. This article provides an overview of the use of SBRT in the management of extracranial oligometastases. PMID- 19445580 TI - Role of intensity-modulated radiation therapy in gastrointestinal cancer. AB - Intensity-modulated radiation therapy (IMRT) represents a powerful advance in the planning and delivery of radiation therapy owing to its ability to deliver highly conformal treatment doses while sparing normal tissues. Dosimetric studies have shown the feasibility and theoretical benefit of treating with IMRT over 3D conformal radiation therapy in gastrointestinal malignancies. Early clinical experience with IMRT in the treatment of gastric, pancreatic, rectal and anal cancers corroborates the dosimetric analyses, with some series reporting lower normal tissue toxicities. This article reviews the radiobiological, physical, technical and clinical aspects of IMRT for gastric, pancreatic, rectal and anal cancer, and summarizes the dosimetric and outcome studies to date. PMID- 19445581 TI - Mode of action and clinical impact of VEGF signaling inhibitors. AB - The established role of VEGF signaling in promoting tumor angiogenesis has led to the development and clinical validation of several agents that selectively target this pathway in patients with advanced-stage malignancies. These include neutralizing anti-VEGF monoclonal antibodies, soluble VEGF receptors and small molecule inhibitors of VEGF receptor function, administered either as monotherapy or in combination with chemotherapy. Several modes of action have been identified, such as inhibition of new vessel growth, regression of newly formed vasculature, alteration of tumor vessel function and direct effects on tumor cells. VEGF-targeting drugs currently play an important role in the treatment of cancer and their impact will probably further increase in the future. PMID- 19445577 TI - Applications of neural and mesenchymal stem cells in the treatment of gliomas. AB - In addition to stem cells providing a better understanding about the biology and origins of gliomas, new therapeutic approaches have been developed based on the use of stem cells as delivery vehicles. The unique ability of stem cells to track down tumor cells makes them a very appealing therapeutic modality. This review introduces neural and mesenchymal stem cells, discusses the advances that have been made in the utilization of these stem cells as therapies and in diagnostic imaging (to track the advancement of the stem cells towards the tumor cells), and concludes by addressing various challenges and concerns regarding these therapies. PMID- 19445582 TI - Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms. AB - The discovery of the Janus kinase (JAK)2 V617F mutation in patients with myeloproliferative neoplasms was a major milestone in understanding the biology of those disorders. Several groups simultaneously reported on the high incidence of this mutation in patients with myeloproliferative neoplasms: almost all patients with polycythemia vera harbor the mutation and about 50% of patients with essential thrombocythemia and primary myelofibrosis have the mutation, making the development of JAK2 tyrosine kinase inhibitors an attractive therapeutic goal. In addition, inhibition of JAK2 kinase may have a therapeutic role in other hematologic malignancies, such as chronic myeloid leukemia or lymphoma. A number of molecules that inhibit JAK2 kinase have been described in the literature, and several are being evaluated in a clinical setting. Here, we summarize current clinical experience with JAK2 inhibitors. PMID- 19445583 TI - Placental ischemia and breast cancer risk after preeclampsia: tying the knot. AB - Although hypertensive disorders of pregnancy, such as preeclampsia, continue to be a significant source of maternal and fetal morbidity and mortality, there is emerging evidence that effects of the preeclamptic syndrome persist into later life. In contrast to recent studies that have reported that formerly preeclamptic women are at increased risk for cardiovascular disease, it appears that preeclampsia may be associated with a decreased risk of breast cancer. Recent investigations have provided exciting new insights into potential mechanisms underlying the pathogenesis of preeclampsia and some of these findings may bear relevance to the anticancer effects reported in the epidemiological literature. Placental ischemia is regarded to be a primary factor in preeclampsia and the ischemic placenta produces a variety of factors that generate profound effects on endothelial cell function and the cardiovascular system during pregnancy. Moreover, several of these factors are reportedly elevated many years after preeclamptic pregnancies. This group of molecules includes factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin/CD105 (sEng) and various cytokines. Many of these factors have been strongly associated with cancer incidence and, hence, could contribute to the modification of cancer risk observed in these women. Therefore, identifying potential connections between placental dysfunction and future cancer risk is an important endeavor towards realizing novel therapeutic regimens for cancer patients. PMID- 19445585 TI - Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. AB - BACKGROUND: It is necessary to clarify the incidence of and risk factors for tuberculosis (TB) among solid-organ transplant (SOT) recipients as well as changes in the chronology, clinical presentation, and prognosis of the disease. METHODS: A total of 4388 SOT recipients were monitored prospectively at 16 transplant centers included in the Spanish Network for Research in Infectious Diseases (REIPI). TB episodes were studied, and the incidence rate was calculated. Certain variables were analyzed, by Cox regression analysis, as potential risk factors for TB. RESULTS: Among the 4388 SOT recipients, 21 cases of TB were reported (0.48%). The median duration of follow-up was 360 days (range, 0-720 days). The global incidence of TB was 512 cases per 10(5) patients per year (95% confidence interval [CI], 317-783), which was higher than that in the general population in Spain (18.9 cases per 10(5) inhabitants per year; relative risk [RR], 26.6). The highest incidence (2072 cases per 10(5) patients per year; 95% CI, 565-5306) was observed among lung transplant recipients (RR, 73.3). Of the TB cases, 95% occurred within the first year after transplant, and 76% were pulmonary forms. Crude mortality was 19.0%, and attributable mortality was 9.5%. Multivariate analysis identified recipient age (RR, 1.05; 95% CI, 1.0 1.1) and receipt of a lung transplant (RR, 5.6; 95%, 1.9-16.9) as independent risk factors. CONCLUSIONS: TB incidence is increased among SOT recipients. The risk factors identified were age and receipt of a lung transplant. TB attributable mortality (9.5%) is still high. PMID- 19445586 TI - Tuberculosis and transplantation: battling the opportunist. PMID- 19445587 TI - Nitric oxide as a partner of reactive oxygen species participates in disease resistance to nectrotophic pathogen Botryis cinerea in Nicotiana benthamiana. AB - Nitric oxide (NO) is an essential regulatory molecule in plant immunity in synergy with reactive oxygen species (ROS). However, little is known about the role of NO in disease resistance to necrotrophic pathogens. NO and oxidative bursts were induced during necrotrophic fungal pathogen Botrytis cinerea and Nicotiana benthamiana compatible interaction. Histochemical analyses showed that both NO and ROS were produced in adjacent cells of invaded areas in N. benthamiana leaves. Activation of salicylic acid-induced protein kinase, which regulates the radical burst, and several defense-related genes were induced after inoculation of B. cinerea. Loss-of-function analyses using inhibitors and virus induced gene silencing were done to investigate the role of the radical burst in pathogenesis. We showed that NO plays a pivotal role in basal defense against B. cinerea and PR-1 gene expression in N. benthamiana. By contrast, ROS function has a negative role in resistance or has a positive role in expansion of disease lesions during B. cinerea-N. benthamiana interaction. PMID- 19445588 TI - Exploiting knowledge of R/Avr genes to rapidly clone a new LZ-NBS-LRR family of late blight resistance genes from potato linkage group IV. AB - In addition to the resistance to Phytophthora infestans (Rpi) genes Rpi-blb1 and Rpi-blb2, Solanum bulbocastanum appears to harbor Rpi-blb3 located at a major late blight resistance locus on LG IV, which also harbors Rpi-abpt, R2, R2-like, and Rpi-mcd1 in other Solanum spp. Here, we report the cloning and functional analyses of four Rpi genes, using a map-based cloning approach, allele-mining strategy, Gateway technology, and transient complementation assays in Nicotiana benthamiana. Rpi-blb3, Rpi-abpt, R2, and R2-like contain all signature sequences characteristic of leucine zipper nucleotide binding site leucine-rich repeat (LZ NBS-LRR) proteins, and share amino-acid sequences 34.9% similar to RPP13 from Arabidopsis thaliana. The LRR domains of all four Rpi proteins are highly homologous whereas LZ and NBS domains are more polymorphic, those of R2 being the most divergent. Clear blocks of sequence affiliation between the four functional resistance proteins and those encoded by additional Rpi-blb3 gene homologs suggest exchange of LZ, NBS, and LRR domains, underlining the modular nature of these proteins. All four Rpi genes recognize the recently identified RXLR effector PiAVR2. PMID- 19445589 TI - The role of the Cucumber mosaic virus 2b protein in viral movement and symptom induction. AB - The Cucumber mosaic virus (CMV) 2b protein is a counter-defense factor and symptom determinant. Conserved domains in the 2b protein sequence were mutated in the 2b gene of strain Fny-CMV. The effects of these mutations were assessed by infection of Nicotiana tabacum, N. benthamiana, and Arabidopsis thaliana (ecotype Col-0) with mutant viruses and by expression of mutant 2b transgenes in A. thaliana. We confirmed that two nuclear localization signals were required for symptom induction and found that the N-terminal domain was essential for symptom induction. The C-terminal domain and two serine residues within a putative phosphorylation domain modulated symptom severity. Further infection studies were conducted using Fny-CMVdelta2b, a mutant that cannot express the 2b protein and that induces no symptoms in N. tabacum, N. benthamiana, or A. thaliana ecotype Col-0. Surprisingly, in plants of A. thaliana ecotype C24, Fny-CMVdelta2b induced severe symptoms similar to those induced by the wild-type virus. However, C24 plants infected with the mutant virus recovered from disease while those infected with the wild-type virus did not. Expression of 2b transgenes from either Fny-CMV or from LS-CMV (a mild strain) in Col-0 plants enhanced systemic movement of Fny CMVdelta2b and permitted symptom induction by Fny-CMVdelta2b. Taken together, the results indicate that the 2b protein itself is an important symptom determinant in certain hosts. However, they also suggest that the protein may somehow synergize symptom induction by other CMV-encoded factors. PMID- 19445590 TI - The Xanthomonas campestris pv. vesicatoria type III effector protein XopJ inhibits protein secretion: evidence for interference with cell wall-associated defense responses. AB - The phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria uses the type III secretion system (T3SS) to inject effector proteins into cells of its Solanaceous host plants. It is generally assumed that these effectors manipulate host pathways to favor bacterial replication and survival. However, the molecular mechanisms by which type III effectors suppress host defense responses are far from being understood. Based on sequence similarity, Xanthomonas outer protein J (XopJ) is a member of the YopJ/AvrRxv family of SUMO peptidases and acetyltranferases, although its biochemical activity has not yet been demonstrated. Confocal laser scanning microscopy revealed that green fluorescent protein (GFP) fusions of XopJ are targeted to the plasma membrane when expressed in plant cells, which most likely involves N-myristoylation. In contrast to a XopJ(C235A) mutant disrupted in the catalytic triad sequence, the wild-type effector GFP fusion protein was also localized in vesicle-like structures colocalizing together with a Golgi marker protein, suggesting an effect of XopJ on vesicle trafficking. To explore an effect of XopJ on protein secretion, we used a GFP-based secretion assay. When a secreted (sec)GFP marker was coexpressed with XopJ in leaves of Nicotiana benthamiana, GFP fluorescence was retained in reticulate structures. In contrast, in plant cells expressing secGFP alone or along with the XopJ(C235A) mutant, no GFP fluorescence accumulated within the cells. Moreover, coexpressing secGFP together with XopJ led to a reduced accumulation of secGFP within the apoplastic fluid of N. benthamiana leaves, further showing that XopJ affects protein secretion. Transgenic expression of XopJ in Arabidopsis suppressed callose deposition elicited by a T3SS-negative mutant of Pseudomonas syringae pv. tomato DC3000. A role of XopJ in the inhibition of cell wall-based defense responses is discussed. PMID- 19445591 TI - A host-selective toxin of Pyrenophora tritici-repentis, Ptr ToxA, induces photosystem changes and reactive oxygen species accumulation in sensitive wheat. AB - Ptr ToxA (ToxA) is a proteinaceous necrotizing host-selective toxin produced by Pyrenophora tritici-repentis, a fungal pathogen of wheat (Triticum aestivum). In this study, we have found that treatment of ToxA-sensitive wheat leaves with ToxA leads to a light-dependent accumulation of reactive oxygen species (ROS) that correlates with the onset of necrosis. Furthermore, the accumulation of ROS and necrosis could be inhibited by the antioxidant N-acetyl cysteine, providing further evidence that ROS production is required for necrosis. Microscopic evaluation of ToxA-treated whole-leaf tissue indicated that ROS accumulation occurs in the chloroplasts. Analysis of total protein extracts from ToxA-treated leaves showed a light-dependent reduction of the chloroplast protein RuBisCo. In addition, Blue native-gel electrophoresis followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis revealed that ToxA induces changes in photosystem I (PSI) and photosystem II (PSII) in the absence of light, and therefore, the absence of ROS. When ToxA-treated leaves were exposed to light, all proteins in both PSI and PSII were extremely reduced. We propose that ToxA induces alterations in PSI and PSII affecting photosynthetic electron transport, which subsequently leads to ROS accumulation and cell death when plants are exposed to light. PMID- 19445592 TI - The N-terminal region of the Plantago asiatica mosaic virus coat protein is required for cell-to-cell movement but is dispensable for virion assembly. AB - Potexvirus cell-to-cell movement requires coat protein (CP) and movement proteins. In this study, mutations in two conserved in-frame AUG codons in the 5' region of the CP open reading frame of Plantago asiatica mosaic virus (PlAMV) were introduced, and virus accumulation of these mutants was analyzed in inoculated and upper noninoculated leaves. When CP was translated only from the second AUG codon, virus accumulation in inoculated leaves was lower than that of wild-type PlAMV, and the viral spread was impaired. Trans-complementation analysis showed that the leucine residue at the third position (Leu-3) of CP is important for cell-to-cell movement of PlAMV. The 14-amino-acid N-terminal region of CP was dispensable for virion formation. Immunoprecipitation assays conducted with an anti-TGBp1 antibody indicated that PlAMV CP interacts with TGBp1 in vivo and that this interaction is not affected by alanine substitution at Leu-3. These results support the concept that the N-terminal region of potexvirus CP can be separated into two distinct functional domains. PMID- 19445593 TI - Identification of bacterial proteins mediating the interactions between Pseudomonas putida UW4 and Brassica napus (Canola). AB - The influence of canola root exudates on the proteome of Pseudomonas putida UW4 and the mutant strain P. putida UW4/AcdS(-), which lacks a functional 1 aminocyclopropane-1-carboxylate deaminase gene, was examined using two dimensional difference in-gel electrophoresis. Seventy-two proteins with significantly altered expression levels in the presence of canola root exudates were identified by mass spectrometry. Many of these proteins are involved in nutrient transport and utilization, cell envelope synthesis, and transcriptional or translational regulation and, hence, may play important roles in plant bacterial interactions. Four proteins showing large changes in expression in response to canola root exudates in both the wild-type and mutant strains of P. putida UW4 (i.e., outer membrane protein F, peptide deformylase, transcription regulator Fis family protein, and a previously uncharacterized protein) were both overexpressed and disrupted in P. putida UW4 in an effort to better understand their functions. Functional studies of these modified strains revealed significantly enhanced or inhibited plant-growth-promoting abilities compared with the wild-type P. putida UW4, in agreement with the suggested involvement of three of these four proteins in plant-bacterial interactions. The work reported here suggests strategies to both identify potential antibacterial agents and develop bacterial strains that might be useful adjuncts to agriculture. This approach may be an effective means of identifying key proteins mediating the interactions of bacteria with their rhizosphere environment. PMID- 19445594 TI - Microcystin production in the tripartite cyanolichen Peltigera leucophlebia. AB - We show that the cyanobacterial symbionts of a tripartite cyanolichen can produce hepatotoxic microcystins in situ. Microcystins were detected with high performance liquid chromatography mass spectrometry both from cephalodia of the tripartite cyanolichen Peltigera leucophlebia and from a symbiotic Nostoc strain isolated from the same lichen specimen. Genetic identities of symbiotic Nostoc strains were studied by amplifying and sequencing the 16S rRNA gene. Also, the presence of the microcystin synthetase gene mcyE was confirmed by sequencing. Three highly toxic microcystins were detected from the lichen specimen. Several different Nostoc 16S rRNA haplotypes were present in the lichen sample but only one was found in the toxin-producing cultures. In culture, the toxin-producing Nostoc strain produced a total of 19 different microcystin variants. In phylogenetic analysis, this cyanobacterium and related strains from the lichen thallus grouped together with a previously known microcystin-producing Nostoc strain and other strains previously isolated from the symbiotic thalloid bryophyte Blasia pusilla. Our finding is the first direct evidence of in situ production of microcystins in lichens or plant-cyanobacterial symbioses. Microcystins may explain why cyanolichens and symbiotic bryophytes are not among the preferred food sources of most animal grazers. PMID- 19445595 TI - Multiple activities of the plant pathogen type III effector proteins WtsE and AvrE require WxxxE motifs. AB - The broadly conserved AvrE-family of type III effectors from gram-negative plant pathogenic bacteria includes important virulence factors, yet little is known about the mechanisms by which these effectors function inside plant cells to promote disease. We have identified two conserved motifs in AvrE-family effectors: a WxxxE motif and a putative C-terminal endoplasmic reticulum membrane retention/retrieval signal (ERMRS). The WxxxE and ERMRS motifs are both required for the virulence activities of WtsE and AvrE, which are major virulence factors of the corn pathogen Pantoea stewartii subsp. stewartii and the tomato or Arabidopsis pathogen Pseudomonas syringae pv. tomato, respectively. The WxxxE and the predicted ERMRS motifs are also required for other biological activities of WtsE, including elicitation of the hypersensitive response in nonhost plants and suppression of defense responses in Arabidopsis. A family of type III effectors from mammalian bacterial pathogens requires WxxxE and subcellular targeting motifs for virulence functions that involve their ability to mimic activated G proteins. The conservation of related motifs and their necessity for the function of type III effectors from plant pathogens indicates that disturbing host pathways by mimicking activated host G-proteins may be a virulence mechanism employed by plant pathogens as well. PMID- 19445596 TI - The S-adenosyl-L-homocysteine hydrolase gene ahcY of Agrobacterium radiobacter K84 is required for optimal growth, antibiotic production, and biocontrol of crown gall disease. AB - Agrobacterium radiobacter K84 is a commercial agent used worldwide to control crown gall disease caused by pathogenic isolates of A. tumefaciens. More than 2,000 transposon insertion derivatives of strain K84 were screened by a standardized greenhouse bioassay to identify mutants defective in biocontrol. Three mutants affected in biocontrol properties were identified. All three mutants displayed normal levels of attachment to tomato seed and root colonization. One of these mutants, M19-164, exhibited partial biocontrol and did not produce detectable levels of agrocin 84. In this mutant, the transposon is located in the agn locus of pAgK84, which codes for agrocin 84 biosynthesis. The second mutant, M19-158, also exhibited partial biocontrol and produced reduced amounts of agrocin 84 as a result of a mutation in a chromosomal gene of unknown function. The third mutant, M9-22, failed to biocontrol, was impaired in both growth in minimal medium and siderophore production, and failed to produce detectable levels of agrocin 84. The chromosomal gene ahcY, which encodes S adenosyl-l-homocysteine hydrolase, was disrupted in this mutant. Expression of a functional copy of ahcY in M9-22 restored all of the altered phenotypes. The fact that all identified biocontrol mutants exhibited a partial or total defect in production of agrocin 84 indicates that this antibiotic is required for optimum biocontrol. This study also identified two chromosomally encoded genes required for agrocin 84 production. That a mutation in ahcY abolishes biocontrol suggests that the intracellular ratio of S-adenosyl-l-methionine to S-adenosyl-l homocysteine is an important factor for agrocin 84 biosynthesis. Finally, we demonstrate that the ahcY gene in strain K84 is also required for optimal growth as well as for antibiotic production and biocontrol of crown gall disease. PMID- 19445597 TI - A key enzyme of the Leloir pathway is involved in pathogenicity of Leptosphaeria maculans toward oilseed rape. AB - Agrobacterium tumefaciens-mediated random insertional mutagenesis was used to investigate pathogenicity determinants in Leptosphaeria maculans. One tagged nonpathogenic mutant, termed m186, is analyzed in detail here. Microscopic analyses of infected plant tissues revealed that m186 is specifically blocked at the invasive growth phase after an unaffected initial penetration stage and is unable to switch to the necrotrophic lifestyle. In addition, m186 exhibits an altered cell wall and seems to be affected in its ability to produce cell-wall degrading enzymes. The T-DNA insertion occurs in the intergenic region between two head-to-tail genes, leading to a constitutive upregulation of their expression. Complementation experiments showed that only one of these two genes, Lmepi, fully accounts for the mutant phenotype. Bioinformatics and expression analyses along with functional studies suggested that the Lmepi gene encodes for the highly conserved UDP-glucose-4-epimerase, a key enzyme of the Leloir pathway involved in galactose metabolism. For the third time, this study highlights the intimate connection between primary metabolism and pathogenicity in L. maculans. This finding, along with similar data obtained from the related species Stagonospora nodorum, indicates the importance of in planta nutrition for the success of infection of plants by fungi belonging to class Dothideomycete. PMID- 19445599 TI - Adhesion and fitness in the bean phyllosphere and transmission to seed of Xanthomonas fuscans subsp. fuscans. AB - Deciphering the mechanisms enabling plant-pathogenic bacteria to disperse, colonize, and survive on their hosts provides the necessary basis to set up new control methods. We evaluated the role of bacterial attachment and biofilm formation in host colonization processes for Xanthomonas fuscans subsp. fuscans on its host. This bacterium is responsible for the common bacterial blight of bean (Phaseolus vulgaris), a seedborne disease. The five adhesin genes (pilA, fhab, xadA1, xadA2, and yapH) identified in X. fuscans subsp. fuscans CFBP4834-R strain were mutated. All mutants were altered in their abilities to adhere to polypropylene or seed. PilA was involved in adhesion and transmission to seed, and mutation of pilA led to lower pathogenicity on bean. YapH was required for adhesion to seed, leaves, and abiotic surfaces but not for in planta transmission to seed or aggressiveness on leaves. Transmission to seed through floral structures did not require any of the known adhesins. Conversely, all mutants tested, except in yapH, were altered in their vascular transmission to seed. In conclusion, we showed that adhesins are implicated in the various processes leading to host phyllosphere colonization and transmission to seed by plant pathogenic bacteria. PMID- 19445598 TI - Interaction with a host ubiquitin-conjugating enzyme is required for the pathogenicity of a geminiviral DNA beta satellite. AB - DNA beta is a single-stranded satellite DNA which encodes a single gene, betaC1. To better understand the role of betaC1 in the pathogenicity of DNA beta, a yeast two-hybrid screen of a tomato cDNA library was carried out using betaC1 from Cotton leaf curl Multan virus (CLCuMV) DNA beta as the bait. A ubiquitin conjugating enzyme, designated SlUBC3, which functionally complemented a yeast mutant deficient in ubiquitin-conjugating enzymes was identified. The authenticity and specificity of the interaction between betaC1 and SlUBC3 was confirmed both in vivo, using a bimolecular fluorescence complementation assay, and in vitro, using a protein-binding assay. Analysis of deletion mutants of the betaC1 protein showed that a myristoylation-like motif is required both for its interaction with SlUBC3 and the induction of DNA-beta-specific symptoms in host plants. The level of polyubiquitinated proteins in transgenic tobacco plants expressing betaC1 was found to be reduced compared with wild-type plants. These results are consistent with the hypothesis that interaction of betaC1 with SlUBC3 is required for DNA-beta-specific symptom induction, and that this is possibly due to downregulation of the host ubiquitin proteasome pathway. PMID- 19445600 TI - Pressure-mediated transfection of murine spleen and liver. AB - Extension of in vivo nucleic acid transfection techniques and increased information about those transfection properties and side effects are urgently needed to advance biological research and drug therapy. Tissue pressure-mediated transfection, involving lightly pressing the target tissue after intravenous injection of plasmid DNA or small-interfering RNA (siRNA), is a promising approach because of its high transfection efficiency and resulting low tissue damage. In this study, the gene expression/silencing properties and proinflammatory cytokine production associated with tissue pressure-mediated transfection were evaluated to extend its application. We have found that tissue pressure-mediated transfection can be applied to plasmid DNA and siRNA transfection to the spleen and siRNA transfection to the liver. In addition, we have demonstrated that these methods induce little production of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6, IL-12, and interferon-gamma. Moreover, we succeeded in controlling and quantifying the degree of pressure on the spleen and kidney and found that 0.59 N/cm(2) is sufficient for efficient and highly reproducible plasmid DNA transfection to the spleen and kidney in mice. Tissue pressure-mediated transfection of the kidney, liver, and spleen exhibits well-balanced characteristics including (1) simple and convenient manipulation, (2) tissue-specific, effective broad transfection properties, and (3) a low inflammatory response. Therefore, this information could be useful for a molecular-level mechanism analysis of diseases at an individual level in mammals, exploration of therapeutic target molecules and evaluation of gene therapy and nucleic acid-based therapy approaches, as well as potential clinical applications. PMID- 19445601 TI - Corticosteroids operate as a switch between memory systems. AB - Stress and corticosteroid hormones are known to affect learning and memory processes. In this study, we examined whether stress and corticosteroids are capable of facilitating the switch between multiple memory systems in mice. For this purpose, we designed a task that allowed measurement of nucleus caudate based stimulus-response and hippocampus-based spatial learning strategies. Naive mice used spatial strategies to locate an exit hole on a circular hole board at a fixed location flagged by a proximal stimulus. When the mice were either stressed or administered corticosterone before the task, 30-50% of the mice switched to a stimulus-response strategy. This switch between learning strategies was accompanied by a rescue of performance, whereas performance declined in the stressed mice that kept using the spatial strategy. Pretreatment with a mineralocorticoid receptor antagonist prevented the switch toward the stimulus response strategy but led to deterioration of hippocampus-dependent performance. These findings (i) show that corticosteroids promote the transition from spatial to stimulus-response memory systems, (ii) provide evidence that the mineralocorticoid receptor underlies this corticosteroid-mediated switch, and (iii) suggest that a stress-induced switch from hippocampus-based to nucleus caudate-based memory systems can rescue performance. PMID- 19445602 TI - The interplay between prosody and syntax in sentence processing: the case of subject- and object-control verbs. AB - This study addresses the question whether prosodic information can affect the choice for a syntactic analysis in auditory sentence processing. We manipulated the prosody (in the form of a prosodic break; PB) of locally ambiguous Dutch sentences to favor one of two interpretations. The experimental items contained two different types of so-called control verbs (subject and object control) in the matrix clause and were syntactically disambiguated by a transitive or by an intransitive verb. In Experiment 1, we established the default off-line preference of the items for a transitive or an intransitive disambiguating verb with a visual and an auditory fragment completion test. The results suggested that subject- and object-control verbs differently affect the syntactic structure that listeners expect. In Experiment 2, we investigated these two types of verbs separately in an on-line ERP study. Consistent with the literature, the PB elicited a closure positive shift. Furthermore, in subject-control items, an N400 effect for intransitive relative to transitive disambiguating verbs was found, both for sentences with and for sentences without a PB. This result suggests that the default preference for subject-control verbs goes in the same direction as the effect of the PB. In object-control items, an N400 effect for intransitive relative to transitive disambiguating verbs was found for sentences with a PB but no effect in the absence of a PB. This indicates that a PB can affect the syntactic analysis that listeners pursue. PMID- 19445604 TI - The interrelations between verbal working memory and visual selection of emotional faces. AB - Working memory (WM) and visual selection processes interact in a reciprocal fashion based on overlapping representations abstracted from the physical characteristics of stimuli. Here, we assessed the neural basis of this interaction using facial expressions that conveyed emotion information. Participants memorized an emotional word for a later recognition test and then searched for a face of a particular gender presented in a display with two faces that differed in gender and expression. The relation between the emotional word and the expressions of the target and distractor faces was varied. RTs for the memory test were faster when the target face matched the emotional word held in WM (on valid trials) relative to when the emotional word matched the expression of the distractor (on invalid trials). There was also enhanced activation on valid compared with invalid trials in the lateral orbital gyrus, superior frontal polar (BA 10), lateral occipital sulcus, and pulvinar. Re-presentation of the WM stimulus in the search display led to an earlier onset of activity in the superior and inferior frontal gyri and the anterior hippocampus irrespective of the search validity of the re-presented stimulus. The data indicate that the middle temporal and prefrontal cortices are sensitive to the reappearance of stimuli that are held in WM, whereas a fronto-thalamic occipital network is sensitive to the behavioral significance of the match between WM and targets for selection. We conclude that these networks are modulated by high-level matches between the contents of WM, behavioral goals, and current sensory input. PMID- 19445603 TI - Neuronal activation for semantically reversible sentences. AB - Semantically reversible sentences are prone to misinterpretation and take longer for typically developing children and adults to comprehend; they are also particularly problematic for those with language difficulties such as aphasia or Specific Language Impairment. In our study, we used fMRI to compare the processing of semantically reversible and nonreversible sentences in 41 healthy participants to identify how semantic reversibility influences neuronal activation. By including several linguistic and nonlinguistic conditions within our paradigm, we were also able to test whether the processing of semantically reversible sentences places additional load on sentence-specific processing, such as syntactic processing and syntactic-semantic integration, or on phonological working memory. Our results identified increased activation for reversible sentences in a region on the left temporal-parietal boundary, which was also activated when the same group of participants carried out an articulation task which involved saying "one, three" repeatedly. We conclude that the processing of semantically reversible sentences places additional demands on the subarticulation component of phonological working memory. PMID- 19445605 TI - Deficits in subprocesses of visual feature search after frontal, parietal, and temporal brain lesions--a modeling approach. AB - Deficits in visuospatial attention are commonly observed after different kinds of brain lesions. However, the structure-function relationships are not well understood. We investigated whether our response time (RT) model, strategies of visual search (STRAVIS), combined with a linear model of brain lesions, enables us to relate specific impairments in cognitive processes to specific sites of focal brain lesions. In STRAVIS, RTs in overt visual feature search with graded target-distractor similarity are decomposed into the durations of successive search steps. Fitting the model to an observer's RTs yields individual estimates of the parameters "attentional focus size," "attentional dwell time," and "movement time of attention or the eyes." In 28 patients with various focal lesions to the frontal, parietal, and/or temporal cortex and 28 matched controls, we determined with the help of linear models which lesions were most predictive for each parameter. Predictions were validated with a second sample of 12 patients and 12 controls. Critical lesion areas for the STRAVIS focus size were the dorsolateral prefrontal cortex and the temporal lobe, with dorsolateral prefrontal cortex lesions reducing the focus and temporal lesions enlarging it. The STRAVIS dwell time was reduced in patients with lesions to the anterior insula and the superior parietal lobe. Lesions to the frontal eye fields, the superior parietal lobe, and the parieto-occipital cortex were most detrimental to the STRAVIS movement time. Applying linear models to a patient sample with heterogeneous lesions may be a promising new method for investigating how different brain areas interplay in a complex task. PMID- 19445606 TI - Age-related neural changes during memory conjunction errors. AB - Human behavioral studies demonstrate that healthy aging is often accompanied by increases in memory distortions or errors. Here we used event-related fMRI to examine the neural basis of age-related memory distortions. We used the memory conjunction error paradigm, a laboratory procedure known to elicit high levels of memory errors. For older adults, right parahippocampal gyrus showed significantly greater activity during false than during accurate retrieval. We observed no regions in which activity was greater during false than during accurate retrieval for young adults. Young adults, however, showed significantly greater activity than old adults during accurate retrieval in right hippocampus. By contrast, older adults demonstrated greater activity than young adults during accurate retrieval in right inferior and middle prefrontal cortex. These data are consistent with the notion that age-related memory conjunction errors arise from dysfunction of hippocampal system mechanisms, rather than impairments in frontally mediated monitoring processes. PMID- 19445607 TI - Arabic morphology in the neural language system. AB - There are two views about morphology, the aspect of language concerned with the internal structure of words. One view holds that morphology is a domain of knowledge with a specific type of neurocognitive representation supported by specific brain mechanisms lateralized to left fronto-temporal cortex. The alternate view characterizes morphological effects as being a by-product of the correlation between form and meaning and where no brain area is predicted to subserve morphological processing per se. Here we provided evidence from Arabic that morphemes do have specific memory traces, which differ as a function of their functional properties. In an MMN study, we showed that the abstract consonantal root, which conveys semantic meaning (similarly to monomorphemic content words in English), elicits an MMN starting from 160 msec after the deviation point, whereas the abstract vocalic word pattern, which plays a range of grammatical roles, elicits an MMN response starting from 250 msec after the deviation point. Topographically, the root MMN has a symmetric fronto-central distribution, whereas the word pattern MMN lateralizes significantly to the left, indicating stronger involvement of left peri-sylvian areas. In languages with rich morphologies, morphemic processing seems to be supported by distinct neural networks, thereby providing evidence for a specific neuronal basis for morphology as part of the cerebral language machinery. PMID- 19445608 TI - Formation of category representations in superior temporal sulcus. AB - The human brain contains cortical areas specialized in representing object categories. Visual experience is known to change the responses in these category selective areas of the brain. However, little is known about how category training specifically affects cortical category selectivity. Here, we investigated the experience-dependent formation of object categories using an fMRI adaptation paradigm. Outside the scanner, subjects were trained to categorize artificial bird types into arbitrary categories (jungle birds and desert birds). After training, neuronal populations in the occipito-temporal cortex, such as the fusiform and the lateral occipital gyrus, were highly sensitive to perceptual stimulus differences. This sensitivity was not present for novel birds, indicating experience-related changes in neuronal representations. Neurons in STS showed category selectivity. A release from adaptation in STS was only observed when two birds in a pair crossed the category boundary. This dissociation could not be explained by perceptual similarities because the physical difference between birds from the same side of the category boundary and between birds from opposite sides of the category boundary was equal. Together, the occipito-temporal cortex and the STS have the properties suitable for a system that can both generalize across stimuli and discriminate between them. PMID- 19445609 TI - Training the brain to weight speech cues differently: a study of Finnish second language users of English. AB - Foreign-language learning is a prime example of a task that entails perceptual learning. The correct comprehension of foreign-language speech requires the correct recognition of speech sounds. The most difficult speech-sound contrasts for foreign-language learners often are the ones that have multiple phonetic cues, especially if the cues are weighted differently in the foreign and native languages. The present study aimed to determine whether non-native-like cue weighting could be changed by using phonetic training. Before the training, we compared the use of spectral and duration cues of English /i/ and /I/ vowels (e.g., beat vs. bit) between native Finnish and English speakers. In Finnish, duration is used phonologically to separate short and long phonemes, and therefore Finns were expected to weight duration cues more than native English speakers. The cross-linguistic differences and training effects were investigated with behavioral and electrophysiological methods, in particular by measuring the MMN brain response that has been used to probe long-term memory representations for speech sounds. The behavioral results suggested that before the training, the Finns indeed relied more on duration in vowel recognition than the native English speakers did. After the training, however, the Finns were able to use the spectral cues of the vowels more reliably than before. Accordingly, the MMN brain responses revealed that the training had enhanced the Finns' ability to preattentively process the spectral cues of the English vowels. This suggests that as a result of training, plastic changes had occurred in the weighting of phonetic cues at early processing stages in the cortex. PMID- 19445610 TI - Visual object representations can be formed outside the focus of voluntary attention: evidence from event-related brain potentials. AB - There is an ongoing debate whether visual object representations can be formed outside the focus of voluntary attention. Recently, implicit behavioral measures suggested that grouping processes can occur for task-irrelevant visual stimuli, thus supporting theories of preattentive object formation (e.g., Lamy, D., Segal, H., & Ruderman, L. Grouping does not require attention. Perception and Psychophysics, 68, 17-31, 2006; Russell, C., & Driver, J. New indirect measures of "inattentive" visual grouping in a change-detection task. Perception and Psychophysics, 67, 606-623, 2005). We developed an ERP paradigm that allows testing for visual grouping when neither the objects nor its constituents are related to the participant's task. Our paradigm is based on the visual mismatch negativity ERP component, which is elicited by stimuli deviating from a regular stimulus sequence even when the stimuli are ignored. Our stimuli consisted of four pairs of colored discs that served as objects. These objects were presented isochronously while participants were engaged in a task related to the continuously presented fixation cross. Occasionally, two color deviances occurred simultaneously either within the same object or across two different objects. We found significant ERP differences for same- versus different-object deviances, supporting the notion that forming visual object representations by grouping can occur outside the focus of voluntary attention. Also our behavioral experiment, in which participants responded to color deviances--thus, this time the discs but, again, not the objects were task relevant--showed that the object status matters. Our results stress the importance of early grouping processes for structuring the perceptual world. PMID- 19445612 TI - Environmental sensitivity in relation to size and sex in birds: meta-regression analysis. AB - Studies of animals often report a greater sensitivity of one sex to poor rearing environments. However, it is unclear whether size differences associated with sex, sex itself, or other factors are responsible for differences in performance. While the greater nutritional requirement of the larger sex is a plausible explanation for increased sensitivity (i.e., size-dependent vulnerability), other hypotheses suggest that size-independent traits may have effects on the fitness of offspring (i.e., sex-dependent vulnerability). For example, the heterogametic sex may be more vulnerable to expression of sex-linked recessives in poor environments, or sex-specific phenotypes may have negative effects (e.g., increased testosterone in males). We examined support for these hypotheses through the use of meta-analytic techniques based on the published literature on avian species. Our results revealed small, nonsignificant effects for hypotheses of size- and sex-dependent susceptibilities alone. Application of a multivariate meta-analytic technique (meta-regression) suggests a joint influence of sexual size dimorphism and clutch size in explaining sex-specific patterns of vulnerability. These findings suggest that none of the proposed hypotheses tested here on their own can sufficiently explain the observed patterns and that additional factors must be considered in order to explain the diversity of patterns of sex-specific sensitivity observed in the literature. PMID- 19445614 TI - Intimate partner violence and functional health status: associations with severity, danger, and self-advocacy behaviors. AB - OBJECTIVE: To assess physical and mental functional health status as associated with the severity of intimate partner violence (IPV) and perceived danger. METHODS: Prospective cross-sectional survey of all patients aged 18-55 in an urban emergency department during a convenience sample of shifts. Instruments included the George Washington Universal Violence Prevention Screening protocol, administered by computer during the initial visit, the Short-Form 12 Health Survey (SF-12), the Conflict Tactics Scale (CTS2), and the Revised Danger Assessment (DA), administered by interview at 1 week follow-up. RESULTS: In total, 548 (20%) participants screened disclosed IPV victimization. Of those, 216 (40%) completed the follow-up assessment 1 week later. This cohort was 91% African American, 70% single, and 63% female, with a mean age of 35 (SD 10.41). Both physical and mental health functioning scores were lower than normative levels (50) compared with national averages: Physical Component Summary (PCS) scale 43.64 (SD 10.86) and Mental Component Summary (MCS) scale 37.46 (SD 12.29). As physical assault, psychological aggression, and reported injury increased on the CTS2, mental health functioning diminished (p < 0.01). Increased physical assault and psychological aggression were also associated with diminished physical health functioning (p < 0.05). As victim-perceived danger increased on the DA, both physical and mental health functioning decreased (p < 0.01, p < 0.001, respectively). Greater self-advocacy activities were associated with lower mental (but not physical) health functioning as well. Females experienced worsening mental health functioning as both physical assault and psychological aggression increased, whereas male victims experienced worsening mental health functioning only as psychological aggression increased. CONCLUSIONS: These findings suggest that IPV takes a greater mental than physical toll (for both sexes) and that as IPV severity increases, mental health functioning diminishes and self-advocacy behaviors increase. Additionally, as perceived danger increases, both physical and mental health status worsens. This has important implications for clinicians to assess and consider IPV victims' perceptions of their situations relative to danger, not just the levels of abuse they are experiencing. PMID- 19445616 TI - Addressing social determinants of health to improve access to early breast cancer detection: results of the Boston REACH 2010 Breast and Cervical Cancer Coalition Women's Health Demonstration Project. AB - BACKGROUND: The Boston Racial and Ethnic Approaches to Community Health (REACH) 2010 Breast and Cervical Cancer Coalition developed a case management intervention for women of African descent to identify and reduce medical and social obstacles to breast cancer screening and following up abnormal results. METHODS: We targeted black women at high risk for inadequate cancer screening and follow-up as evidenced by a prior pattern of missed clinic appointments and frequent urgent care use. Case managers provided referrals to address patient identified social concerns (e.g., transportation, housing, language barriers), as well as navigation to prompt screening and follow-up of abnormal tests. We recruited 437 black women aged 40-75, who received care at participating primary care sites. The study was conducted as a prospective cohort study rather than as a controlled trial and evaluated intervention effects on mammography uptake and longitudinal screening rates via logistic regression and timely follow-up of abnormal tests via Cox proportional hazards models. RESULTS: A significant increase in screening uptake was found (OR 1.53, 95% CI 1.13-2.08). Housing concerns (p < 0.05) and lacking a regular provider (p < 0.01) predicted poor mammography uptake. Years of participation in the intervention increased odds of obtaining recommended screening by 20% (OR 1.20, 95% CI 1.02-1.40), but this effect was attenuated by covariates (p = 0.53). Timely follow-up for abnormal results was achieved by most women (85%) but could not be attributed to the intervention (HR 0.95, 95% CI 0.50-1.80). CONCLUSIONS: Case management was successful at promoting mammography screening uptake, although no change in longitudinal patterns was found. Housing concerns and lacking a regular provider should be addressed to promote mammography uptake. Future research should provide social assessment and address social obstacles in a randomized controlled setting to confirm the efficacy of social determinant approaches to improve mammography use. PMID- 19445615 TI - Persistence of Maternal Depressive Symptoms throughout the Early Years of Childhood. AB - AIMS: The purpose of these analyses was to examine the persistence and predictors of elevated depressive symptoms in 884 women over their children's preschool years. RESULTS: Depressive symptoms in women with young children are surprisingly consistent throughout their children's preschool years. Of the 82.6% of women without elevated depressive symptoms at the initial assessment (study child was 11-42 months of age), 82.4% remained without symptoms over two follow-up assessments. Of 17.4% of women with elevated symptoms at baseline, 35.6% had elevated symptoms at one of the two follow-ups, and 27.4% had elevated symptoms at both follow-ups. Persistently elevated depressive symptoms were related to low education, high levels of anxiety, high parenting distress, and low levels of emotional support at baseline. CONCLUSIONS: Women who report symptoms of depression when their children are young are highly likely to continue to report such symptoms. These results support the need to screen for elevated depressive symptoms at varying intervals depending on prior screening results and for screening in locations where women most at risk routinely visit, such as well child clinics. Further, these results point to the need for a system to identify and manage this common treatable condition because these elevated symptoms continue throughout their children's preschool years for a substantial portion of women. PMID- 19445618 TI - Self-reported medication and herb/supplement use by women with and without fibromyalgia. AB - METHODS: Using a telephone survey of 434 women who self-reported having and 198 women, who denied having fibromyalgia (FM) (aged 18-80 years), we compared women on self-reported number, major types, and effectiveness of currently taken conventional medications and herbs/supplements. RESULTS: Ninety-three percent of women with FM reported taking at least one medication (1855 total, 499 types, on average 4.6 per person) compared with 56% of women without FM (269 total, 172 types, 1.4 per person on average). Half (n = 217) of the women with FM reported taking antidepressant drugs; more reported selective serotonin reuptake inhibitors (SSRI)-type with moderate effectiveness than tricyclic amines deemed to have strong effectiveness. Few were taking dual uptake inhibitors or the now approved pregabalin. Nearly 30% reported taking nonsteroidal anti-inflammatory drugs (NSAID), which have weak efficacy evidence. Less than 8% of controls reported taking either antidepressants or NSAID. Having FM was associated with these medications plus guaifenesen, anticonvulsants, muscle relaxants, narcotics, other analgesics, and benzodiazepines. Highest effectiveness scores were for opioid narcotics and guaifenesin. Forty-three percent of women with FM reported taking at least one herb/supplement compared with 23% of control women. The most common types were omega esterified fatty acids, glucosamine, and gingko. No particular type distinguished between the groups. Both groups tended to rate overall effectiveness lower for herbs/supplements than for conventional medications. CONCLUSIONS: Substantial numbers of women with FM were taking pain medications that often lacked evidence for effectiveness. The variety of medications being taken by women with FM compared with women without FM indicates that there are few medications that consistently provide symptom alleviation for this condition. PMID- 19445617 TI - A prospective study of weight gain after premenopausal hysterectomy. AB - PURPOSE: Many women who have had hysterectomies have the perception that they gained weight after surgery that cannot be attributed to changes in diet or physical activity. The purpose of this analysis was to assess weight gain in premenopausal women in the first year after hysterectomy compared with a control group of women with intact uteri and ovaries. METHODS: As part of a prospective cohort study designed to assess the risk for ovarian failure after premenopausal hysterectomy, weight was measured at baseline and 1-year follow-up in 236 women undergoing hysterectomy and 392 control women. Changes in measured weight and reported weight were assessed. Unconditional logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for weight gains of >10 pounds. RESULTS: Women with hysterectomies weighed more and had a higher mean body mass index (BMI) than control women at baseline. Mean weight gain was 1.36 kg ( approximately 3 pounds) for women with hysterectomies vs. 0.61 kg ( approximately 1.3 pounds) for control women (p = 0.07). Weight gain of >10 pounds occurred in 23% of women with hysterectomies compared with 15% of control women (multivariable OR = 1.61, 95% CI 1.04 = 2.48). CONCLUSIONS: Women undergoing hysterectomies appear to be at higher risk for weight gain in the first year after surgery. Heavier women and women who have had weight fluctuations throughout adulthood may be at greater risk for postsurgical weight gain, suggesting that lifestyle interventions to maintain or lose weight may be particularly helpful for these women in the months following hysterectomy. PMID- 19445619 TI - Clinic-based nutrition and lifestyle counseling for Hispanic women delivered by community health workers: design of the California WISEWOMAN study. AB - BACKGROUND: The Well-Integrated Screening and Evaluation for Women Across the Nation (WISEWOMAN) program in California, named Heart of the Family, implements and evaluates the effectiveness of lifestyle interventions to improve nutrition and physical activity while reducing cardiovascular disease (CVD) risk factors among low-income, uninsured or underinsured Hispanic women aged 40-64 who participate in the Cancer Detection Programs: Every Woman Counts (CDP:EWP). This paper reports the study design and baseline findings of the California WISEWOMAN program. METHODS: Heart of the Family, a within-site randomized controlled study at four community health centers in Los Angeles and San Diego, featured a unique set of strategies meeting the state population in implementing a California WISEWOMAN program. The program exclusively targeted Hispanic women who are at risk of developing CVD, provided lifestyle intervention using a validated intervention material in Spanish and English to motivate behavioral changes, and used bilingual (English and Spanish) community health workers (CHWs) to provide individually based face-to-face counseling. Women meeting enrollment criteria were randomly assigned either to an enhanced intervention group (EIG), who received lifestyle intervention, or usual care group (UCG), who received the usual care for elevated blood pressure or cholesterol. RESULTS: A total of 1093 women enrolled between January 2006 and August 2006. Demographic and baseline CVD risk profiles are similar in both groups. Some notable characteristics of the California participants are lower smoking rate (5%), higher average body mass index (BMI) (31.9), and a significantly higher percentage with less than high school education (70%). CONCLUSIONS: With its unique study design and large number of enrolls, Heart of the Family will enable future public health efforts to better meet the health needs of Hispanic women by addressing education levels, economic considerations, and cultural and linguistic needs. PMID- 19445623 TI - Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. AB - BACKGROUND: Antithyroid drugs (ATDs) are prescribed as the initial therapy for the majority of patients with Graves' disease in many areas of the world. Although, it is well known that agranulocytosis is one of the most serious side effects of ATDs, there has not yet been any conclusive evidence that the prevalence of agranulocytosis induced by ATDs is dose related. This study was performed to determine if the prevalence of agranulocytosis is different depending on the starting dosage of ATDs in patients with Graves' disease. METHODS: Until 1996, we had typically prescribed 30 mg/d of methimazole (MMI) as the initial dosage for the treatment of Graves' disease at our institution. We changed the initial MMI dosage to 15 mg/d as a general rule in 1997. As a consequence, we acquired two groups of patients with Graves' disease who received different dosages of MMI. We retrospectively compared the prevalence of MMI induced agranulocytosis in patients who received 15 mg/d of MMI to those who received 30 mg/d of MMI. RESULTS: There were 2087 subjects treated with 30 mg/d of MMI and 2739 treated with 15 mg/d of MMI. The prevalence of agranulocytosis in the 30 mg/d group was significantly higher than in the 15 mg/d group (0.814% vs. 0.219%, respectively, p < 0.01). The prevalence of agranulocytosis plus neutropenia in the 30 mg/d group was also significantly higher than in the 15 mg/d group (1.581% vs. 0.474%, respectively, p < 0.001). CONCLUSIONS: It is very likely that MMI-induced agranulocytosis occurs with a larger dosage of MMI and is dose related. Considering both the effectiveness and the risk of serious side effects, we recommend 15 mg/d of MMI as the starting dosage for the treatment of Graves' disease. PMID- 19445624 TI - Mohs chemosurgery for local control of giant recurrent papillary thyroid cancer. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) generally has a good prognosis but may have an aggressive course, particularly in the elderly. Standard treatment consists of radioactive iodine and thyrotropin suppression with superphysiological doses of thyroid hormone. Other modalities are less commonly used. We report perhaps the first patient with PTC who was treated with Mohs chemosurgery. SUMMARY: The patient was a 94-year-old woman who was diagnosed at age 67 with PTC and underwent a near-total thyroidectomy. The PTC recurred in the cervical nodes and reached the size of 8 x 5.5 cm by age 89. The tumor had become exposed and was hemorrhaging. By age 92 it measured 10 cm, encompassed the right common carotid artery, and was invading the trachea and larynx. In order to implement local control, we applied Mohs ointment. She also required blood transfusions. After approximately 1 month, the tumor had flattened, and the hemorrhaging stopped, and the patient was able to be discharged from the hospital to home nursing. CONCLUSION: Treatment with Mohs chemosurgery should be considered in the rare patient with exposed locally aggressive PTC for palliation and improved quality of life. PMID- 19445625 TI - Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. AB - BACKGROUND: This is a report of a patient with a novel genotype-phenotype relationship of a c804 mutation of the RET proto-oncogene manifesting as medullary thyroid carcinoma (MTC) and cutaneous lichen amyloidosis (CLA). SUMMARY: Clinical data were obtained for patient appearance and laboratory results. Analyzed were histopathology of the skin lesion and thyroid gland, genetic mutation, and family pedigree. Skin histology and histochemistry were consistent with CLA. Serum calcitonin levels were moderately elevated. Thyroid histology demonstrated a 4 mm focus of MTC. Measurements of serum parathormone, calcium, and plasma metanephrines were normal. DNA analysis demonstrated a mutation in codon 804 of the RET proto-oncogene resulting in a Valine to Methionine (V804M) substitution. Genetic testing in two siblings revealed the same mutation. CONCLUSIONS: This is the first description of a patient with CLA not associated with a mutation in codon 634. The patient is one of the few with a V804M mutation in whom the clinical expression did not fully conform to the definition of familial MTC. PMID- 19445626 TI - Ultrasound-guided fine-needle aspiration in the management of thyroid nodules in children and adolescents. AB - BACKGROUND: The reported incidence of thyroid nodules in children and adolescents is estimated to be between 1% and 2%. However, this incidence may be increasing because diagnostic radiological procedures are detecting incidental thyroid nodules in children. The objective of this study was to assess the diagnostic accuracy, sensitivity, and specificity of ultrasound-guided fine-needle aspiration (US-FNA) of thyroid nodules in children and adolescents. METHODS: Forty-two children (mean age, 14.75 years) underwent US-FNA of 52 thyroid nodules. The specificity, sensitivity, diagnostic accuracy, and unsatisfactory rates were compared to other similar studies. RESULTS: Six patients had a cytological diagnosis of papillary thyroid cancer, which was confirmed at surgery. There were no false-negative specimens, and cytological diagnostic accuracy was 93.7%. The inadequate rate was only 1.9%. CONCLUSIONS: US-FNA of thyroid nodules in children and adolescents is highly accurate in experienced hands and is associated with a very low inadequate rate. PMID- 19445627 TI - Comparison of thyroidectomized calf serum and stripped serum for the study of thyroid hormone action in human skin fibroblasts in vitro. AB - BACKGROUND: Knowledge on the action of thyroid hormone (TH) is augmented by the study of tissue responses to TH in vitro. In order to support the growth of cells in vitro, calf serum (CS) is usually added to the medium to provide necessary nutrients and growth factors. However, the content of endogenous TH in the CS may obfuscate changes with small doses of TH. We therefore compared the use of TH depleted medium, either by resin treatment (stripped-CS) or by the use of CS from a thyroidectomized calf (TxCS) for gene expression studies. METHODS: We describe the method for preparing a thyroidectomized calf, harvesting the blood and preparing the serum. We utilized methimazole in conjunction with the thyroidectomy to prevent TH synthesis in the event of regrowth of the thyroid remnant. RESULTS: Total triiodothyronine (T(3)) and thyroxine concentrations in TxCS were low at <30 ng/dL and <1 microg/dL, respectively. We compared the effect of T(3) on basic transcription element-binding protein (BTEB)1 and stanniocalcin (STC)-1 mRNA expression in human fibroblasts from a normal individual and a subject with resistance to TH (RTH) cultured in stripped-CS to TxCS and demonstrated that with stripped-CS and TxCS differences in the BTEB1 and STC-1 expression of normal and RTH fibroblasts could be detected. CONCLUSIONS: Both stripped-CS and TxCS are suitable to detect subtle differences in TH responsiveness between normal and RTH human skin fibroblasts, yet TxCS is not as costly as stripped-CS and relatively easy to prepare. PMID- 19445628 TI - Lack of GNAQ hotspot mutation in papillary thyroid carcinomas. PMID- 19445629 TI - The usual ultrasonographic features of thyroid cancer are less frequent in small tumors that develop after a long latent period after the Chernobyl radiation release accident. AB - BACKGROUND: The Chernobyl accident resulted in an unprecedented number of radiation-induced thyroid cancers in young individuals as detected by national and international screening programs. The vast majority of thyroid malignancies were papillary carcinomas that, despite being similar by histopathology, displayed large variability in clinical course. The correlations between ultrasound (US) and clinicopathological features in young patients with radiation induced thyroid cancer, however, have not been well studied. Because of the importance of US for deciding which subjects should have fine-needle aspiration biopsy, we assessed the US features of papillary thyroid carcinoma in patients exposed to Chernobyl fallouts. DESIGN: We performed a retrospective multivariate logistic regression analysis of US features, clinicopathological data, and the latency period between radiation exposure and the diagnosis of cancer in 94 patients who were 10.6-34.3 years old (16.5 +/- 6.2, mean +/- standard deviation) at the time of diagnosis and 0.1-18.0 years old (5.6 +/- 4.2) at the time of the Chernobyl accident. RESULTS: Nodules greater than 10 mm were associated with the higher frequency of irregular margins (p = 0.001), longer period of latency (p = 0.016), and bilateral lymph node involvement (p = 0.025). Irregular tumor margins correlated with the shorter period of latency (p = 0.009) and unilateral nodal disease (p = 0.010). Hypoechoic nodules were observed more frequently in female patients (p = 0.012), in the absence of halo (p = 0.003) or calcifications (p = 0.005). Hypoechogenicity also correlated with the shorter latency (p = 0.015) and younger age of patients (p = 0.048). CONCLUSIONS: Irregular nodule margins, a usual sign of malignancy, are less useful in detecting thyroid cancers in radiation-exposed patients with tumors less than 10 mm. Thyroid cancers that are detected after longer latent periods display less of the US features characteristic of a malignant process, while benign US features are observed more frequently. Therefore, we recommend fine-needle aspiration biopsy to ensure early diagnosis of thyroid cancer for patients with a history of radiation exposure, even if their nodules are less than 10 mm. PMID- 19445630 TI - Production of scFv antibody fragments from a hybridoma with functional activity against human vascular endothelial growth factor. AB - Vascular endothelial growth factor (VEGF) plays a major role in the development of aberrant neovascularization in ocular diseases such as diabetic retinopathy and age-related macular degeneration (ARMD), and is an important therapeutic target for these diseases. Monoclonal antibodies specific for VEGF are in clinical use for some patients with ARMD, delivered by intraocular injection. We have shown previously that single chain antibody fragments (scFv) penetrate into the eye when applied topically to the ocular surface. Here we describe the production of a scFv from a monoclonal antibody specific for human VEGF and demonstrate its ability to decrease proliferation of human umbilical vein endothelial cells in culture. A suitably formulated anti-VEGF scFv may have potential as a less invasive topical treatment for potentially blinding neovascular diseases of the eye. PMID- 19445631 TI - Factors influencing internet addiction in a sample of freshmen university students in China. AB - The prevalence of Internet addiction and influential factors associated with Internet addiction among freshmen college students were investigated in this study. A total of 3557 first-year university students from a university in northwest China were surveyed with Young's 20-item Internet Addiction Test (IAT) questionnaire, a Self-Rating Depression scale (SDS), a Self-Rating Anxiety scale (SAS), and a basic information questionnaire. A rate of 6.44% of the participants surveyed showed Internet addiction. The students with Internet addiction had higher scores of SDS and SAS compared with those without Internet addiction (p < 0.01). There were significant positive correlations between SDS and SAS scores and Internet addiction (p < 0.001). Multiple logistic regression analyses showed that a single-parent family, the age of first exposure to Internet use, the age of the student, city residence, and homesickness were significantly associated with Internet addiction (p < 0.01). Special and closer attention should be paid to these factors, and a risk-focus approach should be implemented in university freshmen with depression, anxiety, and other influential factors associated with Internet addiction at the beginning of their university life to guarantee the fulfillment of their academic study and graduation. PMID- 19445632 TI - How avatar customizability affects children's arousal and subjective presence during junk food-sponsored online video games. AB - The purpose of this study was to determine how children cognitively and emotionally process interactive marketing of snack food products in advergames. Children (N = 30) aged 10 to 12 were asked to play advergames with (a) avatars that were assigned to them, (b) avatars chosen from a pool, and (c) self-designed avatars. The children's skin conductance levels were collected during play. After gameplay, at each customization level, self-reported presence was collected. The results of this study indicate that customization of game avatars can affect both subjective feelings of presence and psychophysiological indicators of emotion during gameplay, which may make the gameplay experience more enjoyable. This may have implications for game sponsors and producers. Self-reported presence had no effect on psychophysiological indicators of emotion during gameplay. Implications of this finding and limitations of this study are discussed. PMID- 19445633 TI - An e-health system for the elderly (Butler Project): a pilot study on acceptance and satisfaction. AB - The Butler Project is a technological e-health platform that uses the Internet to connect various users; it was designed to deliver health care to the elderly. The Butler platform has three levels of implementation: diagnosis (mood monitoring, alert system, management reports), therapy (training in inducing positive moods, memory work), and entertainment (e-mail, chat, video, photo albums, music, friend forums, accessibility to the Internet). The objective of this work is to describe the psychological aspects of the platform and to present data obtained from four users. Results show that after using the system, the participants increased their positive emotions and decreased their negative ones; in addition, they obtained high levels of satisfaction and experienced little difficulty in using the system. PMID- 19445634 TI - Spirituality, gender and age factors in cybergossip among Nigerian adolescents. AB - This study investigated the patterns of spirituality, gender, and age in cybergossip practices among Nigerian adolescents. The study utilized a descriptive survey method. Five hundred thirty adolescent students, randomly selected from four major cities in Nigeria, participated in the study. Their age range was 16 to 21. General Spirituality and Gossip Purpose scales were used to collect data from the participants. Data collected were subjected to t test statistics. Findings showed that there is no significant difference in the cybergossiping practices of adolescents based on their levels of spirituality. This reveals that spirituality is not an inhibiting factor in cybergossiping practices among the adolescents. However, there is significant difference between male and female youths in their cybergossiping practices. The results showed that females are more likely than males to be involved in cybergossiping activities. There is also significant difference between early and late adolescents' cybergossiping activities. The implication is that gossip and cybergossip is a natural tendency that involves communicative expression with a pleasure-seeking purpose. It is a habit that excludes no one despite spiritual, gender, or age factors. Therefore, this behavior should be positively directed away from abusive computing and communication. This work is unique because of the need for parents, guardians, and psychologists to design measures to identify and manage various moderating variables in children's computing practices for optimal positive outcomes. PMID- 19445635 TI - Extraversion, impulsivity, and online group membership as predictors of problematic internet use. AB - The present study investigated predictors of problematic Internet use. Undergraduate students (N = 272) completed a self-report questionnaire measuring extraversion, impulsivity, online group membership, frequency of use, and gender as predictors of problematic Internet use. Males and females differed significantly in their use of the Internet, with males significantly more likely to be Gamers than were females, and females significantly more likely to be Workers. Professional users reported significantly less problematic Internet use than nonprofessional users. Hierarchical regression analysis indicated that higher frequency of use, lack of perseverance (an aspect of impulsivity), and online group membership significantly predicted problematic Internet use. Given recent concerns about the growth of Internet addiction, this study extends our knowledge of the role played by personality, usage profile, and gender in this developing field of study. PMID- 19445636 TI - The combined influence of central and peripheral routes in the online persuasion process. AB - The elaboration likelihood model (ELM) is one of the most widely used psychological theories in academic literature to account for how advertising information is processed. The current work seeks to overturn one of the basic principles of the ELM and takes account of new variables in the model that help to explain the online persuasion process more clearly. Specifically, we posit that in a context of high-involvement exposure to advertising (e.g., Web pages), central and peripheral processing routes may act together. In a repeated-measures experimental design, 112 participants were exposed to two Web sites of a fictitious travel agency, differing only in their design--serious versus amusing. Findings evidence that a peripheral cue, such as how the Web pages are presented, does prove relevant when attempting to reflect the level of effectiveness. Moreover, if we take account of individuals' motivation when accessing the Internet, whether cognitive or affective, the motivation will impact their response to the Web site design. The work contributes to ELM literature and may help firms to pinpoint those areas and features of Internet advertising that prove most efficient. PMID- 19445637 TI - You can't take it with you? Effects of handheld portable media consoles on physiological and psychological responses to video game and movie content. AB - Portable media consoles are becoming extremely popular devices for viewing a number of different types of media content, both for entertainment and for educational purposes. Given the increasingly heavy use of portable consoles as an alternative to traditional television-style monitors, it is important to investigate how physiological and psychological effects of portable consoles may differ from those of television-based consoles, because such differences in physiological and psychological responses may precipitate differences in the delivered content's effectiveness. Because portable consoles are popular as a delivery system for multiple types of media content, such as movies and video games, it is also important to investigate whether differences between the effects of portable and television-based consoles are consistent across multiple types of media. This article reports a 2 x 2 (console: portable or television based x medium: video game or movie) mixed factorial design experiment with physiological arousal and self-reported flow experience as dependent variables, designed to explore whether console type affects media experiences and whether these effects are consistent across different media. Results indicate that portable media consoles evoke lower levels of physiological arousal and flow experience and that this effect is consistent for both video games and movies. These findings suggest that even though portable media consoles are often convenient compared to television-based consoles, the convenience may come at a cost in terms of the user experience. PMID- 19445638 TI - Detection of concealed information: combining a virtual mock crime with a P300 based Guilty Knowledge Test. AB - The present study examined the detection of concealed information by combining a virtual mock crime with a P300-based Guilty Knowledge Test (GKT). Thirty-eight male participants were assigned to one of two groups: a guilty group that committed a mock crime to conceal a lost roll of bills in a computer simulation of a virtual library and an innocent group that was free from concealed information. Remarkably, the guilty group reacted with stronger P300 peak amplitudes to crime-relevant than to irrelevant stimuli, whereas the innocent group had similar P300 responses between crime-relevant and irrelevant stimuli. Deception-related cognitive activity based on P300 was revealed as a valid marker to differentiate between guilty and innocent. This is a highly empirical study combining a virtual mock crime with a P300-based GKT to detect deception. These results may be applied to a variety of areas dealing with not only forensic investigation but also health and medical research concerning deception as a symptom. PMID- 19445639 TI - Ureteroscope cleaning and sterilization by the urology operating room team: the effect on repair costs. AB - BACKGROUND AND PURPOSE: Flexible ureteroscopes are fragile devices, and the costs associated with their repair and replacement can be considerable. Although surgical use can degrade ureteroscope function, the cleaning and sterilization process can also cause great damage. We performed a study to define the effect of having the urology nursing staff process and sterilize all ureteroscopes, rather than the central processing core; the total repair cost and cost per use were analyzed. MATERIALS AND METHODS: From April 2007 to March 2008, all ureteroscopes were processed by the urology nursing staff. We analyzed the average cost per use as a measure of the effectiveness of this strategy. For all endoscopic stone removal cases, a flexible ureteroscope is opened onto the operative field; therefore, after every endoscopic procedure, the flexible ureteroscope needs processing and sterilizing. The number of times each ureteroscope was processed and the type and cost of repairs were recorded. RESULTS: From April 2007 to March 2008, 11 ureteroscopes were processed 478 times; average uses before repair was 28.1. Seven ureteroscopes were returned for repair because of: loss of deflection (2); loss of fiberoptic bundles (2); failed leak test (3). No ureteroscope damage was because of processing. The total repair cost in this 12-month period was $57,664.50. Amortizing repair costs over use gives a value of $120.63 cost per use. CONCLUSIONS: Training the urology nursing staff to clean and sterilize ureteroscopes is a reasonable means to reduce processing-related damages. PMID- 19445640 TI - Emergency room management of ureteral calculi: current practices. AB - OBJECTIVE: To evaluate current practice patterns in U.S. emergency departments (EDs) for the diagnosis, treatment, and counseling of patients with ureteral calculi. METHODS: Hospital-based ED physicians were invited by e-mail to participate in a Survey-Monkey survey. E-mails were delivered in March 2008 by Direct Medical Data using a listserv provided by the American Medical Association. Of the e-mails sent, 173 e-mails were opened, and 135 physicians responded. Physicians were compensated with a $10 Amazon.com gift card. RESULTS: Ninety percent of ED physicians use noncontrast CT as their initial imaging modality, and 63% use alpha-blockers for medical expulsive therapy. Only 13% of evaluated EDs have guidelines for the management of renal colic, and only 58% of these guidelines that recommend the use of an alpha-blocker. Alpha-blocker use was more common with physicians who have been practicing fewer than 5 years (81%) compared with those with more than 10 years of experience (56%). The majority of physicians used ketorolac and morphine to achieve effective analgesia. Although the average responses concerning the chance of spontaneous stone passage for stones 4 mm (44%) were close to evidence-based values, great variation in the answers was noted (standard deviations: 12% and 22%, respectively). Indeed, 38% of respondents stated that stones 95% chance of passage. Twenty-eight percent of ED physicians would arrange follow-up with a primary care physician, while the remainder would arrange follow-up with a urologist. CONCLUSIONS: This study establishes a need for educational opportunities for ED physicians in the management of renal colic. The development of collaborative practice guidelines between urology and emergency medicine associations may be warranted. PMID- 19445641 TI - An innovative approach to serving the needs of IPV survivors: description of a CDC-Funded study examining the Volunteers of America Home Free rent assistance program. AB - Abstract The purpose of this paper is to describe a CDC-funded study examining the effectiveness and cost-effectiveness of the Volunteers of America Home Free program, an innovative program that offers survivors of intimate partner violence (IPV) permanent housing rent assistance coupled with client-centered advocacy. We briefly discuss the challenges and barriers faced by women who try to separate from abusive partners and who have an immediate need for housing, describe the innovative approach to service provision adopted by the Volunteers of America Home Free program in Portland, Oregon, and describe the CDC-funded cooperative agreement to compare the effectiveness and cost-effectiveness of this approach with the usual housing services available to women fleeing abusive relationships. PMID- 19445642 TI - The effect of auricular acupuncture in obese women: a randomized controlled trial. AB - BACKGROUND: The aims of this randomized study are to examine the effect of auricular acupuncture on obese women and to explore the relationship between the effect of auricular acupuncture and obesity-related hormone peptides. METHODS: Forty-five of 60 obese women aged between 16 and 65 years with body mass index (BMI) >27 kg/m2 and who had not received any other weight control maneuvers within the last 3 months completed this study. The subjects were blinded and randomly divided into groups A and B. Group A (n = 23) received auricular acupuncture, and group B (n = 22) received sham auricular acupuncture using placebo needles, twice each week for 6 weeks. The subjects' body weight (BW), BMI, waist circumference (WC), and obesity-related hormone peptides were measured at the beginning of the study and after 6 weeks of treatment. The data were compared and expressed as percent reductions. RESULTS: This study found no statistical difference in percent reduction in BW, BMI, and WC between the group receiving 6 weeks of auricular acupuncture treatment and the control group. After treatment, group A revealed a significant increase in ghrelin level and decrease in leptin level. On the other hand, group B, who received sham auricular acupuncture, showed no significant difference in ghrelin and leptin levels. CONCLUSIONS: This study found no statistical difference in percent reduction in BW, BMI, and WC between the two groups. No adverse effects of short-term auricular acupuncture treatment were seen in the study. Auricular acupuncture may have potential benefit on obesity-related hormone peptides. PMID- 19445643 TI - Treatment patterns for early pregnancy failure in Michigan. AB - AIMS: We describe current treatment patterns for early pregnancy failure (EPF) among women enrolled in two Michigan health plans. METHODS: We conducted a retrospective review of EPF treatment among Michigan Medicaid enrollees between January 1, 2001, and December 31, 2004, and enrollees of a university-affiliated health plan between January 1, 2001, and December 31, 2005. Episodes were identified by the presence of a diagnostic code for EPF. Surgical treatment was distinguished from nonsurgical management using procedure codes. Facility charges, procedure, and place of service codes were used to determine whether a procedure was done in an office as opposed to an operating room. Cases without a claim for surgical uterine evacuation were examined for a misoprostol pharmacy claim and, if present, were classified as medical management. Cases without a procedure or pharmacy claim were classified as expectant management. RESULTS: Respectively, we identified 21,311 and 1,493 episodes of EPF in the Medicaid and university-affiliated health plan databases, respectively. Women enrolled in Medicaid were more likely to be treated with surgery than were enrollees of the university-affiliated health plan (35.3 vs. 18.0%, respectively, p < 0.000). Among Medicaid enrollees, only 0.5% of surgical evacuations occurred in the office, but office procedures were common among enrollees of the university affiliated health plan (30.5%, p < 0.000). The proportion of cases managed with misoprostol was <1% in both groups. Caucasian race and age were both associated with having a surgical uterine evacuation (p < 0.001). CONCLUSIONS: EPF is primarily being treated with expectant management or surgical evacuation in an operating room and may not reflect evidence-based practices or patient preferences. PMID- 19445646 TI - Small RNA identification in Enterobacteriaceae using synteny and genomic backbone retention II. AB - Small RNAs are bacterial counterparts of noncoding RNAs. Increasing evidence being added in the literature indicates that these small RNAs play major roles in prokaryotes both at the transcriptome and proteome levels. Based on comparative genomic studies, we present manually curated small RNA regions in 25 recently completed genomes from Enterobacteriaceae. The study is a continuation of our earlier work that uses the presence of small RNAs sandwiched between specific conserved flanking genes retaining genomic backbone and gene synteny. Based on this study, a total of 931 identified sRNA/sRNA regions are reported. This data contains 498 small RNA homologs, 80 putative small RNA regions containing partial stretches of homologous sequences, and 353 putative nonhomologous sRNA regions. This homologs/partial homologs includes, 84 putative small RNA homologous regions retaining at least one of the conserved flanking genes pair which may possibly act as hotspots for genetic pool insertion/deletion in genomes. Nonhomologous CsrB sRNA region reported by us in Yersinia pseudotuberculosis IP32953 has been experimentally confirmed by Kulkarni's group and sraH and ryeE sRNAs from Erwinia carotovora subsp. atroseptica SCRI1043 recently added to the Rfam database are indicative proof of our positive approach. PMID- 19445645 TI - Prepregnancy depressive mood and preterm birth in black and white women: findings from the CARDIA Study. AB - OBJECTIVES: We examine associations among race, prepregnancy depressive mood, and preterm birth (<37 weeks gestation) in a cohort study of black and white women. METHODS: We tested for mediation of the association between race and preterm birth by prepregnancy depressive mood among 555 women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. RESULTS: Black women had significantly higher levels of prepregnancy depressive mood (modified CES-D score 13.0 vs. 9.5, t = -4.64, p < 0.001). After adjustment for covariates, black women had 2.70 times the odds of preterm birth as white women (95% confidence interval [CI] 1.41, 5.17). When adding prepregnancy depressive mood to this model, higher depressive mood was associated with greater odds of preterm birth (odds ratio [OR] 1.04; 95% CI 1.01, 1.07), and the effect of black race was attenuated (OR 2.47, 95% CI 1.28, 4.77). CONCLUSIONS: Our data suggest that prepregnancy depressive mood may be a risk factor for preterm birth among black and white women. PMID- 19445647 TI - Unsupervised selection of highly coexpressed and noncoexpressed genes using a consensus clustering approach. AB - In this paper we explore the concept of consensus clustering to identify, within a set of differentially expressed genes, a subset of genes that are either highly coexpressed or highly noncoexpressed based on the hypothesis that this subset would serve as a better starting point for further analyses. A number of core clustering methods form the basis for the assertion of an agreement matrix (AM) characterizing the level of coexpression between any two probesets. In order to overcome the limitations of using a single distance metric, we explore different metrics and examine the sensitivity of the AM as a function of the input number of clusters to find a suggestive number of clusters that best describes a particular dataset. The result of this level of analysis is a systematic framework for eliminating probesets that cannot be clearly characterized as either coexpressed or noncoexpressed with others, thus eliminating a number of probesets from further analysis. Subsequently, an agglomerative hierarchical clustering approach is applied to cluster the selected subset using the agreement metric information as the similarity measure. Thus, the goal of the proposed methodology is twofold: (1) we opt to identify a more "clusterable" subset of the original set; and (2) we aim at further refining the subset in order to identify a core of genes that contains genes that are either coexpressed or noncoexpressed within a certain confidence level. The approach is tested with a number of data sets, both synthetic and real, and it is demonstrated that it is successful in identifying more clusterable, also hypothesized to be more biologically relevant, subsets of genes and expression profiles. PMID- 19445648 TI - Systemic cytokine response following exercise-induced muscle damage in humans. AB - BACKGROUND: Muscle adaptation which occurs following eccentric exercise-induced muscle damage has been associated with an acute inflammatory response. The purpose of this study was to investigate serum interleukin-6 (IL-6), osteoprotegerin and receptor activator of nuclear factor kB ligand (OPG/RANKL) concentrations following muscle damage. We measured changes for several days following muscle damage. METHODS: Ten healthy young males performed an eccentric exercise protocol using their quadriceps. Blood samples were withdrawn before and at 6 h, 2 days, 5 days and 16 days post-exercise. Functional and clinical measurements were performed before, and on days 1, 2, 5, 8, 12 and 16 post exercise. RESULTS: The exercise protocol resulted in muscle damage, indicated by changes in biochemical markers. An increase in IL-6 and OPG, and a decrease in RANKL concentrations were seen at 6 h and on day 2 post-exercise; the OPG:RANKL ratio was increased at 6 h post-exercise (p < 0.05). CONCLUSIONS: Changes in IL-6 and OPG/RANKL system may represent systemic responses in muscle inflammation and repair processes. However, further studies are needed to elucidate a potential systemic and/or local role of the OPG/RANKL system in skeletal muscle repair. PMID- 19445649 TI - Proficiency test of plasma free and total metanephrines: report from a study group. PMID- 19445650 TI - Mass spectrometry based proteomics profiling as diagnostic tool in oncology: current status and future perspective. AB - Proteomics analysis has been heralded as a novel tool for identifying new and specific biomarkers that may improve diagnosis and monitoring of various disease states. Recent years have brought a number of proteomics profiling technologies. Although proteomics profiling has resulted in the detection of disease-associated differences and modification of proteins, current proteomics technologies display certain limitations that are hampering the introduction of these new technologies into clinical laboratory diagnostics and routine applications. In this review, we summarize current advances in mass spectrometry based biomarker discovery. The promises and challenges of this new technology are discussed with particular emphasis on diagnostic perspectives of mass-spectrometry based proteomics profiling for malignant diseases. PMID- 19445651 TI - Interpreting clinical trial results of patient-perceived onset of effect in asthma: methods and results of a Delphi panel. AB - OBJECTIVE: The purpose of this study was to determine if empirically observed differences in patient perception of, and satisfaction with, onset of effect between an active maintenance treatment and placebo are clinically meaningful to practicing clinicians. A secondary objective was to determine the lowest threshold for a clinically meaningful difference in terms of both between-group differences and maximum acceptable placebo effect. METHODS: Twelve community based healthcare professionals participated in a Delphi consensus panel. Panelists were provided with blinded results of two clinical trials showing statistically significant treatment effects for treatment A (budesonide/formoterol [Symbicort*]) over placebo in the proportion of patients who could perceive the medication working right away and the proportion of patients satisfied with this perception. Panelists were then asked to respond to a series of questions to identify a threshold for clinically important differences in patient-perceived onset of effect and satisfaction with speed of onset of effect. All expert panelists participated in two rounds of the Delphi process. RESULTS: Panelists were unanimous in their conclusion that the statistically significant results from the two trials were clinically meaningful. According to these practitioners, the empirical results presented to them, showing that patients could feel a maintenance inhaler therapy work right away, were meaningful to clinical decision-making, and the attribute could potentially improve patient adherence with therapy. A group consensus was reached that a minimum active treatment response for these outcomes should range from 50% to 75% and be 2-3 times larger than the placebo response, with a maximum placebo effect of 26-40%. CONCLUSION: A Delphi panel study of practitioners was used to establish a meaningful range of response and a minimal important difference for interpreting results of clinical trials in which patient perception of onset of effect and satisfaction with this perception are tested. While the views of this panel may not be generalized to the entire population of practitioners in the United States, results provide insight into how a typical practitioner is likely to view clinical trial results and how the information might be used in clinical practice. PMID- 19445652 TI - A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. AB - OBJECTIVE: To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy). METHODS: Randomized patients (N = 901) received oral tapentadol IR 50 or 75 mg, oxycodone HCl IR 10 mg, or placebo every 4-6 h over a 72-h period following surgery. Acetaminophen (< or =2 g) was allowed in the first 12 h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75 mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10 mg (using sum of pain intensity difference [SPID] over 48 h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting). RESULTS: Statistically significantly higher mean SPID(48) values were observed with tapentadol IR (50 and 75 mg) and oxycodone HCl IR 10 mg than placebo (all p < 0.001). The efficacy of tapentadol IR 50 mg and 75 mg was non inferior to oxycodone HCl IR 10 mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50 mg versus oxycodone IR 10 mg (35 vs. 59%; p < 0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75 mg and oxycodone IR 10 mg (51 vs. 59%; p = 0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups. CONCLUSIONS: Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50 mg and 75 mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50 mg and 75 mg were non-inferior to oxycodone HCl IR 10 mg for the treatment of acute pain based on the primary efficacy endpoint of SPID(48) and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50 mg and numerically lower for tapentadol IR 75 mg than for oxycodone HCl IR 10 mg. PMID- 19445653 TI - Proliferation and multi-differentiation potentials of human mesenchymal stem cells on thermoresponsive PDMS surfaces grafted with PNIPAAm. AB - The thermo-responsivity of PNIPAAm [poly(N-isopropylcarylamide)]-grafted PDMS [poly(dimethylsiloxane)] surface is a property that could be feasibly used for detaching cells adhered on the surface. We used benzophenone-initiated photopolymerization to graft PNIPAAm on PDMS substrates to construct the PNIPAAm grafted PDMS surface and this PDMS surface was highly thermo-responsive. hMSCs (human mesenchymal stem cells) were used to analyse the proliferation and multi differentiation of stem cells on the PNIPAAm-grafted PDMS surface. The results showed that hMSCs could adhere on the PNIPAAm-grafted PDMS surface at 37 degrees C and form cell colonies, and then become fibroblastic. The proliferation potential of hMSCs on the PNIPAAm-grafted PDMS surface was not significantly different from that on a plate surface coated with gelatin. However, as it proved easier to detach cells from the surface, by changing temperature, a higher viability of detached cells could be obtained with the PNIPAAm-grafted PDMS surface, using a temperature shift, compared with a gelatin-coated surface, where cells are detached by treatment with trypsin. hMSCs on the PNIPAAm-grafted PDMS surface were induced into osteoblasts, adipocytes and neurocytes under osteogenic medium, adipogenic medium and neurogenic medium respectively. The PNIPAAm-grafted PDMS surface was favourable for osteogenesis of hMSCs, although the potentials of adipogenesis and neurogenesis of hMSCs on the PNIPAAm-grafted PDMS surface were similar to those on the plate surface coated with gelatin. The above results demonstrate that the PNIPAAm-grafted PDMS surface not only kept the potentials of proliferation and multi-differentiation of hMSCs, but also increased the viability of hMSCs. PMID- 19445654 TI - Delivery by Caesarean section, rather than vaginal delivery, promotes hepatic steatosis in piglets. AB - There has been a marked increase in the number of babies born by elective CS (Caesarean section). Following CS, the lack of normal stimuli that occur at birth alters the thermogeneic response, but any effects on hepatic metabolism have not been identified. In the present study, we compared the effect of delivery on hepatic metabolism in piglets, born either by CS or VD (vaginal delivery) and fed by TPN (total parenteral nutrition), by measuring lipid metabolism and enzyme activity coupled with metabolomic and genomic approaches. Hepatic lipid in the CS piglets at 7 days post-partum was in excess of 5 mg/g of liver consistent with hepatic steatosis, whereas in the VD piglets the amount of lipid was markedly lower (3 mg/g of liver) and below the threshold for a diagnosis of steatosis. Metabolomic analysis indicated that CS resulted in higher hepatic glycerol and lower glycerol phosphate dehydrogenase activity, suggesting that CS causes a decrease in hepatic gluconeogenesis from glycerol. CS also resulted in altered cholesterol handling and gene expression, despite the same dietary intake for 7 days post-partum. Furthermore, the CS piglets had a lower expression of interferon-responsive genes, but a higher expression of markers of immature hepatocytes. In conclusion, the results suggest that VD promotes normal liver maturation and hepatic metabolism, thereby reducing the accumulation of hepatic lipid. PMID- 19445655 TI - How does healthcare worker hand hygiene behaviour impact upon the transmission of MRSA between patients?: an analysis using a Monte Carlo model. AB - BACKGROUND: Good hand hygiene has for many years been considered to be the most important measure that can be applied to prevent the spread of healthcare associated infection (HAI). Continuous emphasis on this intervention has lead to the widespread opinion that HAI rates can be greatly reduced by increased hand hygiene compliance alone. However, this assumes that the effectiveness of hand hygiene is not constrained by other factors and that improved compliance in excess of a given level, in itself, will result in a commensurate reduction in the incidence of HAI. However, there is evidence that the law of diminishing returns applies to hand hygiene, with the greatest benefits occurring in the first 20% or so of compliance. While this raises intriguing questions about the extent to which increasing compliance alone can further reduce rates of HAI, analysis of this subject has been hampered by a lack of quantifiable data relating to the risk of transmission between patients on wards. METHODS: In order to gain a greater understanding of the transmission of infection between patients via the hands of healthcare workers (HCWs), we constructed a stochastic Monte Carlo model to simulate the spread of methicillin-resistant Staphylococcus aureus (MRSA) between patients. We used the model to calculate the risk of transmission occurring, firstly between two patients in adjacent beds, and then between patients in a four-bedded bay. The aim of the study was to quantify the probability of transmission under a variety of conditions and thus to gain an understanding of the contribution made by the various factors which influence transmission. RESULTS: The study revealed that on a four-bedded bay, the average probability of transmitting an infection by the handborne route is generally low (i.e. in the region 0.002 - 0.013 depending on the hand hygiene behaviour of HCWs and other factors). However, because transmission is strongly influenced by stochastic events, it is the frequency with which 'high-risk events' occur, rather than average probability, that governs whether or not transmission will take place. The study revealed that increased hand hygiene compliance has a dramatic impact on the frequency with which 'high-risk events' occur. As compliance increases, so the rate at which 'high-risk events' occur, rapidly decreases, until a point is reached, beyond which, further hand hygiene is unlikely to yield any greater benefit. CONCLUSION: The findings of the study confirm those of other researchers and suggest that the greatest benefits derived from hand hygiene occur as a result of the first tranche of compliance, with higher levels (>50%) of hand hygiene events yielding only marginal benefits. This suggests that in most situations relatively little benefit is accrued from seeking to achieve very high levels of hand hygiene compliance. PMID- 19445656 TI - Urgent care centers in the U.S.: findings from a national survey. AB - BACKGROUND: Due to long waits for primary care appointments and extended emergency department wait times, newer sites for episodic primary care services, such as urgent care centers, have developed. However, little is known about these centers. The purpose of this study is to provide information about the organization and functioning of urgent care centers based on a nationally representative U.S. sample. METHODS: We conducted a mail survey with telephone follow-up of urgent care centers identified via health insurers' websites, internet searches, and a trade association mailing list. Descriptive statistics are presented. RESULTS: Urgent care centers are open beyond typical office hours, and their scope of services is broader than that of many primary care offices. While these characteristics are similar to hospital emergency departments, such centers employ significant numbers of family physicians. The payer distribution is similar to that of primary care, and physicians' average salaries are comparable to those for family physicians overall. Urgent care centers report early adoption of electronic health records, though our findings are qualified by a lack of strictly comparable data. CONCLUSION: While their hours and scope of services reflect some characteristics of emergency departments, urgent care centers are in many ways similar to family medicine practices. As the health care system evolves to cope with expanding demands in the face of limited resources, it is unclear how patients with episodic care needs will be treated, and what role urgent care centers will play in their care. PMID- 19445657 TI - Fatal cardiac arrest in an adult patient with euthyroid anti-SSA/Ro-positive connective tissue disease: a case report. AB - BACKGROUND: Until recently, anti-SSA/Ro antibodies were not considered pathogenic for severe heart disease in adults. Prolongation of the mean QTc interval in electrocardiograms of adult patients with anti-SSA/Ro-positive connective tissue disease has been reported and could contribute to complex arrhythmias in such patients. Furthermore, complete heart block may also be related to these autoantibodies. CASE PRESENTATION: We describe the occurrence of fatal complete heart block in a euthyroid adult patient with undifferentiated connective tissue disease and polyglandular autoimmune syndrome type 2 associated with cardiovascular autonomic dysfunction who had normal QTc interval. The patient's serum contained anti-SSA/Ro. CONCLUSION: This case might indicate that, although the adult heart conduction system may be relatively resistant to the development of anti-Ro-associated complete heart block, cardiac arrest may develop and even be fatal. PMID- 19445658 TI - Role of the tachykinin NK1 receptor in a murine model of cigarette smoke-induced pulmonary inflammation. AB - BACKGROUND: The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK1 receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD. METHODS: Tachykinin NK1 receptor knockout (NK1-R-/-) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were evaluated. RESULTS: Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK1-R-/- mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK1-R-/- mice, compared to WT controls, and correlated with an attenuated release of MIP-3alpha/CCL20 and TGF-beta1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK1-R-/ mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK1-R-/- mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS exposure was observed in these KO mice. In a pharmacological validation experiment using the NK1 receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK1 receptor on CS-induced pulmonary inflammation. CONCLUSION: These data suggest that the tachykinin NK1 receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease. PMID- 19445660 TI - Perceptions, attitudes and knowledge of evidence-based medicine in primary care in Spain: a study protocol. AB - BACKGROUND: The philosophy of evidence-based medicine (EBM) was introduced in the early 90s as a new approach to the practice of medicine, using the best available evidence to make decisions about health care. Despite ongoing controversy, EBM has developed enormously and physicians' attitude towards it is generally positive. Nevertheless, in Spain little is known about this topic. We will therefore undertake a study to explore perceptions, attitudes and knowledge about EBM among primary care physicians. METHODS AND DESIGN: A mixed-method study combining qualitative and quantitative designs will target family practitioners in Spain with the objective of evaluating current attitudes and perceptions about evidence-based medicine. The project will consist of two phases: a first phase running focus groups to identify perceptions and attitudes of participants, and a second phase assessing their attitudes and knowledge about EBM by means of a survey. Both phases will explore these issues in three different subgroups: family practitioners, with or without previous formal education in EBM; members of working groups that formulate healthcare recommendations; and physicians in charge of training family practice residents. Additionally, we will undertake a systematic review to identify and synthesize the available evidence on this topic. DISCUSSION: The study will identify and gain insight into the perceived problems and barriers to the practice of evidence-based medicine among general practitioners in Spain. The project will also evaluate the main knowledge gaps and training needs, and explore how evidence-based medicine is being taught to family medicine residents, the medical practitioners of the future. Our results will aid researchers and health care planners in developing strategies to improve the practice of evidence-based medicine in our country. PMID- 19445662 TI - RNAi in the cereal weevil Sitophilus spp: systemic gene knockdown in the bacteriome tissue. AB - BACKGROUND: The weevils Sitophilus spp. are among the most important cosmopolitan pests of stored cereal grains. However, their biology and physiology are poorly understood, mainly because the insect developmental stages take place within cereal grains and because of the lack of gene specific molecular manipulation. RESULTS: To gain access to the different insect developmental stages, weevil females were allowed to lay their eggs on starch pellets and hatched embryos were collected by dissolving starch with water. Embryos were transferred between two Glass Plates filled with packed Flour (GPF) to mimic compact texture of the cereal grain, and this system allowed us to recover specific developmental stages. To knockdown the gene expressed in the bacteria-bearing organ (the bacteriome), whole larvae were injected with dsRNA to target the wpgrp1 gene and they were then left to develop for a further 4 days period. Quantitative RT-PCR and Western blot analyses on the bacteriome of these animals revealed a down regulation of the wpgrp1 expression, both at transcript and protein levels. CONCLUSION: These results demonstrate that whole larval injection with dsRNA results in a high and systemic decrease of both mRNA and protein in the bacteriome tissue. This, along with the possibility of access to the insect developmental stages, opens up a new research avenue for exploring gene specific functions in the cereal weevils. PMID- 19445661 TI - The CHOLEGAS study: multicentric randomized, blinded, controlled trial of gastrectomy plus prophylactic cholecystectomy versus gastrectomy only, in adults submitted to gastric cancer surgery with curative intent. AB - BACKGROUND: The incidence of gallstones and gallbladder sludge is known to be higher in patients after gastrectomy than in general population. This higher incidence is probably related to surgical dissection of the vagus nerve branches and the anatomical gastrointestinal reconstruction. Therefore, some surgeons perform routine concomitant cholecystectomy during standard surgery for gastric malignancies. However, not all the patients who are diagnosed to have cholelithiasis after gastric cancer surgery will develop symptoms or require additional surgical treatments and a standard laparoscopic cholecystectomy is feasible even in those patients who underwent previous gastric surgery. At the present, no randomized study has been published and the decision of gallbladder management is left to each surgeon preference. DESIGN: The study is a randomized controlled investigation. The study will be performed in the General and Oncologic Surgery, Department of Oncology-Azienda Ospedaliero-Universitaria Careggi-Florence-Italy, a large teaching institution, with the participation of all surgeons who accept to be involved in, together with other Italian Surgical Centers, on behalf of the GIRCG (Italian Research Group for Gastric Cancer).The patients will be randomized into two groups: in the first group the patient will be submitted to prophylactic cholecystectomy during standard surgery for curable gastric cancer (subtotal or total gastrectomy), while in the second group he/she will be submitted to standard gastric surgery only. TRIAL REGISTRATION: ClinicalTrials.gov ID. NCT00757640. PMID- 19445659 TI - Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia. AB - BACKGROUND: One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. METHODS/DESIGN: The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. DISCUSSION: The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia. PMID- 19445663 TI - Extension of Murray's law using a non-Newtonian model of blood flow. AB - BACKGROUND: So far, none of the existing methods on Murray's law deal with the non-Newtonian behavior of blood flow although the non-Newtonian approach for blood flow modelling looks more accurate. MODELING: In the present paper, Murray's law which is applicable to an arterial bifurcation, is generalized to a non-Newtonian blood flow model (power-law model). When the vessel size reaches the capillary limitation, blood can be modeled using a non-Newtonian constitutive equation. It is assumed two different constraints in addition to the pumping power: the volume constraint or the surface constraint (related to the internal surface of the vessel). For a seek of generality, the relationships are given for an arbitrary number of daughter vessels. It is shown that for a cost function including the volume constraint, classical Murray's law remains valid (i.e. SigmaR(c) = cste with c = 3 is verified and is independent of n, the dimensionless index in the viscosity equation; R being the radius of the vessel). On the contrary, for a cost function including the surface constraint, different values of c may be calculated depending on the value of n. RESULTS: We find that c varies for blood from 2.42 to 3 depending on the constraint and the fluid properties. For the Newtonian model, the surface constraint leads to c = 2.5. The cost function (based on the surface constraint) can be related to entropy generation, by dividing it by the temperature. CONCLUSION: It is demonstrated that the entropy generated in all the daughter vessels is greater than the entropy generated in the parent vessel. Furthermore, it is shown that the difference of entropy generation between the parent and daughter vessels is smaller for a non-Newtonian fluid than for a Newtonian fluid. PMID- 19445664 TI - Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a Slovak population using osteoarthritis patients as controls. AB - INTRODUCTION: Both genetic and environmental factors contribute to rheumatoid arthritis (RA), a common and complex autoimmune disease. As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA. This study was initiated to investigate the association between defined genetic markers and RA in a Slovak population. In contrast to recent studies, we included intensively-characterized osteoarthritis (OA) patients as controls. METHODS: We used material of 520 RA and 303 OA samples in a case-control setting. Six SNPs were genotyped using TaqMan assays. HLA-DRB1 alleles were determined by employing site-specific polymerase chain reaction (PCR) amplification. RESULTS: No statistically significant association of TRAF1/C5 SNPs rs3761847 and rs10818488 with RA was detected. However, we were able to replicate the association signals between RA and HLA-DRB1 alleles, STAT4 (rs7574865), PTPN22 (rs2476601) and OLIG3/TNFAIP3 (rs10499194 and rs6920220). The strongest signal was detected for HLA-DRB1*04 with an allelic P = 1.2*10-13 (OR = 2.92, 95% confidence interval (CI) = 2.18 - 3.91). Additionally, SNPs rs7574865STAT4 (P = 9.2*10-6; OR = 1.71, 95% CI = 1.35 - 2.18) and rs2476601PTPN22 (P = 9.5*10-4; OR = 1.67, 95% CI = 1.23 - 2.26) were associated with susceptibility to RA, whereas after permutation testing OLIG3/TNFAIP3 SNPs rs10499194 and rs6920220 missed our criteria for significance (Pcorr = 0.114 and Pcorr = 0.180, respectively). CONCLUSIONS: In our Slovak population, HLA-DRB1 alleles as well as SNPs in STAT4 and PTPN22 genes showed a strong association with RA. PMID- 19445665 TI - A stimulus to define informatics and health information technology. AB - BACKGROUND: Despite the growing interest by leaders, policy makers, and others, the terminology of health information technology as well as biomedical and health informatics is poorly understood and not even agreed upon by academics and professionals in the field. DISCUSSION: The paper, presented as a Debate to encourage further discussion and disagreement, provides definitions of the major terminology used in biomedical and health informatics and health information technology. For informatics, it focuses on the words that modify the term as well as individuals who practice the discipline. Other categories of related terms are covered as well, from the associated disciplines of computer science, information technology and health information management to the major application categories of applications used. The discussion closes with a classification of individuals who work in the largest segment of the field, namely clinical informatics. SUMMARY: The goal of presenting in Debate format is to provide a starting point for discussion to reach a documented consensus on the definition and use of these terms. PMID- 19445666 TI - Bioaccumulation and toxicity of selenium compounds in the green alga Scenedesmus quadricauda. AB - BACKGROUND: Selenium is a trace element performing important biological functions in many organisms including humans. It usually affects organisms in a strictly dosage-dependent manner being essential at low and toxic at higher concentrations. The impact of selenium on mammalian and land plant cells has been quite extensively studied. Information about algal cells is rare despite of the fact that they could produce selenium enriched biomass for biotechnology purposes. RESULTS: We studied the impact of selenium compounds on the green chlorococcal alga Scenedesmus quadricauda. Both the dose and chemical forms of Se were critical factors in the cellular response. Se toxicity increased in cultures grown under sulfur deficient conditions. We selected three strains of Scenedesmus quadricauda specifically resistant to high concentrations of inorganic selenium added as selenite (Na2SeO3) - strain SeIV, selenate (Na2SeO4) - strain SeVI or both - strain SeIV+VI. The total amount of Se and selenomethionine in biomass increased with increasing concentration of Se in the culturing media. The selenomethionine made up 30-40% of the total Se in biomass. In both the wild type and Se-resistant strains, the activity of thioredoxin reductase, increased rapidly in the presence of the form of selenium for which the given algal strain was not resistant. CONCLUSION: The selenium effect on the green alga Scenedesmus quadricauda was not only dose dependent, but the chemical form of the element was also crucial. With sulfur deficiency, the selenium toxicity increases, indicating interference of Se with sulfur metabolism. The amount of selenium and SeMet in algal biomass was dependent on both the type of compound and its dose. The activity of thioredoxin reductase was affected by selenium treatment in dose dependent and toxic-dependent manner. The findings implied that the increase in TR activity in algal cells was a stress response to selenium cytotoxicity. Our study provides a new insight into the impact of selenium on green algae, especially with regard to its toxicity and bioaccumulation. PMID- 19445667 TI - Proteasome-independent degradation of HIV-1 in naturally non-permissive human placental trophoblast cells. AB - BACKGROUND: The human placenta-derived cell line BeWo has been demonstrated to be restrictive to cell-free HIV-1 infection. BeWo cells are however permissive to infection by VSV-G pseudotyped HIV-1, which enters cells by a receptor independent mechanism, and to infection by HIV-1 via a cell-to-cell route. RESULTS: Here we analysed viral entry in wild type BeWo (CCR5+, CXCR4+) and BeWo CD4+ (CD4+, CCR5+, CXCR4+) cells. We report that HIV-1 internalisation is not restricted in either cell line. Levels of internalised p24 antigen between VSV-G HIV-1 pseudotypes and R5 or X4 virions were comparable. We next analysed the fate of internalised virions; X4 and R5 HIV-1 virions were less stable over time in BeWo cells than VSV-G HIV-1 pseudotypes. We then investigated the role of the proteasome in restricting cell-free HIV-1 infection in BeWo cells using proteasome inhibitors. We observed an increase in the levels of VSV-G pseudotyped HIV-1 infection in proteasome-inhibitor treated cells, but the infection by R5 Env or X4-Env pseudotyped virions remains restricted. CONCLUSION: Collectively these results suggest that cell-free HIV-1 infection encounters a surface block leading to a non-productive entry route, which either actively targets incoming virions for non-proteasomal degradation, and impedes their release into the cytoplasm, or causes the inactivation of mechanisms essential for viral replication. PMID- 19445668 TI - Prospective multi-centre Voxel Based Morphometry study employing scanner specific segmentations: procedure development using CaliBrain structural MRI data. AB - BACKGROUND: Structural Magnetic Resonance Imaging (sMRI) of the brain is employed in the assessment of a wide range of neuropsychiatric disorders. In order to improve statistical power in such studies it is desirable to pool scanning resources from multiple centres. The CaliBrain project was designed to provide for an assessment of scanner differences at three centres in Scotland, and to assess the practicality of pooling scans from multiple-centres. METHODS: We scanned healthy subjects twice on each of the 3 scanners in the CaliBrain project with T1-weighted sequences. The tissue classifier supplied within the Statistical Parametric Mapping (SPM5) application was used to map the grey and white tissue for each scan. We were thus able to assess within scanner variability and between scanner differences. We have sought to correct for between scanner differences by adjusting the probability mappings of tissue occupancy (tissue priors) used in SPM5 for tissue classification. The adjustment procedure resulted in separate sets of tissue priors being developed for each scanner and we refer to these as scanner specific priors. RESULTS: Voxel Based Morphometry (VBM) analyses and metric tests indicated that the use of scanner specific priors reduced tissue classification differences between scanners. However, the metric results also demonstrated that the between scanner differences were not reduced to the level of within scanner variability, the ideal for scanner harmonisation. CONCLUSION: Our results indicate the development of scanner specific priors for SPM can assist in pooling of scan resources from different research centres. This can facilitate improvements in the statistical power of quantitative brain imaging studies. PMID- 19445669 TI - Information criterion-based clustering with order-restricted candidate profiles in short time-course microarray experiments. AB - BACKGROUND: Time-course microarray experiments produce vector gene expression profiles across a series of time points. Clustering genes based on these profiles is important in discovering functional related and co-regulated genes. Early developed clustering algorithms do not take advantage of the ordering in a time course study, explicit use of which should allow more sensitive detection of genes that display a consistent pattern over time. Peddada et al. 1 proposed a clustering algorithm that can incorporate the temporal ordering using order restricted statistical inference. This algorithm is, however, very time-consuming and hence inapplicable to most microarray experiments that contain a large number of genes. Its computational burden also imposes difficulty to assess the clustering reliability, which is a very important measure when clustering noisy microarray data. RESULTS: We propose a computationally efficient information criterion-based clustering algorithm, called ORICC, that also takes account of the ordering in time-course microarray experiments by embedding the order restricted inference into a model selection framework. Genes are assigned to the profile which they best match determined by a newly proposed information criterion for order-restricted inference. In addition, we also developed a bootstrap procedure to assess ORICC's clustering reliability for every gene. Simulation studies show that the ORICC method is robust, always gives better clustering accuracy than Peddada's method and saves hundreds of times computational time. Under some scenarios, its accuracy is also better than some other existing clustering methods for short time-course microarray data, such as STEM 2 and Wang et al. 3. It is also computationally much faster than Wang et al. 3. CONCLUSION: Our ORICC algorithm, which takes advantage of the temporal ordering in time-course microarray experiments, provides good clustering accuracy and is meanwhile much faster than Peddada's method. Moreover, the clustering reliability for each gene can also be assessed, which is unavailable in Peddada's method. In a real data example, the ORICC algorithm identifies new and interesting genes that previous analyses failed to reveal. PMID- 19445670 TI - siRNA-based targeting of antiapoptotic genes can reverse chemoresistance in P glycoprotein expressing chondrosarcoma cells. AB - BACKGROUND: High expression of P-glycoprotein is one of the well-known mechanisms of chemoresistance in chondrosarcomas. However, the role of antiapoptotic proteins, a common mechanism responsible for chemoresistance in other tumors, has not been well studied in chondrosarcomas. We examined the importance of P glycoprotein and antiapoptotic proteins in the chemoresistance to doxorubicin of two Grade II chondrosarcoma cell lines, JJ012 and SW1353. RESULTS: We confirmed that both chondrosarcoma cell types expressed P-glycoprotein and antiapoptotic proteins (Bcl-2, Bcl-xL and XIAP). siRNA knockdown as well as pharmacologic inhibitors of cell survival proteins (Bcl-2, Bcl-xL and XIAP) enhanced apoptosis of chemoresistant chondrosarcoma cells by up to 5.5 fold at 0.1 micromol and 5.5 fold at 1 micromol doxorubicin. These chemosensitizing effects were comparable to those of P-glycoprotein inhibition by siRNA or pharmacologic inhibitor. CONCLUSION: These findings suggest that antiapoptotic proteins play a significant role in the chemoresistance of chondrosarcoma cells independent of P glycoprotein. Based on the results, a new siRNA-based therapeutic strategy targeting antiapoptotic genes can be designed to overcome the chemoresistance of chondrosarcomas which is often conferred by P-glycoprotein. PMID- 19445672 TI - Effect of continuous light on diurnal rhythms in Cyanothece sp. ATCC 51142. AB - BACKGROUND: Life on earth is strongly affected by alternating day and night cycles. Accordingly, many organisms have evolved an internal timekeeping system with a period of approximately 24 hours. Cyanobacteria are the only known prokaryotes with robust rhythms under control of a central clock. Numerous studies have been conducted to elucidate components of the circadian clock and to identify circadian-controlled genes. However, the complex interactions between endogenous circadian rhythms and external cues are currently not well understood, and a direct and mathematical based comparison between light-mediated and circadian-controlled gene expression is still outstanding. Therefore, we combined and analyzed data from two independent microarray experiments, previously performed under alternating light-dark and continuous light conditions in Cyanothece sp. ATCC 51142, and sought to classify light responsive and circadian controlled genes. RESULTS: Fourier Score-based methods together with random permutations and False Discovery Rates were used to identify genes with oscillatory expression patterns, and an angular distance based criterion was applied to recognize transient behaviors in gene expression under constant light conditions. Compared to previously reported mathematical approaches, the combination of these methods also facilitated the detection of modified amplitudes and phase-shifts of gene expression. Our analysis showed that the majority of diurnally regulated genes, essentially those genes that are maximally expressed during the middle of the light and dark period, are in fact light responsive. In contrast, most of the circadian controlled genes are up-regulated during the beginning of the dark or subjective dark, and are greatly enriched for genes associated with energy metabolism. Many of the circadian controlled and light responsive genes are found in gene clusters within the Cyanothece sp. ATCC 51142 genome. Interestingly, in addition to cyclic expression patterns with a period of 24 hours, we also found several genes that oscillate with an ultradian period of 12 hours, a novel finding among cyanobacteria. CONCLUSION: We demonstrate that a combination of different analytical methods significantly improved the identification of cyclic and transient gene expression in Cyanothece sp. ATCC 51142. Our analyses provide an adaptable and novel analytical tool to study gene expression in a variety of organisms with diurnal, circadian and ultradian behavior. PMID- 19445671 TI - Genes within the serotonergic system are differentially expressed in human brain. AB - BACKGROUND: Serotonin is an important neurotransmitter with wide-ranging functions throughout the central nervous system. There is strong evidence to suggest that regulation of serotonergic gene expression might be related to genetic variability, and several studies have focused on understanding the functional effects of specific polymorphisms within these genes on expression levels. However, the combination of genotype together with gender and brain region could have an overall effect on gene expression. In this study, we report expression patterns of five serotonergic genes (TPH1, TPH2, 5-HT2A, 5-HT2C, 5 HTT) in seven different human post-mortem brain regions (superior frontal gyrus, superior temporal gyrus, striatum, cerebellum, hippocampus, midbrain and thalamus) using TaqMan real-time quantitative PCR. In addition, the effect of genotype and gender on their expression levels was determined. RESULTS: The data revealed that mRNA from the five genes investigated was detected in all brain regions and showed an overall significant difference in expression levels. Furthermore, the expression of 5-HT2C, 5-HT2A and TPH2 was found to be significantly different between the various brain regions. However, neither gender nor genotype showed significant effects on the expression levels of any of the genes assayed. Interestingly, TPH1 and TPH2 were expressed in all brain regions similarly except for within the striatum and cerebellum, where TPH1 was expressed at a significantly higher level than TPH2. CONCLUSION: The effect of brain region has a greater influence on serotonergic gene expression than either genotype or gender. These data add to the growing body of evidence that effects of functional polymorphisms on gene expression in vitro are not observed ex vivo, and provide information that will aid in the design of expression studies of the serotonergic gene system within human post-mortem brain. PMID- 19445673 TI - Phenotypic and fine genetic characterization of the D locus controlling fruit acidity in peach. AB - BACKGROUND: Acidity is an essential component of the organoleptic quality of fleshy fruits. However, in these fruits, the physiological and molecular mechanisms that control fruit acidity remain unclear. In peach the D locus controls fruit acidity; low-acidity is determined by the dominant allele. Using a peach progeny of 208 F2 trees, the D locus was mapped to the proximal end of linkage group 5 and co-localized with major QTLs involved in the control of fruit pH, titratable acidity and organic acid concentration and small QTLs for sugar concentration. To investigate the molecular basis of fruit acidity in peach we initiated the map-based cloning of the D locus. RESULTS: In order to generate a high-resolution linkage map in the vicinity of the D locus, 1,024 AFLP primer combinations were screened using DNA of bulked acid and low-acid segregants. We also screened a segregating population of 1,718 individuals for chromosomal recombination events linked to the D locus and identified 308 individuals with recombination events close to D. Using these recombinant individuals we delimited the D locus to a genetic interval of 0.4 cM. We also constructed a peach BAC library of 52,000 clones with a mean insert size of 90 kb. The screening of the BAC library with markers tightly linked to D locus indicated that 1 cM corresponds to 250 kb at the vicinity of the D locus. CONCLUSION: In the present work we presented the first high-resolution genetic map of D locus in peach. We also constructed a peach BAC library of approximately 15x genome equivalent. This fine genetic and physical characterization of the D locus is the first step towards the isolation of the gene(s) underlying fruit acidity in peach. PMID- 19445674 TI - Schizophrenia pathophysiology: are we any closer to a complete model? AB - Schizophrenia, a severe brain disorder that involves hallucinations, disordered thinking and deficiencies in cognition, has been studied for decades in order to determine the early events that lead to this neurological disorder. In this review, we interpret the developmental and genetic models that have been proposed and treatment options associated with these models. Schizophrenia was initially thought to be hereditary based on studies of high incidence in certain families. Additionally, studies on specific genes such as ZDHHC8 and DTNBP1 seem to suggest susceptibility to the onset of this disorder. However, no single gene variation has been linked to schizophrenia, and recent evidence on sporadic cases of schizophrenia refutes genetics as being a singular cause of the disease. In addition, current data suggests neurodevelopmental or environmental causes such as viral infections and prenatal/perinatal complications. Before any brain disorder can be understood, however, multiple cognitive neuroscientific models that accommodate evidence from many biomedical research fields should be considered, and unfortunately, many of these models are in the earliest stages of development. Consequently, it makes us question whether we are any closer to an adequate understanding of the pathophysiology of schizophrenia. PMID- 19445675 TI - Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia. AB - BACKGROUND: A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in MLL-related leukemia. Recently, we have established the MLL-SEPT2 gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified MLL and SEPT2 gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of MLL-SEPT2-associated myeloid neoplasms so far described in the literature. METHODS: Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: CBFB-MYH11 (n = 13), PML-RARA (n = 12); RUNX1 RUNX1T1 (n = 12), normal karyotype (n = 11), and MLL gene fusions other than MLL SEPT2 (n = 10). We also studied all three MLL-SEPT2 myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient. RESULTS: When compared with normal controls, we found a 12.8-fold reduction of wild-type SEPT2 and MLL-SEPT2 combined expression in cases with the MLL-SEPT2 gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type MLL and MLL-SEPT2 combined expression (p = 0.028). The down-regulation of SEPT2 in MLL-SEPT2 myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other MLL gene fusions). In addition, MLL expression was also down-regulated in the group of MLL fusions other than MLL-SEPT2, when compared with the normal control group (p = 0.023) CONCLUSION: We found a significant down-regulation of both SEPT2 and MLL in MLL SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2. PMID- 19445676 TI - Chaotic expression dynamics implies pluripotency: when theory and experiment meet. AB - BACKGROUND: During normal development, cells undergo a unidirectional course of differentiation that progressively decreases the number of cell types they can potentially become. Pluripotent stem cells can differentiate into several types of cells, but terminally differentiated cells cannot differentiate any further. A fundamental problem in stem cell biology is the characterization of the difference in cellular states, e.g., gene expression profiles, between pluripotent stem cells and terminally differentiated cells. PRESENTATION OF THE HYPOTHESIS: To address the problem, we developed a dynamical systems model of cells with intracellular protein expression dynamics and interactions with each other. According to extensive simulations, cells with irregular (chaotic) oscillations in gene expression dynamics have the potential to differentiate into other cell types. During development, such complex oscillations are lost successively, leading to a loss of pluripotency. These simulation results, together with recent single-cell-level measurements in stem cells, led us to the following hypothesis regarding pluripotency: Chaotic oscillation in the expression of some genes leads to cell pluripotency and affords cellular state heterogeneity, which is supported by itinerancy over quasi-stable states. Differentiation stabilizes these states, leading to a loss of pluripotency. TESTING THE HYPOTHESIS: To test the hypothesis, it is crucial to measure the time course of gene expression levels at the single-cell level by fluorescence microscopy and fluorescence-activated cell sorting (FACS) analysis. By analyzing the time series of single-cell-level expression data, one can distinguish whether the variation in protein expression level over time is due only to stochasticity in expression dynamics or originates from the chaotic dynamics inherent to cells, as our hypothesis predicts. By further analyzing the expression in differentiated cell types, one can examine whether the loss of pluripotency is accompanied by a loss of oscillation. IMPLICATIONS OF THE HYPOTHESIS: Recovery of pluripotency from determined cells is a long-standing aspiration, from both scientific and clinical perspectives. Our hypothesis suggests a feasible route to recover the potential to differentiate, i.e., by increasing the variety of expressed genes to restore chaotic expression dynamics, as is consistent with the recent generation of induced pluripotent stem (iPS) cells. PMID- 19445678 TI - Methamphetamine use and correlates in two villages of the highland ethnic Karen minority in northern Thailand: a cross sectional study. AB - BACKGROUND: The prevalence of methamphetamine use and human immunodeficiency virus (HIV) incidence are high in lowland Thai society. Despite increasing social and cultural mixing among residents of highland and lowland Thai societies, however, little is known about methamphetamine use among ethnic minority villagers in the highlands. METHODS: A cross-sectional survey examined Karen villagers from a developed and a less-developed village on February 24 and March 26, 2003 to evaluate the prevalence and social correlates of methamphetamine use in northern Thailand. Data were collected in face-to-face interviews using a structured questionnaire. RESULTS: The response rate was 79.3% (n = 548). In all, 9.9% (males 17.6%, females 1.7%) of villagers reported methamphetamine use in the previous year. Methamphetamine was used mostly by males and was significantly related to primary or lower education; to ever having worked in town; to having used opium, marijuana, or heroin in the past year; and to ever having been diagnosed with a sexually transmitted infection (STI). CONCLUSION: Since labor migration to towns is increasingly common among ethnic minorities, the prevention of methamphetamine use and of HIV/STI infection among methamphetamine users should be prioritized to prevent HIV in this minority population in Thailand. PMID- 19445677 TI - The interaction between the measles virus nucleoprotein and the Interferon Regulator Factor 3 relies on a specific cellular environment. AB - BACKGROUND: The genome of measles virus consists of a non-segmented single stranded RNA molecule of negative polarity, which is encapsidated by the viral nucleoprotein (N) within a helical nucleocapsid. The N protein possesses an intrinsically disordered C-terminal domain (aa 401-525, N(TAIL)) that is exposed at the surface of the viral nucleopcapsid. Thanks to its flexible nature, N(TAIL) interacts with several viral and cellular partners. Among these latter, the Interferon Regulator Factor 3 (IRF-3) has been reported to interact with N, with the interaction having been mapped to the regulatory domain of IRF-3 and to N(TAIL). This interaction was described to lead to the phosphorylation-dependent activation of IRF-3, and to the ensuing activation of the pro-immune cytokine RANTES gene. RESULTS: After confirming the reciprocal ability of IRF-3 and N to be co-immunoprecipitated in 293T cells, we thoroughly investigated the N(TAIL) IRF-3 interaction using a recombinant, monomeric form of the regulatory domain of IRF-3. Using a large panel of spectroscopic approaches, including circular dichroism, fluorescence spectroscopy, nuclear magnetic resonance and electron paramagnetic resonance spectroscopy, we failed to detect any direct interaction between IRF-3 and either full-length N or NTAIL under conditions where these latter interact with the C-terminal X domain of the viral phosphoprotein. Furthermore, such interaction was neither detected in E. coli nor in a yeast two hybrid assay. CONCLUSION: Altogether, these data support the requirement for a specific cellular environment, such as that provided by 293T human cells, for the N(TAIL)-IRF-3 interaction to occur. This dependence from a specific cellular context likely reflects the requirement for a human or mammalian cellular co factor. PMID- 19445679 TI - Two-stimuli manipulation of a biological motor. AB - F1-ATPase is an enzyme acting as a rotary nano-motor. During catalysis subunits of this enzyme complex rotate relative to other parts of the enzyme. Here we demonstrate that the combination of two input stimuli causes stop of motor rotation. Application of either individual stimulus did not significantly influence motor motion. These findings may contribute to the development of logic gates using single biological motor molecules. PMID- 19445680 TI - Occurrence and enumeration of Campylobacter spp. during the processing of Chilean broilers. AB - BACKGROUND: Thermotolerant Campylobacter is among the more prevalent bacterial pathogens that cause foodborne diseases. This study aimed at evaluating the occurrence of thermotolerant Campylobacter contamination in chicken carcasses and processing plant stations (chilling water, scalding water, defeathering machinery, evisceration machine, and transport crates) in two of the Chilean main slaughterhouses. In addition, the isolation rates of thermotolerant Campylobacter during evisceration and following chiller processing were compared. RESULTS: The overall slaughterhouse contamination with thermotolerant Campylobacter was 54%. Differences were evident when the results from each plant were compared (plant A and plant B was 72% and 36%, respectively). The sampling points with the greatest contamination rates in both plants were after evisceration (90% and 54%, for plants A and B respectively). The decrease of thermotolerant Campylobacter contamination after chilling was significant (2 and 1.6 logs for plant A and B respectively P < 0.05). CONCLUSION: Our findings indicate that chilling process has a limited effect in the final products Campylobacter contamination because poultry enter the slaughter processing with high counts of contamination. This may represent a health risk to consumers, if proper cooking practices are not employed. The levels and frequencies of Campylobacter found during the processing of Chilean poultry appear to be similar to those reported elsewhere in the world. PMID- 19445681 TI - Validation of commonly used reference genes for sleep-related gene expression studies. AB - BACKGROUND: Sleep is a restorative process and is essential for maintenance of mental and physical health. In an attempt to understand the complexity of sleep, multidisciplinary strategies, including genetic approaches, have been applied to sleep research. Although quantitative real time PCR has been used in previous sleep-related gene expression studies, proper validation of reference genes is currently lacking. Thus, we examined the effect of total or paradoxical sleep deprivation (TSD or PSD) on the expression stability of the following frequently used reference genes in brain and blood: beta-actin (b-actin), beta-2 microglobulin (B2M), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and hypoxanthine guanine phosphoribosyl transferase (HPRT). RESULTS: Neither TSD nor PSD affected the expression stability of all tested genes in both tissues indicating that b-actin, B2M, GAPDH and HPRT are appropriate reference genes for the sleep-related gene expression studies. In order to further verify these results, the relative expression of brain derived neurotrophic factor (BDNF) and glycerol-3-phosphate dehydrogenase1 (GPD1) was evaluated in brain and blood, respectively. The normalization with each of four reference genes produced similar pattern of expression in control and sleep deprived rats, but subtle differences in the magnitude of expression fold change were observed which might affect the statistical significance. CONCLUSION: This study demonstrated that sleep deprivation does not alter the expression stability of commonly used reference genes in brain and blood. Nonetheless, the use of multiple reference genes in quantitative RT-PCR is required for the accurate results. PMID- 19445682 TI - Brain natriuretic peptide levels have diagnostic and prognostic capability for cardio-renal syndrome type 4 in intensive care unit patients. AB - INTRODUCTION: Limited data are available regarding the diagnostic and prognostic utility of brain natriuretic peptide (BNP) in patients with chronic kidney disease (CKD) in the intensive care unit (ICU) setting. METHODS: All patients with CKD and a serum creatinine (Cr) of 2.0 mg/dl or higher admitted to the ICU between January 2006 and September 2007 were enrolled in this study. The CKD group was divided according to the presence or absence of acute decompensated heart failure (ADHF) into CKD + ADHF and CKD-ADHF groups, respectively. Other patients with ADHF having low Cr (<1.2 mg/dl) in the coronary care unit were also recruited as a control group during the same period. BNP levels at the time of admission (admission BNP) were compared amongst these groups. We then sought to determine whether BNP levels could predict the outcome in patients with CKD. RESULTS: Of 136 patients with CKD for whom data were available, including 58 on dialysis (42.6%), 81 (59.6%) had ADHF and their estimated glomerular filtration rate (eGFR) was 12.8 +/- 7.3 ml/min/1.73 m2. BNP levels at admission were 2708.6 +/- 1246.9, 567.9 +/- 491.7 and 1418.9 +/- 1126.5 pg/ml in the CKD + ADHF, CKD - ADHF and control groups (n = 33), respectively (P = 0.000). The optimal cutoff level in patients with CKD was 1020.5 pg/ml (area under the curve = 0.944) to detect ADHF from the receiver operating characteristic (ROC) curve. This level was not associated with in-hospital mortality, all-cause death or a composite event (all-cause death and/or new cardiac event). However, a borderline significant association was observed with new cardiac events (hazard ratio (HR) = 4.551; P = 0.078) during the follow-up period (521.1 +/- 44.7 days). Furthermore, continuous variables of BNP and BNP quartiles were significantly associated with new cardiac events in the multivariate Cox model (HR = 1.001, P = 0.041; HR = 2.212, P = 0.018). CONCLUSIONS: The findings suggest that the level of BNP at the time of admission may be a useful marker for detecting ADHF and predicting cardiac events in patients with CKD in the ICU setting. PMID- 19445683 TI - Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-alpha and matrix metalloproteinase-13 in human chondrocytes. AB - INTRODUCTION: The major risk factor for osteoarthritis (OA) is aging, but the mechanisms underlying this risk are only partly understood. Age-related accumulation of advanced glycation end products (AGEs) can activate chondrocytes and induce the production of proinflammatory cytokines and matrix metalloproteinases (MMPs). In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG) on AGE-modified-BSA (AGE-BSA)-induced activation and production of TNFalpha and MMP-13 in human OA chondrocytes. METHODS: Human chondrocytes were derived from OA cartilage by enzymatic digestion and stimulated with in vitro-generated AGE-BSA. Gene expression of TNFalpha and MMP-13 was measured by quantitative RT-PCR. TNFalpha protein in culture medium was determined using cytokine-specific ELISA. Western immunoblotting was used to analyze the MMP-13 production in the culture medium, phosphorylation of mitogen activated protein kinases (MAPKs), and the activation of NF-kappaB. DNA binding activity of NF-kappaB p65 was determined using a highly sensitive and specific ELISA. IkappaB kinase (IKK) activity was determined using an in vitro kinase activity assay. MMP-13 activity in the culture medium was assayed by gelatin zymography. RESULTS: EGCG significantly decreased AGE-stimulated gene expression and production of TNFalpha and MMP-13 in human chondrocytes. The inhibitory effect of EGCG on the AGE-BSA-induced expression of TNFalpha and MMP-13 was mediated at least in part via suppression of p38-MAPK and JNK activation. In addition, EGCG inhibited the phosphorylating activity of IKKbeta kinase in an in vitro activity assay and EGCG inhibited the AGE-mediated activation and DNA binding activity of NF-kappaB by suppressing the degradation of its inhibitory protein IkappaBalpha in the cytoplasm. CONCLUSIONS: These novel pharmacological actions of EGCG on AGE-BSA-stimulated human OA chondrocytes provide new suggestions that EGCG or EGCG-derived compounds may inhibit cartilage degradation by suppressing AGE-mediated activation and the catabolic response in human chondrocytes. PMID- 19445684 TI - Fluorescent labeling of NASBA amplified tmRNA molecules for microarray applications. AB - BACKGROUND: Here we present a novel promising microbial diagnostic method that combines the sensitivity of Nucleic Acid Sequence Based Amplification (NASBA) with the high information content of microarray technology for the detection of bacterial tmRNA molecules. The NASBA protocol was modified to include aminoallyl UTP (aaUTP) molecules that were incorporated into nascent RNA during the NASBA reaction. Post-amplification labeling with fluorescent dye was carried out subsequently and tmRNA hybridization signal intensities were measured using microarray technology. Significant optimization of the labeled NASBA protocol was required to maintain the required sensitivity of the reactions. RESULTS: Two different aaUTP salts were evaluated and optimum final concentrations were identified for both. The final 2 mM concentration of aaUTP Li-salt in NASBA reaction resulted in highest microarray signals overall, being twice as high as the strongest signals with 1 mM aaUTP Na-salt. CONCLUSION: We have successfully demonstrated efficient combination of NASBA amplification technology with microarray based hybridization detection. The method is applicative for many different areas of microbial diagnostics including environmental monitoring, bio threat detection, industrial process monitoring and clinical microbiology. PMID- 19445685 TI - Assessing clinical communication skills in physicians: are the skills context specific or generalizable. AB - BACKGROUND: Communication skills are essential for physicians to practice Medicine. Evidence for the validity and domain specificity of communication skills in physicians is equivocal and requires further research. This research was conducted to adduce evidence for content and context specificity of communication skills and to assess the usefulness of a generic instrument for assessing communication skills in International Medical Graduates (IMGs). METHODS: A psychometric design was used for identifying the reliability and validity of the communication skills instruments used for high-stakes exams for IMG's. Data were collected from 39 IMGs (19 men--48.7%; 20 women--51.3%; Mean age = 41 years) assessed at 14 station OSCE and subsequently in supervised clinical practice with several instruments (patient surveys; ITERs; Mini-CEX). RESULTS: All the instruments had adequate reliability (Cronbach's alpha: .54 - .96). There were significant correlations (r range: 0.37 - 0.70, p < .05) of communication skills assessed by examiner with standardized patients, and of mini-CEX with patient surveys, and ITERs. The intra-item reliability across all cases for the 13 items was low (Cronbach's alpha: .20 - .56). The correlations of communication skills within method (e.g., OSCE or clinical practice) were significant but were non-significant between methods (e.g., OSCE and clinical practice). CONCLUSION: The results provide evidence of context specificity of communication skills, as well as convergent and criterion-related validity of communication skills. Both in OSCEs and clinical practice, communication checklists need to be case specific, designed for content validity. PMID- 19445687 TI - Effects of sample size on robustness and prediction accuracy of a prognostic gene signature. AB - BACKGROUND: Few overlap between independently developed gene signatures and poor inter-study applicability of gene signatures are two of major concerns raised in the development of microarray-based prognostic gene signatures. One recent study suggested that thousands of samples are needed to generate a robust prognostic gene signature. RESULTS: A data set of 1,372 samples was generated by combining eight breast cancer gene expression data sets produced using the same microarray platform and, using the data set, effects of varying samples sizes on a few performances of a prognostic gene signature were investigated. The overlap between independently developed gene signatures was increased linearly with more samples, attaining an average overlap of 16.56% with 600 samples. The concordance between predicted outcomes by different gene signatures also was increased with more samples up to 94.61% with 300 samples. The accuracy of outcome prediction also increased with more samples. Finally, analysis using only Estrogen Receptor positive (ER+) patients attained higher prediction accuracy than using both patients, suggesting that sub-type specific analysis can lead to the development of better prognostic gene signatures CONCLUSION: Increasing sample sizes generated a gene signature with better stability, better concordance in outcome prediction, and better prediction accuracy. However, the degree of performance improvement by the increased sample size was different between the degree of overlap and the degree of concordance in outcome prediction, suggesting that the sample size required for a study should be determined according to the specific aims of the study. PMID- 19445686 TI - Enhanced synaptic long-term potentiation in the anterior cingulate cortex of adult wild mice as compared with that in laboratory mice. AB - Activation of N-methyl D-aspartate (NMDA) receptor is important for learning, memory and persistent pain. Genetic enhancement of NMDA receptor function by overexpressing NR2B subunit significantly enhances hippocampal long-term potentiation (LTP), behavioral learning as well as persistent pain. Recent studies found that NMDA NR2B subunits can undergo long-term upregulation in the brain under certain conditions including peripheral injury and environmental enrichment. Considering the fact that laboratory grown animals live in an artificial comfort environment, we wondered if NMDA receptor functions and its related LTP would differ in animals living in a natural wild environment. In this report we performed whole-cell patch-clamp recordings from both laboratory wild type mice and wild mice from a natural environment. We found that LTP was significantly enhanced in the anterior cingulate cortex (ACC) of the wild mice as compared with that of laboratory mice. In parallel, NMDA receptor NR2B/total NMDA receptor mediated EPSC ratio was significantly increased in slices of wild mice. Our findings provide the first evidence that NMDA NR2B receptors play an important role in experience-dependent synaptic potentiation within the ACC in wild mice as previously reported in laboratory mice. PMID- 19445688 TI - Phylogeographical patterns of a generalist acorn weevil: insight into the biogeographical history of broadleaved deciduous and evergreen forests. AB - BACKGROUND: Climatic changes during glacial periods have had a major influence on the recent evolutionary history of living organisms, even in temperate forests on islands, where the land was not covered with ice sheets. We investigated the phylogeographical patterns of the weevil Curculio sikkimensis (Curculionidae), a generalist seed predator of Fagaceae plants living in both deciduous oak and evergreen forests of Japan. Its genetic structure was compared to that of another host-specific seed predator, C. hilgendorfi, inhabiting only evergreen forests. RESULTS: We examined 921 bp of mitochondrial DNA for 115 individuals collected from 33 populations of C. sikkimensis from 11 plant species of three genera, Quercus, Lithocarpus, and Castanopsis. An analysis of molecular variance revealed that a large proportion (almost 50%, P < 0.001) of the total genetic variance could be explained by differences between two geographical regions, the southwestern and northeastern parts of the main islands of Japan. In contrast, no significant genetic differentiation of the weevil was observed among vegetation types of their utilized host plant species. The phylogeographical patterns of the generalist and the host-specific seed predator exhibited a congruent genetic boundary in the Chugoku-Shikoku region. CONCLUSION: Our results suggest that geology and historical environment have contributed to shaping the present genetic structure of C. sikkimensis. The geographical patterns of genetic differentiation in the Chugoku-Shikoku region observed in the two types of Fagaceae-associated Curculio in this study have also been observed in several plant species growing in warm and cool temperate zones of Japan. The occurrence of this common pattern suggests that deciduous oak and evergreen forests of Japan survived together, or adjacent to each other, in small refugia during glacial ages, in the southwestern and northeastern parts of the main islands, although these two types of forests are presently distributed in cool and warm temperate zones of Japan, respectively. PMID- 19445689 TI - Returning home: forced conscription, reintegration, and mental health status of former abductees of the Lord's Resistance Army in northern Uganda. AB - BACKGROUND: Since the late 1980s, the Lord's Resistance Army (LRA), a spiritualist rebel group in northern Uganda, has killed and mutilated thousands of civilians and abducted an estimated 52,000 to 75,000 people to serve as soldiers, porters, and sex slaves for its commanders. This study examines the types of violence to which former abductees have been exposed and the extent to which these acts have affected their psychological well-being. METHODS: This is a cross-sectional study of 2,875 individuals selected through a multi-stage stratified cluster sampling design conducted in 8 districts of northern Uganda. Multivariate logistic regressions were performed with symptoms for Post-traumatic Stress Disorder (PTSD) and depression as the main outcome measures. RESULTS: One third of the respondents (33%) self-reported having experienced abduction (49% among the Acholi, the largest tribal group in northern Uganda). Over half (56%) of all the respondents and over two-thirds of those who experienced abduction met the criteria for symptoms of post-traumatic stress disorder (PTSD). Multivariate analysis shows that several factors increased the risk of former LRA abductees developing symptoms of PTSD. These factors included gender (females were more susceptible than males), being a member of the Acholi ethnic group, participating in or witnessing a cumulative number of traumatic events, and encountering difficulties re-integrating into communities after abduction. Factors associated with increased risk of meeting criteria for symptoms of depression included older age of males at the time of abduction, lower score on social relationship scale, high incidence of general traumatic event exposure, high incidence of forced acts of violence, and problems reintegrating into communities after abduction. CONCLUSION: Abduction and forced conscription of civilians has affected the psychological well-being of a significant number of northern Ugandans. The sources of psychological trauma are multiple, ranging from witnessing to being forced to commit violent acts, and compounded by prolonged exposure to violence, often for months or years. Community-based mental health care services and reintegration programs are needed to facilitate the reintegration of former abductees back into their communities. PMID- 19445690 TI - Identification of ColR binding consensus and prediction of regulon of ColRS two component system. AB - BACKGROUND: Conserved two-component system ColRS of Pseudomonas genus has been implicated in several unrelated phenotypes. For instance, deficiency of P. putida ColRS system results in lowered phenol tolerance, hindrance of transposition of Tn4652 and lysis of a subpopulation of glucose-grown bacteria. In order to discover molecular mechanisms behind these phenotypes, we focused here on identification of downstream components of ColRS signal transduction pathway. RESULTS: First, highly similar ColR binding sites were mapped upstream of outer membrane protein-encoding oprQ and a putative methyltransferase-encoding PP0903. These two ColR binding sequences were used as an input in computational genome wide screening for new potential ColR recognition boxes upstream of different genes in P. putida. Biological relevance of a set of in silico predicted ColR binding sites was analysed in vivo by studying the effect of ColR on transcription from promoters carrying these sites. This analysis disclosed seven novel genes of which six were positively and one negatively regulated by ColR. Interestingly, all promoters tested responded more significantly to the over expression than to the absence of ColR suggesting that either ColR is limiting or ColS-activating signal is low under the conditions applied. The binding sites of ColR in the promoters analysed were validated by gel mobility shift and/or DNase I footprinting assays. ColR binding consensus was defined according to seven ColR binding motifs mapped by DNase I protection assay and this consensus was used to predict minimal regulon of ColRS system. CONCLUSION: Combined usage of experimental and computational approach enabled us to define the binding consensus for response regulator ColR and to discover several new ColR-regulated genes. For instance, genes of outer membrane lipid A 3-O-deacylase PagL and cytoplasmic membrane diacylglycerol kinase DgkA are the members of ColR regulon. Furthermore, over 40 genes were predicted to be putatively controlled by ColRS two-component system in P. putida. It is notable that many of ColR-regulated genes encode membrane-related products thus confirming the previously proposed role of ColRS system in regulation of membrane functionality. PMID- 19445691 TI - Aromatase expression is increased in BRCA1 mutation carriers. AB - BACKGROUND: Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls. METHODS: We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women. RESULTS: We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II specific transcripts. CONCLUSION: Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers. PMID- 19445692 TI - The relationship between social capital in hospitals and physician job satisfaction. AB - BACKGROUND: Job satisfaction in the hospital is an important predictor for many significant management ratios. Acceptance in professional life or high workload are known as important predictors for job satisfaction. The influence of social capital in hospitals on job satisfaction within the health care system, however, remains to be determined. Thus, this article aimed at analysing the relationship between overall job satisfaction of physicians and social capital in hospitals. METHODS: The results of this study are based upon questionnaires sent by mail to 454 physicians working in the field of patient care in 4 different German hospitals in 2002. 277 clinicians responded to the poll, for a response rate of 61%. Analysis was performed using three linear regression models with physician overall job satisfaction as the dependent variable and age, gender, professional experience, workload, and social capital as independent variables. RESULTS: The first regression model explained nearly 9% of the variance of job satisfaction. Whereas job satisfaction increased slightly with age, gender and professional experience were not identified as significant factors to explain the variance. Setting up a second model with the addition of subjectively-perceived workload to the analysis, the explained variance increased to 18% and job satisfaction decreased significantly with increasing workload. The third model including social capital in hospital explained 36% of the variance with social capital, professional experience and workload as significant factors. CONCLUSION: This analysis demonstrated that the social capital of an organisation, in addition to professional experience and workload, represents a significant predictor of overall job satisfaction of physicians working in the field of patient care. Trust, mutual understanding, shared aims, and ethical values are qualities of social capital that unify members of social networks and communities and enable them to act cooperatively. PMID- 19445693 TI - Long-term symptoms in dizzy patients examined in a university clinic. AB - BACKGROUND: The long-term course of dizziness was investigated combining medical chart and survey data. The survey was undertaken median (interquartile range (IQR)) 4.6 (4.3) years after the initial medical examination. METHODS: Chart data comprised sex, age, diagnosis, symptom duration, postural sway and neck pain. Survey data comprised symptom severity assessed by the Vertigo Symptom Scale - Short Form (VSS-SF), and data regarding current state of dizziness, medication, neck pain and other chronic conditions. RESULTS: The sample consisted of 503 patients, the mean (standard deviation (SD)) age was 50.0 (11.6) years, women being slightly overrepresented (60%). Severe problems with dizziness (VSS-SF mean (SD) 13.9, (10.8)) were indicated in the total group and in 5 of 6 diagnostic sub groups. Vertigo/balance- and autonomic/anxiety-related symptoms were present in all groups. Current dizziness was confirmed by 73% who had significantly more severe problems than the non-dizzy (VSS-SF mean (SD): 17.2 (10.1) versus 5.0 (7.3)). Symptoms were related to vertigo/balance more than to autonomic/anxiety (test of interaction p < 0.001).Based on simple logistic regression analysis, sex, symptom duration, neck pain, sway and diagnoses predicted dizziness. Symptom duration and neck pain remained predictors in the adjusted analysis. Age, symptom duration, neck pain, sway and diagnoses predicted vertigo/balance-related dizziness in both regression analyses. Sex, neck pain and sway predicted development of autonomic/anxiety-related dizziness according to simple regression analysis, while only neck pain remained a significant predictor in the adjusted analysis. With respect to diagnosis, simple regression analysis showed significant reduced likelihood for development of dizziness in all vestibular sub groups when compared to the non-otogenic dizziness group. With respect to vertigo/balance- and autonomic/anxiety-related symptoms, the implication of diagnostic belonging varied. No effect of diagnoses was seen in adjusted analyses. CONCLUSION: The majority of patients had persistent and severe problems with dizziness. The wait-and-see attitude before referral to specialist institutions may be questioned. Early, active movements seem necessary, and attention should be paid to the presence of neck pain. Diagnoses had limited prognostic value. Questionnaire-based evaluations could assist in classification and identification of type of dizziness and thereby provide a better basis for specific rehabilitation. PMID- 19445694 TI - Pancreas sparing duodenectomy as an emergency procedure. AB - BACKGROUND: The operative techniques to close extensive wounds to the duodenum are well described. However, postoperative morbidity is common and includes suture line leak and the formation of fistulae. The aim of this case series is to present pancreas sparing duodenectomy as a safe and viable alternative procedure in the emergency milieu. METHODS: Five patients underwent emergency pancreas sparing duodenal excisions. Re-implantation of the papilla of Vater or the papilla with a surrounding mucosal patch was performed in two patients. In one, the procedure was further supplemented with a duodenocholangiostomy, stapled pyloric exclusion and enterogastrostomy to defunction the pylorus. In another three patients, distal duodenal excisions were done. RESULTS: In four patients, an uneventful recovery was made. One patient died following a myocardial infarction. The surgery lasted meanly 160 minutes with average blood loss of approximately 500 milliliters. The mean hospital stay was 12 days. Enteral nutrition was introduced within the 20 hours after the surgery. Long term follow up of all surviving patients confirmed a good outcome and normal nutritional status. CONCLUSION: Based on the presented series of patients, we suggest that pancreas-sparing duodenectomy can be considered in selected patients with laceration of the duodenum deemed unsuitable for surgical reconstruction. PMID- 19445695 TI - Host markers in QuantiFERON supernatants differentiate active TB from latent TB infection: preliminary report. AB - BACKGROUND: Interferon gamma release assays, including the QuantiFERON TB Gold In Tube (QFT) have been shown to be accurate in diagnosing Mycobacterium tuberculosis infection. These assays however, do not discriminate between latent TB infection (LTBI) and active TB disease. METHODS: We recruited twenty-three pulmonary TB patients and 34 household contacts from Cape Town, South Africa and performed the QFT test. To investigate the ability of new host markers to differentiate between LTBI and active TB, levels of 29 biomarkers in QFT supernatants were evaluated using a Luminex multiplex cytokine assay. RESULTS: Eight out of 29 biomarkers distinguished active TB from LTBI in a pilot study. Baseline levels of epidermal growth factor (EGF) soluble CD40 ligand (sCD40L), antigen stimulated levels of EGF, and the background corrected antigen stimulated levels of EGF and macrophage inflammatory protein (MIP)-1beta were the most informative single markers for differentiation between TB disease and LTBI, with AUCs of 0.88, 0.84, 0.87, 0.90 and 0.79 respectively. The combination of EGF and MIP-1beta predicted 96% of active TB cases and 92% of LTBIs. Combinations between EGF, sCD40L, VEGF, TGF-alpha and IL-1alpha also showed potential to differentiate between TB infection states. EGF, VEGF, TGF-alpha and sCD40L levels were higher in TB patients. CONCLUSION: These preliminary data suggest that active TB may be accurately differentiated from LTBI utilizing adaptations of the commercial QFT test that includes measurement of EGF, sCD40L, MIP-1beta, VEGF, TGF-alpha or IL 1alpha in supernatants from QFT assays. This approach holds promise for development as a rapid diagnostic test for active TB. PMID- 19445696 TI - Chromosomal imbalance in the progression of high-risk non-muscle invasive bladder cancer. AB - BACKGROUND: Non-muscle invasive bladder neoplasms with invasion of the lamina propria (stage T1) or high grade of dysplasia are at "high risk" of progression to life-threatening cancer. However, the individual course is difficult to predict. Chromosomal instability (CI) is associated with high tumor stage and grade, and possibly with the risk of progression. METHODS: To investigate the relationship between CI and subsequent disease progression, we performed a case control-study of 125 patients with "high-risk" non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases.We used Affymetrix GeneChip Mapping 10 K and 50 K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50 K SNP microarrays). RESULTS: Chromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a "high risk" tumor). However, about 25% of the "high-risk" tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes. CONCLUSION: Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression. Recurrences after "high-risk" tumors had fewer chromosomal alterations, but there was no association with the risk of progression in this group either. Thus, the prediction of progression of "high risk" non-muscle invasive bladder tumors using chromosomal changes is difficult. Loss of chromosome 8p11 may play a role in the progression process. About 25% of the "high risk" tumors were chromosomal stable. PMID- 19445697 TI - Life cycle and population growth rate of Caenorhabditis elegans studied by a new method. AB - BACKGROUND: The free-living nematode Caenorhabditis elegans is the predominant model organism in biological research, being used by a huge number of laboratories worldwide. Many researchers have evaluated life-history traits of C. elegans in investigations covering quite different aspects such as ecotoxicology, inbreeding depression and heterosis, dietary restriction/supplement, mutations, and ageing. Such traits include juvenile growth rates, age at sexual maturity, adult body size, age-specific fecundity/mortality, total reproduction, mean and maximum lifespan, and intrinsic population growth rates. However, we found that in life-cycle experiments care is needed regarding protocol design. Here, we test a recently developed method that overcomes some problems associated with traditional cultivation techniques. In this fast and yet precise approach, single individuals are maintained within hanging drops of semi-fluid culture medium, allowing the simultaneous investigation of various life-history traits at any desired degree of accuracy. Here, the life cycles of wild-type C. elegans strains N2 (Bristol, UK) and MY6 (Munster, Germany) were compared at 20 degrees C with 5 x 10(9) Escherichia coli ml-1 as food source. RESULTS: High-resolution life tables and fecundity schedules of the two strains are presented. Though isolated 700 km and 60 years apart from each other, the two strains barely differed in life-cycle parameters. For strain N2 (n = 69), the intrinsic rate of natural increase (r m d(-1)), calculated according to the Lotka equation, was 1.375, the net reproductive rate (R 0) 291, the mean generation time (T) 90 h, and the minimum generation time (T min) 73.0 h. The corresponding values for strain MY6 (n = 72) were r m = 1.460, R0 = 289, T = 84 h, and T min = 67.3 h. Peak egg laying rates in both strains exceeded 140 eggs d(-1). Juvenile and early adulthood mortality was negligible. Strain N2 lived, on average, for 16.7 d, while strain MY6 died 2 days earlier; however, differences in survivorship curves were statistically non-significant. CONCLUSION: We found no evidence that adaptation to the laboratory altered the life history traits of C. elegans strain N2. Our results, discussed in the light of earlier studies on C. elegans, demonstrate certain advantages of the hanging drop method in investigations of nematode life cycles. Assuming that its reproducibility is validated in further studies, the method will reduce the inter-laboratory variability of life-history estimates and may ultimately prove to be more convenient than the current standard methods used by C. elegans researchers. PMID- 19445698 TI - plantsUPS: a database of plants' Ubiquitin Proteasome System. AB - BACKGROUND: The ubiquitin 26S/proteasome system (UPS), a serial cascade process of protein ubiquitination and degradation, is the last step for most cellular proteins. There are many genes involved in this system, but are not identified in many species. The accumulating availability of genomic sequence data is generating more demands in data management and analysis. Genomics data of plants such as Populus trichocarpa, Medicago truncatula, Glycine max and others are now publicly accessible. It is time to integrate information on classes of genes for complex protein systems such as UPS. RESULTS: We developed a database of higher plants' UPS, named 'plantsUPS'. Both automated search and manual curation were performed in identifying candidate genes. Extensive annotations referring to each gene were generated, including basic gene characterization, protein features, GO (gene ontology) assignment, microarray probe set annotation and expression data, as well as cross-links among different organisms. A chromosome distribution map, multi-sequence alignment, and phylogenetic trees for each species or gene family were also created. A user-friendly web interface and regular updates make plantsUPS valuable to researchers in related fields. CONCLUSION: The plantsUPS enables the exploration and comparative analysis of UPS in higher plants. It now archives > 8000 genes from seven plant species distributed in 11 UPS-involved gene families. The plantsUPS is freely available now to all users at http://bioinformatics.cau.edu.cn/plantsUPS. PMID- 19445699 TI - Females prefer the scent of outbred males: good-genes-as-heterozygosity? AB - BACKGROUND: There is increasing interest to determine the relative importance of non-additive genetic benefits as opposed to additive ones for the evolution of mating preferences and maintenance of genetic variation in sexual ornaments. The 'good-genes-as-heterozygosity' hypothesis predicts that females should prefer to mate with more heterozygous males to gain more heterozygous (and less inbred) offspring. Heterozygosity increases males' sexual ornamentation, mating success and reproduction success, yet few experiments have tested whether females are preferentially attracted to heterozygous males, and none have tested whether females' own heterozygosity influences their preferences. Outbred females might have the luxury of being more choosey, but on the other hand, inbred females might have more to gain by mating with heterozygous males. We manipulated heterozygosity in wild-derived house mice (Mus musculus musculus) through inbreeding and tested whether the females are more attracted to the scent of outbred versus inbred males, and whether females' own inbreeding status affects their preferences. We also tested whether infecting both inbred and outbred males with Salmonella would magnify females' preferences for outbred males. RESULTS: Females showed a significant preference for outbred males, and this preference was more pronounced among inbred females. We found no evidence that Salmonella infection increased the relative attractiveness of outbred versus inbred males; however, we found no evidence that inbreeding affected males' disease resistance in this study. CONCLUSION: Our findings support the idea that females are more attracted to outbred males, and they suggest that such preferences may be stronger among inbred than outbred females, which is consistent with the 'good genes-as-heterozygosity' hypothesis. It is unclear whether this odour preference reflects females' actual mating preferences, though it suggests that future studies should consider females' as well as males' heterozygosity. Our study has implications for efforts to understand how mate choice can provide genetic benefits without eroding genetic diversity (lek paradox), and also conservation efforts to determine the fitness consequences of inbreeding and the maintenance of genetic diversity in small, inbred populations. PMID- 19445700 TI - Treatment of schizophrenia with antipsychotics in Norwegian emergency wards, a cross-sectional national study. AB - BACKGROUND: Surveys on prescription patterns for antipsychotics in the Scandinavian public health system are scarce despite the prevalent use of these drugs. The clinical differences between antipsychotic drugs are mainly in the areas of safety and tolerability, and international guidelines for the treatment of schizophrenia offer rational strategies to minimize the burden of side effects related to antipsychotic treatment. The implementation of treatment guidelines in clinical practice have proven difficult to achieve, as reflected by major variations in the prescription patterns of antipsychotics between different comparable regions and countries. The objective of this study was to evaluate the practice of treatment of schizophrenic patients with antipsychotics at discharge from acute inpatient settings at a national level. METHODS: Data from 486 discharges of patients from emergency inpatient treatment of schizophrenia were collected during a three-month period in 2005; the data were collected in a large national study that covered 75% of Norwegian hospitals receiving inpatients for acute treatment. Antipsychotic treatment, demographic variables, scores from the Global Assessment of Functioning and Health of the Nation Outcome Scales and information about comorbid conditions and prior treatment were analyzed to seek predictors for nonadherence to guidelines. RESULTS: In 7.6% of the discharges no antipsychotic treatment was given; of the remaining discharges, 35.6% were prescribed antipsychotic polypharmacy and 41.9% were prescribed at least one first-generation antipsychotic (FGA). The mean chlorpromazine equivalent dose was 450 (SD 347, range 25-2800). In the multivariate regression analyses, younger age, previous inpatient treatment in the previous 12 months before index hospitalization, and a comorbid diagnosis of personality disorder or mental retardation predicted antipsychotic polypharmacy, while previous inpatient treatment in the previous 12 months also predicted prescription of at least one FGA. CONCLUSION: Our national survey of antipsychotic treatment at discharge from emergency inpatient treatment revealed antipsychotic drug regimens that are to some degree at odds with current guidelines, with increased risk of side effects. Patients with high relapse rates, comorbid conditions, and previous inpatient treatment are especially prone to be prescribed antipsychotic drug regimens not supported by international guidelines. PMID- 19445701 TI - Elective high-frequency oscillatory ventilation in preterm infants with respiratory distress syndrome: an individual patient data meta-analysis. AB - BACKGROUND: Despite the considerable amount of evidence from randomized controlled trials and meta-analyses, uncertainty remains regarding the efficacy and safety of high-frequency oscillatory ventilation as compared to conventional ventilation in the early treatment of respiratory distress syndrome in preterm infants. This results in a wide variation in the clinical use of high-frequency oscillatory ventilation for this indication throughout the world. The reasons are an unexplained heterogeneity between trial results and a number of unanswered, clinically important questions. Do infants with different risk profiles respond differently to high-frequency oscillatory ventilation? How does the ventilation strategy affect outcomes? Does the delay--either from birth or from the moment of intubation--to the start of high-frequency oscillation modify the effect of the intervention? Instead of doing new trials, those questions can be addressed by re analyzing the individual patient data from the existing randomized controlled trials. METHODS/DESIGN: A systematic review with meta-analysis based on individual patient data. This involves the central collection, validation and re analysis of the original individual data from each infant included in each randomized controlled trial addressing this question.The study objective is to estimate the effect of high-frequency oscillatory ventilation on the risk for the combined outcome of death or bronchopulmonary dysplasia or a severe adverse neurological event. In addition, it will explore whether the effect of high frequency oscillatory ventilation differs by the infant's risk profile, defined by gestational age, intrauterine growth restriction, severity of lung disease at birth and whether or not corticosteroids were given to the mother prior to delivery. Finally, it will explore the importance of effect modifying factors such as the ventilator device, ventilation strategy and the delay to the start of high-frequency ventilation. DISCUSSION: An international collaborative group, the PreVILIG Collaboration (Prevention of Ventilator Induced Lung Injury Group), has been formed with the investigators of the original randomized trials to conduct this systematic review. In the field of neonatology, individual patient data meta analysis has not been used previously. Final results are expected to be available by the end of 2009. PMID- 19445703 TI - The High Throughput Sequence Annotation Service (HT-SAS) - the shortcut from sequence to true Medline words. AB - BACKGROUND: Advances in high-throughput technologies available to modern biology have created an increasing flood of experimentally determined facts. Ordering, managing and describing these raw results is the first step which allows facts to become knowledge. Currently there are limited ways to automatically annotate such data, especially utilizing information deposited in published literature. RESULTS: To aid researchers in describing results from high-throughput experiments we developed HT-SAS, a web service for automatic annotation of proteins using general English words. For each protein a poll of Medline abstracts connected to homologous proteins is gathered using the UniProt-Medline link. Overrepresented words are detected using binomial statistics approximation. We tested our automatic approach with a protein test set from SGD to determine the accuracy and usefulness of our approach. We also applied the automatic annotation service to improve annotations of proteins from Plasmodium bergei expressed exclusively during the blood stage. CONCLUSION: Using HT-SAS we created new, or enriched already established annotations for over 20% of proteins from Plasmodium bergei expressed in the blood stage, deposited in PlasmoDB. Our tests show this approach to information extraction provides highly specific keywords, often also when the number of abstracts is limited. Our service should be useful for manual curators, as a complement to manually curated information sources and for researchers working with protein datasets, especially from poorly characterized organisms. PMID- 19445702 TI - Characterization of the prohormone complement in cattle using genomic libraries and cleavage prediction approaches. AB - BACKGROUND: Neuropeptides are cell to cell signalling molecules that regulate many critical biological processes including development, growth and reproduction. These peptides result from the complex processing of prohormone proteins, making their characterization both challenging and resource demanding. In fact, only 42 neuropeptide genes have been empirically confirmed in cattle. Neuropeptide research using high-throughput technologies such as microarray and mass spectrometry require accurate annotation of prohormone genes and products. However, the annotation and associated prediction efforts, when based solely on sequence homology to species with known neuropeptides, can be problematic. RESULTS: Complementary bioinformatic resources were integrated in the first survey of the cattle neuropeptide complement. Functional neuropeptide characterization was based on gene expression profiles from microarray experiments. Once a gene is identified, knowledge of the enzymatic processing allows determination of the final products. Prohormone cleavage sites were predicted using several complementary cleavage prediction models and validated against known cleavage sites in cattle and other species. Our bioinformatics approach identified 92 cattle prohormone genes, with 84 of these supported by expressed sequence tags. Notable findings included an absence of evidence for a cattle relaxin 1 gene and evidence for a cattle galanin-like peptide pseudogene. The prohormone processing predictions are likely accurate as the mammalian proprotein convertase enzymes, except for proprotein convertase subtilisin/kexin type 9, were also identified. Microarray analysis revealed the differential expression of 21 prohormone genes in the liver associated with nutritional status and 8 prohormone genes in the placentome of embryos generated using different reproductive techniques. The neuropeptide cleavage prediction models had an exceptional performance, correctly predicting cleavage in more than 86% of the prohormone sequence positions. CONCLUSION: A substantial increase in the number of cattle prohormone genes identified and insights into the expression profiles of neuropeptide genes were obtained from the integration of bioinformatics tools and database resources and gene expression information. Approximately 20 prohormones with no empirical evidence were detected and the prohormone cleavage sites were predicted with high accuracy. Most prohormones were supported by expressed sequence tag data and many were differentially expressed across nutritional and reproductive conditions. The complete set of cattle prohormone sequences identified and the cleavage prediction approaches are available at http://neuroproteomics.scs.uiuc.edu/neuropred.html. PMID- 19445705 TI - Immunohistochemical localization of mdm-2, p27Kip1 and bcl-2 in Warthin's tumor of the parotid gland. AB - BACKGROUND: Warthin's tumor is a benign monomorphic adenoma with unclear origin that almost occur exclusively in the parotid gland. Etiology of Warthin's tumor as well as its malignant potential are still unclear. Therefore immunohistochemical assessment of Warthin's tumor may be useful to detect its origin or its malignant transformation potential. AIMS AND OBJECTIVES: The present study aims to investigate the immunohistochemical expression of murine double minute-2 (mdm-2), p27Kip1 and B cell lymphoma-2 (bcl-2) in Warthin's tumor of parotid gland and also to clarify the role of these proteins in the behavior of that tumor. METHODS: Twenty paraffin blocks of cases previously diagnosed as Warthin's tumor were collected for immunohistochemical staining with primary antibodies against mdm-2, p27Kip1 and bcl-2 using streptavidin-biotin immunoperoxidase staining system. RESULTS: All cases showed immunopositivity for mdm-2 and p27Kip1 while 18/20 showed bcl-2 immunopositivity. Both layers of the neoplastic epithelial cells that line the cystic spaces showed immunopositivity with all antibodies used. Goblet cells were mdm-2 immunonegative while myoepithelial cells were p27Kip-1 immunonegative. Areas of epithelial proliferation that formed buds were p27Kip-1 and bcl-2 immunopositive. CONCLUSION: Mdm-2 played a tumor-suppressor role that might be implicated with the benign behavior of Warthin's tumor. The mutual expression of both p27Kip1 and bcl-2 suggested a protective role of these slowly proliferating cells from apoptosis to maintain their survival and elevated bcl-2 expression offers a significant protection against p27Kip1-mediated apoptosis. PMID- 19445704 TI - Pilot study for a trial of ursodeoxycholic acid and/or early delivery for obstetric cholestasis. AB - BACKGROUND: Obstetric cholestasis (OC) is a serious problem in pregnancy. It affects about 4500 women per year in the UK. Affected women develop itching and occasionally jaundice. More importantly, the condition is associated with premature delivery, fetal distress and is believed to be an important cause of stillbirth. However, even now, there is no clear evidence as to whether the most popular treatment, a drug called ursodeoxycholic acid is beneficial to the baby, or even if it is safe in pregnancy. Nor do we know whether planned early delivery of the baby at 37-38 weeks, another popular treatment, does more good than harm. A randomised trial to evaluate both ursodeoxycholic acid and timed delivery is needed but will be complicated and expensive. We plan a preliminary study, Pilot study for a trial of ursodeoxycholic acid and/or early delivery for obstetric cholestasis (Acronym PITCH- Pregnancy Intervention Trial in Cholestasis) trial, to evaluate the feasibility of a larger trial. The trial is funded by the NHS Research for Patient Benefit (RfPB) Programme. METHODS: PITCH is a multi-centre, double blinded, randomised, controlled, factorial design trial. The trial is being run in six UK centres and women with obstetric cholestasis will be recruited for eighteen months. In this pilot trial we aim to collect data to finalize the design for the main trial. This will include measuring trial recruitment rate, including recruitment to each factorial comparison separately. We will also measure the spectrum of disease among recruits and non-recruits and compliance with the four possible treatment allocations. We will use these data to design the main trial. DISCUSSION: The ultimate aim of the main trial is to enable clinicians to manage this condition more effectively. If it transpires that ursodeoxycholic acid and early delivery are both safe and effective then steps will be taken to ensure that all women with OC who could benefit from them receives this treatment. Conversely, if one or both the treatments turn out to be ineffective or even harmful, they will be stopped and researchers will work at developing other modes of treatment. PMID- 19445706 TI - An integrative multi-platform analysis for discovering biomarkers of osteosarcoma. AB - BACKGROUND: SELDI-TOF-MS (Surface Enhanced Laser Desorption/Ionization-Time of Flight-Mass Spectrometry) has become an attractive approach for cancer biomarker discovery due to its ability to resolve low mass proteins and high-throughput capability. However, the analytes from mass spectrometry are described only by their mass-to-charge ratio (m/z) values without further identification and annotation. To discover potential biomarkers for early diagnosis of osteosarcoma, we designed an integrative workflow combining data sets from both SELDI-TOF-MS and gene microarray analysis. METHODS: After extracting the information for potential biomarkers from SELDI data and microarray analysis, their associations were further inferred by link-test to identify biomarkers that could likely be used for diagnosis. Immuno-blot analysis was then performed to examine whether the expression of the putative biomarkers were indeed altered in serum from patients with osteosarcoma. RESULTS: Six differentially expressed protein peaks with strong statistical significances were detected by SELDI-TOF-MS. Four of the proteins were up-regulated and two of them were down-regulated. Microarray analysis showed that, compared with an osteoblastic cell line, the expression of 653 genes was changed more than 2 folds in three osteosarcoma cell lines. While expression of 310 genes was increased, expression of the other 343 genes was decreased. The two sets of biomarkers candidates were combined by the link-test statistics, indicating that 13 genes were potential biomarkers for early diagnosis of osteosarcoma. Among these genes, cytochrome c1 (CYC-1) was selected for further experimental validation. CONCLUSION: Link-test on datasets from both SELDI-TOF-MS and microarray high-throughput analysis can accelerate the identification of tumor biomarkers. The result confirmed that CYC-1 may be a promising biomarker for early diagnosis of osteosarcoma. PMID- 19445707 TI - Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent. AB - BACKGROUND: Deletion or mutation(s) of the survival motor neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA). The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts. RESULTS: Camptothecin treatment reduced the DNA relaxation activity of DNA topoisomerase I in human fibroblasts. In contrast, kinase activity of DNA topoisomerase I was not affected by camptothecin, because levels of phosphorylated SR proteins were not decreased. Upon camptothecin treatment, levels of p53 were markedly increased. To determine if p53 plays a role in the increased sensitivity of SMA fibroblasts to camptothecin, we analyzed the sensitivity of SMA fibroblasts to another DNA topoisomerase I inhibitor, beta-lapachone. This compound is known to induce death via a p53-independent pathway in several cancer cell lines. We found that beta lapachone did not induce p53 activation in human fibroblasts. In addition, SMA and control fibroblasts showed essentially identical sensitivity to this compound. By immunofluorescence staining, SMN and p53 co-localized in gems within the nucleus, and this co-localization was overall reduced in SMA fibroblasts. However, depletion of p53 by siRNA did not lessen the camptothecin sensitivity in SMA fibroblasts. CONCLUSION: Even though p53 and SMN are associated, the increased sensitivity of SMA fibroblasts to camptothecin does not occur through a p53-dependent mechanism. PMID- 19445708 TI - Unveiling cryptic species diversity of flowering plants: successful biological species identification of Asian Mitella using nuclear ribosomal DNA sequences. AB - BACKGROUND: Although DNA sequence analysis is becoming a powerful tool for identifying species, it is not easy to assess whether the observed genetic disparity corresponds to reproductive isolation. Here, we compared the efficiency of biological species identification between nuclear ribosomal and chloroplast DNA sequences, focusing on an Asian endemic perennial lineage of Mitella (Asimitellaria; Saxifragaceae). We performed artificial cross experiments for 43 pairs of ten taxonomic species, and examined their F1 hybrid pollen fertility in vitro as a quantitative measure of postzygotic reproductive isolation. RESULTS: A nonlinear, multiple regression analysis indicated that the nuclear ribosomal DNA distances are sufficient to explain the observed pattern of F1 hybrid pollen fertility, and supplementation with chloroplast DNA distance data does not improve the explanatory power. Overall, with the exception of a recently diverged species complex with more than three biological species, nuclear ribosomal DNA sequences successfully circumscribed ten distinct biological species, of which two have not been described (and an additional one has not been regarded as a distinct taxonomic species) to date. CONCLUSION: We propose that nuclear ribosomal DNA sequences contribute to reliable identification of reproductively isolated and cryptic species of Mitella. More comparable studies for other plant groups are needed to generalize our findings to flowering plants. PMID- 19445710 TI - Cost-effectiveness comparison between palpation- and ultrasound-guided thyroid fine-needle aspiration biopsies. AB - BACKGROUND: The aim of this study is to perform a cost-effectiveness comparison between palpation-guided thyroid fine-needle aspiration biopsies (P-FNA) and ultrasound-guided thyroid FNA biopsies (USG-FNA). METHODS: Each nodule was considered as a case. Diagnostic steps were history and physical examination, TSH measurement, Tc99m thyroid scintigraphy for nodules with a low TSH level, initial P-FNA versus initial USG-FNA, repeat USG-FNA for nodules with initial inadequate P-FNA or USG-FNA, hemithyroidectomy for inadequate repeat USG-FNA. American Thyroid Association thyroid nodule management guidelines were simulated in estimating the cost of P-FNA strategy. American Association of Clinical Endocrinologists guidelines were simulated for USG-FNA strategy. Total costs were estimated by adding the cost of each diagnostic step to reach a diagnosis for 100 nodules. Strategy cost was found by dividing the total cost to 100. Incremental cost-effectiveness ratio (ICER) was calculated by dividing the difference between strategy cost of USG-FNA and P-FNA to the difference between accuracy of USG-FNA and P-FNA. A positive ICER indicates more and a negative ICER indicates less expense to achieve one more additional accurate diagnosis of thyroid cancer for USG-FNA. RESULTS: Seventy-eight P-FNAs and 190 USG-FNAs were performed between April 2003 and May 2008. There were no differences in age, gender, thyroid function, frequency of multinodular goiter, nodule location and diameter (median nodule diameter: 18.4 mm in P-FNA and 17.0 mm in USG-FNA) between groups. Cytology results in P-FNA versus USG-FNA groups were as follows: benign 49% versus 62% (p = 0.04), inadequate 42% versus 29% (p = 0.03), malignant 3% (p = 1.00) and indeterminate 6% (p = 0.78) for both. Eleven nodules from P-FNA and 18 from USG-FNA group underwent surgery. The accuracy of P-FNA was 0.64 and USG-FNA 0.72. Unit cost of P-FNA was 148 Euros and USG-FNA 226 Euros. The cost of P-FNA strategy was 534 Euros and USG-FNA strategy 523 Euros. Strategy cost includes the expense of repeat USG-FNA for initial inadequate FNAs and surgery for repeat inadequate USG-FNAs. ICER was -138 Euros. CONCLUSION: Universal application of USG-FNA for all thyroid nodules is cost-effective and saves 138 Euros per additional accurate diagnosis of benign versus malignant thyroid nodular disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00571090. PMID- 19445709 TI - A supervised learning approach for taxonomic classification of core-photosystem II genes and transcripts in the marine environment. AB - BACKGROUND: Cyanobacteria of the genera Synechococcus and Prochlorococcus play a key role in marine photosynthesis, which contributes to the global carbon cycle and to the world oxygen supply. Recently, genes encoding the photosystem II reaction center (psbA and psbD) were found in cyanophage genomes. This phenomenon suggested that the horizontal transfer of these genes may be involved in increasing phage fitness. To date, a very small percentage of marine bacteria and phages has been cultured. Thus, mapping genomic data extracted directly from the environment to its taxonomic origin is necessary for a better understanding of phage-host relationships and dynamics. RESULTS: To achieve an accurate and rapid taxonomic classification, we employed a computational approach combining a multi class Support Vector Machine (SVM) with a codon usage position specific scoring matrix (cuPSSM). Our method has been applied successfully to classify core photosystem-II gene fragments, including partial sequences coming directly from the ocean, to seven different taxonomic classes. Applying the method on a large set of DNA and RNA psbA clones from the Mediterranean Sea, we studied the distribution of cyanobacterial psbA genes and transcripts in their natural environment. Using our approach, we were able to simultaneously examine taxonomic and ecological distributions in the marine environment. CONCLUSION: The ability to accurately classify the origin of individual genes and transcripts coming directly from the environment is of great importance in studying marine ecology. The classification method presented in this paper could be applied further to classify other genes amplified from the environment, for which training data is available. PMID- 19445711 TI - Assessing the feasibility, acceptability and potential effectiveness of Dignity Therapy for people with advanced cancer referred to a hospital-based palliative care team: Study protocol. AB - BACKGROUND: Loss of dignity for people with advanced cancer is associated with high levels of psychological and spiritual distress and the loss of the will to live. Dignity Therapy is a brief psychotherapy, which has been developed to help promote dignity and reduce distress. It comprises a recorded interview, which is transcribed, edited then returned to the patient, who can bequeath it to people of their choosing. Piloting in Canada, Australia and the USA, has suggested that Dignity Therapy is beneficial to people with advanced cancer and their families. The aims of this study are to assess the feasibility, acceptability and potential effectiveness of Dignity Therapy to reduce psychological and spiritual distress in people with advanced cancer who have been referred to hospital-based palliative care teams in the UK, and to pilot the methods for a Phase III RCT. DESIGN: A randomised controlled open-label trial. Forty patients with advanced cancer are randomly allocated to one of two groups: (i) Intervention (Dignity Therapy offered in addition to any standard care), and (ii) Control group (standard care). Recipients of the 'generativity' documents are asked their views on taking part in the study and the therapy. Both quantitative and qualitative outcomes are assessed in face-to-face interviews at baseline and at approximately one and four weeks after the intervention (equivalent in the control group). The primary outcome is patients' sense of dignity (potential effectiveness) assessed by the Patient Dignity Inventory. Secondary outcomes for patients include distress, hopefulness and quality of life. In view of the relatively small sample size, quantitative analyses are mainly descriptive. The qualitative analysis uses the Framework method. DISCUSSION: Dignity Therapy is brief, can be delivered at the bedside and may help both patients and their families. This detailed exploratory research shows if it is feasible to offer Dignity Therapy to patients with advanced cancer, many of whom are likely to be in the terminal stage of their illness, whether it is acceptable to them and their families, if it is likely to be effective, and determine whether a Phase III RCT is desirable. TRIAL REGISTRATION: Current Controlled Clinical Trials: ISRCTN29868352. PMID- 19445712 TI - Effectiveness and economic analysis of the whole cell/recombinant B subunit (WC/rbs) inactivated oral cholera vaccine in the prevention of traveller's diarrhoea. AB - BACKGROUND: Nowadays there is a debate about the indication of the oral whole cell/recombinant B-subunit cholera vaccine (WC/rBS) in traveller's diarrhoea. However, a cost-benefit analysis based on real data has not been published. METHODS: A cost-effectiveness and cost-benefit study of the oral cholera vaccine (WC/rBS), Dukoral for the prevention of traveller's diarrhoea (TD) was performed in subjects travelling to cholera risk areas. The effectiveness of WC/rBS vaccine in the prevention of TD was analyzed in 362 travellers attending two International Vaccination Centres in Spain between May and September 2005. RESULTS: The overall vaccine efficacy against TD was 42,6%. Direct healthcare related costs as well as indirect costs (lost vacation days) subsequent to the disease were considered. Preventive vaccination against TD resulted in a mean saving of 79.26 euro per traveller. CONCLUSION: According to the cost-benefit analysis performed, the recommendation for WC/rBS vaccination in subjects travelling to zones at risk of TD is beneficial for the traveller, regardless of trip duration and visited continent. PMID- 19445713 TI - How to find simple and accurate rules for viral protease cleavage specificities. AB - BACKGROUND: Proteases of human pathogens are becoming increasingly important drug targets, hence it is necessary to understand their substrate specificity and to interpret this knowledge in practically useful ways. New methods are being developed that produce large amounts of cleavage information for individual proteases and some have been applied to extract cleavage rules from data. However, the hitherto proposed methods for extracting rules have been neither easy to understand nor very accurate. To be practically useful, cleavage rules should be accurate, compact, and expressed in an easily understandable way. RESULTS: A new method is presented for producing cleavage rules for viral proteases with seemingly complex cleavage profiles. The method is based on orthogonal search-based rule extraction (OSRE) combined with spectral clustering. It is demonstrated on substrate data sets for human immunodeficiency virus type 1 (HIV-1) protease and hepatitis C (HCV) NS3/4A protease, showing excellent prediction performance for both HIV-1 cleavage and HCV NS3/4A cleavage, agreeing with observed HCV genotype differences. New cleavage rules (consensus sequences) are suggested for HIV-1 and HCV NS3/4A cleavages. The practical usability of the method is also demonstrated by using it to predict the location of an internal cleavage site in the HCV NS3 protease and to correct the location of a previously reported internal cleavage site in the HCV NS3 protease. The method is fast to converge and yields accurate rules, on par with previous results for HIV-1 protease and better than previous state-of-the-art for HCV NS3/4A protease. Moreover, the rules are fewer and simpler than previously obtained with rule extraction methods. CONCLUSION: A rule extraction methodology by searching for multivariate low-order predicates yields results that significantly outperform existing rule bases on out-of-sample data, but are more transparent to expert users. The approach yields rules that are easy to use and useful for interpreting experimental data. PMID- 19445714 TI - Can differences in medical drug compliance between European countries be explained by social factors: analyses based on data from the European Social Survey, round 2. AB - BACKGROUND: Non-compliance with medication is a major health problem. Cultural differences may explain different compliance patterns. The size of the compliance burden and the impact of socio-demographic and socio-economic status within and across countries in Europe have, however, never been analysed in one survey. The aim of this study was to analyse 1) medical drug compliance in different European countries with respect to socio-demographic and socio-economic factors, and to examine 2) whether cross-national differences could be explained by these factors. METHODS: A multi-country interview survey European Social Survey, Round 2 was conducted in 2004/05 comprising questions about compliance with last prescribed drug. Non-compliance was classified as primary and secondary, depending whether the drug was purchased or not. Statistical weighting allowed for adjustment for national differences in sample mechanisms. A multiple imputation strategy was used to compensate for missing values. The analytical approach included multivariate and multilevel analyses. RESULTS: The survey comprised 45,678 participants. Response rate was 62.5% (range 43.6-79.1%). Reported compliance was generally high (82%) but the pattern of non-compliance showed large variation between countries. Some 3.2% did not purchase the most recently prescribed medicine, and 13.6% did not take the medicine as prescribed. Multiple regression analyses showed that each variable had very different and in some cases opposite impact on compliance within countries. The multilevel analysis showed that the variation between countries did not change significantly when adjusted for increasing numbers of covariates. CONCLUSION: Reported compliance was generally high but showed wide variation between countries. Cross national differences could, however, not be explained by the socio-demographic and socio-economic variables measured. PMID- 19445716 TI - Compensatory evolution for a gene deletion is not limited to its immediate functional network. AB - BACKGROUND: Genetic disruption of an important phenotype should favor compensatory mutations that restore the phenotype. If the genetic basis of the phenotype is modular, with a network of interacting genes whose functions are specific to that phenotype, compensatory mutations are expected among the genes of the affected network. This perspective was tested in the bacteriophage T3 using a genome deleted of its DNA ligase gene, disrupting DNA metabolism. RESULTS: In two replicate, long-term adaptations, phage compensatory evolution accommodated the low ligase level provided by the host without reinventing its own ligase. In both lines, fitness increased substantially but remained well below that of the intact genome. Each line accumulated over a dozen compensating mutations during long-term adaptation, and as expected, many of the compensatory changes were within the DNA metabolism network. However, several compensatory changes were outside the network and defy any role in DNA metabolism or biochemical connection to the disruption. In one line, these extra-network changes were essential to the recovery. The genes experiencing compensatory changes were moderately conserved between T3 and its relative T7 (25% diverged), but the involvement of extra-network changes was greater in T3. CONCLUSION: Compensatory evolution was only partly limited to the known functionally interacting partners of the deleted gene. Thus gene interactions contributing to fitness were more extensive than suggested by the functional properties currently ascribed to the genes. Compensatory evolution offers an easy method of discovering genome interactions among specific elements that does not rest on an a priori knowledge of those elements or their interactions. PMID- 19445715 TI - Proteomic and network analysis characterize stage-specific metabolism in Trypanosoma cruzi. AB - BACKGROUND: Trypanosoma cruzi is a Kinetoplastid parasite of humans and is the cause of Chagas disease, a potentially lethal condition affecting the cardiovascular, gastrointestinal, and nervous systems of the human host. Constraint-based modeling has emerged in the last decade as a useful approach to integrating genomic and other high-throughput data sets with more traditional, experimental data acquired through decades of research and published in the literature. RESULTS: We present a validated, constraint-based model of the core metabolism of Trypanosoma cruzi strain CL Brener. The model includes four compartments (extracellular space, cytosol, mitochondrion, glycosome), 51 transport reactions, and 93 metabolic reactions covering carbohydrate, amino acid, and energy metabolism. In addition, we make use of several replicate high throughput proteomic data sets to specifically examine metabolism of the morphological form of T. cruzi in the insect gut (epimastigote stage). CONCLUSION: This work demonstrates the utility of constraint-based models for integrating various sources of data (e.g., genomics, primary biochemical literature, proteomics) to generate testable hypotheses. This model represents an approach for the systematic study of T. cruzi metabolism under a wide range of conditions and perturbations, and should eventually aid in the identification of urgently needed novel chemotherapeutic targets. PMID- 19445717 TI - Non-invasive neurosensory testing used to diagnose and confirm successful surgical management of lower extremity deep distal posterior compartment syndrome. AB - BACKGROUND: Chronic exertional compartment syndrome (CECS) is characterized by elevated pressures within a closed space of an extremity muscular compartment, causing pain and/or disability by impairing the neuromuscular function of the involved compartment. The diagnosis of CECS is primarily made on careful history and physical exam. The gold standard test to confirm the diagnosis of CECS is invasive intra-compartmental pressure measurements. Sensory nerve function is often diminished during symptomatic periods of CECS. Sensory nerve function can be documented with the use of non-painful, non-invasive neurosensory testing. METHODS: Non-painful neurosensory testing of the myelinated large sensory nerve fibers of the lower extremity were obtained with the Pressure Specified Sensory Device in a 25 year old male with history and invasive compartment pressures consistent with CECS both before and after running on a tread mill. After the patient's first operation to release the deep distal posterior compartment, the patient failed to improve. Repeat sensory testing revealed continued change in his function with exercise. He was returned to the operating room where a repeat procedure revealed that the deep posterior compartment was not completely released due to an unusual anatomic variant, and therefore complete release was accomplished. RESULTS: The patient's symptoms numbness in the plantar foot and pain in the distal calf improved after this procedure and his repeat sensory testing performed before and after running on the treadmill documented this improvement. CONCLUSION: This case report illustrates the principal that non invasive neurosensory testing can detect reversible changes in sensory nerve function after a provocative test and may be a helpful non-invasive technique to managing difficult cases of persistent lower extremity symptoms after failed decompressive fasciotomies for CECS. It can easily be performed before and after exercise and be repeated at multiple intervals without patient dissatisfaction. It is especially helpful when other traditional testing has failed. PMID- 19445718 TI - Characterization of two Arabidopsis thaliana acyltransferases with preference for lysophosphatidylethanolamine. AB - BACKGROUND: Two previously uncharacterized Arabidopsis genes that encode proteins with acyltransferase PlsC regions were selected for study based on their sequence similarity to a recently identified lung lysophosphatidylcholine acyltransferase (LPCAT). To identify their substrate specificity and biochemical properties, the two Arabidopsis acyltransferases, designated AtLPEAT1, (At1g80950), and AtLPEAT2 (At2g45670) were expressed in yeast knockout lines ale1 and slc1 that are deficient in microsomal lysophosphatidyl acyltransferase activities. RESULTS: Expression of AtLPEAT1 in the yeast knockout ale1 background exhibited strong acylation activity of lysophosphatidylethanolamine (LPE) and lysophosphatidate (LPA) with lower activity on lysophosphatidylcholine (LPC) and lysophosphatidylserine (LPS). AtLPEAT2 had specificities in the order of LPE > LPC > LPS and had no or very low activity with LPA. Both acyltransferases preferred 18:1-LPE over 16:0-LPE as acceptor and preferred palmitoyl-CoA as acyl donor in combination with 18:1-LPE. Both acyltransferases showed no or minor responses to Ca2+, despite the presence of a calcium binding EF-hand region in AtLPEAT2. AtLPEAT1 was more active at basic pH while AtLPEAT2 was equally active between pH 6.0 - 9.0. CONCLUSION: This study represents the first description of plant acyltransferases with a preference for LPE. In conclusion it is suggested that the two AtLPEATs, with their different biochemical and expression properties, have different roles in membrane metabolism/homoeostasis. PMID- 19445719 TI - Comparison of the Glidescope and Pentax AWS laryngoscopes to the Macintosh laryngoscope for use by advanced paramedics in easy and simulated difficult intubation. AB - BACKGROUND: Intubation of the trachea in the pre-hospital setting may be lifesaving in severely ill and injured patients. However, tracheal intubation is frequently difficult to perform in this challenging environment, is associated with a lower success rate, and failed tracheal intubation constitutes an important cause of morbidity. Novel indirect laryngoscopes, such as the Glidescope and the AWS laryngoscopes may reduce this risk. METHODS: We compared the efficacy of these devices to the Macintosh laryngoscope when used by 25 Advanced Paramedics proficient in direct laryngoscopy, in a randomized, controlled, manikin study. Following brief didactic instruction with the Glidescope and the AWS laryngoscopes, each participant took turns performing laryngoscopy and intubation with each device, in an easy intubation scenario and following placement of a hard cervical collar, in a SimMan manikin. RESULTS: Both the Glidescope and the AWS performed better than the Macintosh, and demonstrate considerable promise in this context. The AWS had the least number of dental compressions in all three scenarios, and in the cervical spine immobilization scenario it required fewer maneuvers to optimize the view of the glottis. CONCLUSION: The Glidescope and AWS devices possess advantages over the conventional Macintosh laryngoscope when used by Advanced Paramedics in normal and simulated difficult intubation scenarios in this manikin study. Further studies are required to extend these findings to the clinical setting. PMID- 19445720 TI - Selective microdochectomy after ductoscopic wire marking in women with pathological nipple discharge. AB - BACKGROUND: To investigate the diagnostic reliability of selective microdochectomy after direct ductoscopic wire marking of suspect lesions in patients with pathological nipple discharge. METHODS: Selective microdochectomy due to pathological discharge was performed in 33 patients with mean age of 51.7 years. Ductoscopes of 0.9 and 1.1 mm in diameter with a channel for wire marking were used. Only patients without sonographic or mammographic correlation for the discharge were included. The pathologic mammary duct was wire marked and extirpated under direct visual guidance via the ductoscope. The histological results were compared with cytology, galactography and ductoscopy. RESULTS: In 24 out of 33 cases (72%) an intraductal, epithelial proliferation was found histologically. The following sensitivities for intraductal, epithelial proliferations could be determined: cytology 4%, galactography 74%, and ductoscopy 78%. CONCLUSION: The method allows selective microdochectomy of the pathological duct and the intraductal proliferation under visual guidance. The resection volume can be reduced in contrast to the unselective ductectomy after injection of methylene blue. PMID- 19445721 TI - Protein-protein interaction based on pairwise similarity. AB - BACKGROUND: Protein-protein interaction (PPI) is essential to most biological processes. Abnormal interactions may have implications in a number of neurological syndromes. Given that the association and dissociation of protein molecules is crucial, computational tools capable of effectively identifying PPI are desirable. In this paper, we propose a simple yet effective method to detect PPI based on pairwise similarity and using only the primary structure of the protein. The PPI based on Pairwise Similarity (PPI-PS) method consists of a representation of each protein sequence by a vector of pairwise similarities against large subsequences of amino acids created by a shifting window which passes over concatenated protein training sequences. Each coordinate of this vector is typically the E-value of the Smith-Waterman score. These vectors are then used to compute the kernel matrix which will be exploited in conjunction with support vector machines. RESULTS: To assess the ability of the proposed method to recognize the difference between "interacted" and "non-interacted" proteins pairs, we applied it on different datasets from the available yeast saccharomyces cerevisiae protein interaction. The proposed method achieved reasonable improvement over the existing state-of-the-art methods for PPI prediction. CONCLUSION: Pairwise similarity score provides a relevant measure of similarity between protein sequences. This similarity incorporates biological knowledge about proteins and it is extremely powerful when combined with support vector machine to predict PPI. PMID- 19445722 TI - Factor structure of the Hospital Anxiety and Depression Scale in Japanese psychiatric outpatient and student populations. AB - BACKGROUND: The Hospital Anxiety and Depression Scale (HADS) is a common screening instrument excluding somatic symptoms of depression and anxiety, but previous studies have reported inconsistencies of its factor structure. The construct validity of the Japanese version of the HADS has yet to be reported. To examine the factor structure of the HADS in a Japanese population is needed. METHODS: Exploratory and confirmatory factor analyses were conducted in the combined data of 408 psychiatric outpatients and 1069 undergraduate students. The data pool was randomly split in half for a cross validation. An exploratory factor analysis was performed on one half of the data, and the fitness of the plausible model was examined in the other half of the data using a confirmatory factor analysis. Simultaneous multi-group analyses between the subgroups (outpatients vs. students, and men vs. women) were subsequently conducted. RESULTS: A two-factor model where items 6 and 7 had dual loadings was supported. These factors were interpreted as reflecting anxiety and depression. Item 10 showed low contributions to both of the factors. Simultaneous multi-group analyses indicated a factor pattern stability across the subgroups. CONCLUSION: The Japanese version of HADS indicated good factorial validity in our samples. However, ambiguous wording of item 7 should be clarified in future revisions. PMID- 19445723 TI - Use of communities of practice in business and health care sectors: a systematic review. AB - BACKGROUND: Since being identified as a concept for understanding knowledge sharing, management, and creation, communities of practice (CoPs) have become increasingly popular within the health sector. The CoP concept has been used in the business sector for over 20 years, but the use of CoPs in the health sector has been limited in comparison. OBJECTIVES: First, we examined how CoPs were defined and used in these two sectors. Second, we evaluated the evidence of effectiveness on the health sector CoPs for improving the uptake of best practices and mentoring new practitioners. METHODS: We conducted a search of electronic databases in the business, health, and education sectors, and a hand search of key journals for primary studies on CoP groups. Our research synthesis for the first objective focused on three areas: the authors' interpretations of the CoP concept, the key characteristics of CoP groups, and the common elements of CoP groups. To examine the evidence on the effectiveness of CoPs in the health sector, we identified articles that evaluated CoPs for improving health professional performance, health care organizational performance, professional mentoring, and/or patient outcome; and used experimental, quasi-experimental, or observational designs. RESULTS: The structure of CoP groups varied greatly, ranging from voluntary informal networks to work-supported formal education sessions, and from apprentice training to multidisciplinary, multi-site project teams. Four characteristics were identified from CoP groups: social interaction among members, knowledge sharing, knowledge creation, and identity building; however, these were not consistently present in all CoPs. There was also a lack of clarity in the responsibilities of CoP facilitators and how power dynamics should be handled within a CoP group. We did not find any paper in the health sector that met the eligibility criteria for the quantitative analysis, and so the effectiveness of CoP in this sector remained unclear. CONCLUSION: There is no dominant trend in how the CoP concept is operationalized in the business and health sectors; hence, it is challenging to define the parameters of CoP groups. This may be one of the reasons for the lack of studies on the effectiveness of CoPs in the health sector. In order to improve the usefulness of the CoP concept in the development of groups and teams, further research will be needed to clarify the extent to which the four characteristics of CoPs are present in the mature and emergent groups, the expectations of facilitators and other participants, and the power relationship within CoPs. PMID- 19445724 TI - Impact of movement training on upper limb motor strategies in persons with shoulder impingement syndrome. AB - BACKGROUND: Movement deficits, such as changes in the magnitude of scapulohumeral and scapulathoracic muscle activations or perturbations in the kinematics of the glenohumeral, sternoclavicular and scapulothoracic joints, have been observed in people with shoulder impingement syndrome. Movement training has been suggested as a mean to contribute to the improvement of the motor performance in persons with musculoskeletal impairments. However, the impact of movement training on the movement deficits of persons with shoulder impingement syndrome is still unknown. The aim of this study was to evaluate the short-term effects of supervised movement training with feedback on the motor strategies of persons with shoulder impingement syndrome. METHODS: Thirty-three subjects with shoulder impingement were recruited. They were involved in two visits, one day apart. During the first visit, supervised movement training with feedback was performed. The upper limb motor strategies were evaluated before, during, immediately after and 24 hours after movement training. They were characterized during reaching movements in the frontal plane by EMG activity of seven shoulder muscles and total excursion and final position of the wrist, elbow, shoulder, clavicle and trunk. Movement training consisted of reaching movements performed under the supervision of a physiotherapist who gave feedback aimed at restoring shoulder movements. One-way repeated measures ANOVAs were run to analyze the effect of movement training. RESULTS: During, immediately after and 24 hours after movement training with feedback, the EMG activity was significantly decreased compared to the baseline level. For the kinematics, total joint excursion of the trunk and final joint position of the trunk, shoulder and clavicle were significantly improved during and immediately after training compared to baseline. Twenty-four hours after supervised movement training, the kinematics of trunk, shoulder and clavicle were back to the baseline level. CONCLUSION: Movement training with feedback brought changes in motor strategies and improved temporarily some aspects of the kinematics. However, one training session was not enough to bring permanent improvement in the kinematic patterns. These results demonstrate the potential of movement training in the rehabilitation of movement deficits associated with shoulder impingement syndrome. PMID- 19445725 TI - Psychometric properties of the Brazilian version of the Child Perceptions Questionnaire (CPQ11-14) - short forms. AB - BACKGROUND: The need to evaluate the impact of oral health has led to the development of instruments for measuring oral health-related quality of life (OHQoL). One such instrument is the Child Perceptions Questionnaire (CPQ(11-14)), developed specifically for 11-to-14-year-old children. As this questionnaire was considered long (37 items), shorter forms were developed with 8 (Impact Short Form: 8--ISF:8) and 16 items (Impact Short Form: 16--ISF:16) to facilitate use in the clinical setting and population-based health surveys. The aim of the present study was to translate and cross-culturally adapt these CPQ(11-14) short forms for Brazilian Portuguese and evaluate the measurement properties of these versions for use on Brazilian children. METHODS: Following translation and cross cultural adaptation, the ISF:8 and ISF:16 were tested on 136 children from 11 to 14 years of age in the city of Belo Horizonte, Brazil. The instrument was administered by a trained researcher who also performed clinical examinations. The measurement properties (i.e. criterion validity, construct validity, internal consistency reliability, test-retest reliability) were determined. Discriminant validity was tested between groups, which were divided into children with no cavities and no malocclusion; children with cavities and without malocclusion; and children with malocclusion and without cavities. RESULTS: The mean total score was 6.8 [standard deviation (SD) 4.2] for the ISF:8 and 11.9 (SD 7.6) for the ISF:16 (p < 0.001). Statistically significant associations were found between oral abnormalities and the subscales of the ISF:8 and ISF:16 (p < 0.05). Both test-retest stability and internal consistency, as measured by the intra-class correlation coefficient (ICC) (ISF:8 = 0.98 and ISF:16 = 0.97) and Cronbach's alpha (ISF:8 = 0.70 and ISF:16 = 0.84) proved to be adequate. Construct validity was confirmed from the correlation between the short form scores and oral health and overall well-being ratings. The score on the short forms of the CPQ(11-14) was able to discriminate between different oral conditions. Criterion validity was satisfactory (p < 0.05). CONCLUSION: The Brazilian versions of CPQ(11-14) ISF:8 and ISF:16 have satisfactory psychometric properties, similar to those of the original instrument. PMID- 19445726 TI - An investigation of theory-practice gap in undergraduate paramedic education. AB - BACKGROUND: Bachelor of Emergency Health (Paramedic) (BEH) students at Monash University undertake clinical placements to assist with the transition from student to novice paramedic. Anecdotally, students report a lack of opportunity to practise their clinical skills whilst on placements. The barriers to participation and the theory-practice gap have not been previously documented in Australian paramedic literature. The purpose of this study was to investigate the theory-practice gap for paramedic students by linking education and skill level to case exposure and skills praxis during clinical placements. METHODS: A cross sectional retrospective study using a convenience sample of second and third year BEH undergraduate students. Ethics approval was granted. RESULTS: Eighty four second and third year BEH students participated. 59.5% were female (n = 50), 40.5% were male (n = 34). Overall, students most commonly reported exposure to cardiac and respiratory cases and were satisfied with the number of cases encountered during placement. However, over half (n = 46) reported being exposed to < 50% of cases that allowed skills praxis. The most common barrier to participation (34.5%) was the opportunity to participate in patient care and 68% of student's were unsure if paramedics understood their role during clinical placements. CONCLUSION: This study demonstrates that the majority of students were satisfied with their clinical placement experience; even though they were exposed to < 50% of cases that allowed skills practice. Identifying these educational barriers will assist in improving the quality and theory-practice gap of paramedic clinical education. PMID- 19445727 TI - Expression of phospho-ERK1/2 and PI3-K in benign and malignant gallbladder lesions and its clinical and pathological correlations. AB - BACKGROUND: An increasing number of studies have shown that ERK and PI3-K/AKT signaling pathways are involved in various human cancers including hepatocellular carcinoma and cholangiocarcinoma. However, few studies have examined gallbladder cancer specimens, and little is known about the clinical and pathological significance of ERK1/2 and PI3-K/AKT signaling changes in gallbladder adenocarcinoma. In this study, we examined phospho-ERK1/2 (p-ERK1/2) and PI3K expression and analyzed its clinicopathological impact in gallbladder adenocarcinoma. METHODS: Immunohistochemistry was used to detect and compare the frequency of p-ERK1/2 and PI3-K expression in gallbladder adenocarcinoma, peri tumor tissues, adenomatous polyps, and chronic cholecystitis specimens. RESULTS: The positive staining for p-EKR1/2 and PI3-K were 63/108 (58.3%) and 55/108 (50.9%) in gallbladder adenocarcinoma; 14/46 (30.4%) and 5/46 (10.1%) in peri tumor tissues; 3/15 (20%) and 3/15 (20%) in adenomatous polyps; and 4/35 (11.4%) and 3/35 (8.6%) in chronic cholecystitis. The positive rate of p-ERK1/2 or PI3-K in gallbladder adenocarcinoma was significantly higher than that in peri-tumor tissue (both, P < 0.01), adenomatous polyps (p-ERK1/2, P < 0.01; PI3-K, P < 0.05), and chronic cholecystitis (both, P < 0.01). The positive staining for p ERK1/2 or PI3-K was significantly lower in well/highly-differentiated adenocarcinomas with maximal diameter < 2.0 cm, no metastasis to lymph node, and no infiltration of regional tissues or organs compared to poorly-differentiated adenocarcinomas which are characterized by a maximal diameter >or= 2.0 cm, with metastasis to lymph node and infiltration of regional tissues or organs (P < 0.05 or P < 0.01). Moreover, the frequency of p-ERK1/2 expression in gallbladder adenocarcinomas without gallstone was significantly lower than those with gallstones. Increased expression of p-ERK1/2 (P < 0.05) and PI3K (P = 0.062) was associated with decreased overall survival. Multivariate Cox regression analysis showed that increased p-ERK1/2 expression was an independent prognostic predictor in gallbladder carcinoma (P = 0.028). CONCLUSION: Increased expression of p ERK1/2 and PI3K might contribute to gallbladder carcinogenesis. p-ERK1/2 over expression is correlated with decreased survival and therefore may serve as an important biological marker in development of gallbladder adenocarcinoma. PMID- 19445728 TI - Health facilities at the district level in Indonesia. AB - BACKGROUND: At Independence the Government of Indonesia inherited a weak and unevenly distributed health system to which much of the population had only limited access. In response, the government decided to increase the number of facilities and to locate them closer to the people. To staff these health facilities the government introduced obligatory government service for all new graduates in medicine, nursing and midwifery. Most of these staff also established private practices in the areas in which they were located. The health information system contains little information on the health care facilities established for private practice by these staff. This article reports on the results of enumerating all health facilities in 15 districts in Java. METHODS: We enumerated all healthcare facilities, public and private, by type in each of 15 districts in Java. RESULTS: The enumeration showed a much higher number of healthcare facilities in each district than is shown in most reports and in the health information system which concentrates on public, multi-provider facilities. Across the 15 districts: 86% of facilities were solo-provider facilities for outpatient services; 13% were multi-provider facilities for outpatient services; and 1% were multi-provider facilities offering both outpatient and inpatient services. CONCLUSION: The relatively good distribution of health facilities in Indonesia was achieved through establishing public health centers at the sub-district level and staffing them through a system of compulsory service for doctors, nurses and midwives. Subsequently, these public sector staff also established solo-provider facilities for their own private practice; these solo-provider facilities, of which those for nurses are almost half, comprise the largest category of outpatient care facilities, most are not included in official statistics. Now that Indonesia no longer has mandatory service for newly graduated doctors, nurses and midwives, it will have difficulty maintaining the distribution of facilities and providers established through the 1980s. The current challenge is to envision a new health system that responds to the changing disease patterns as well as the changes in distribution of health facilities. PMID- 19445729 TI - A dual role of Cdk2 in DNA damage response. AB - Once it was believed that Cdk2 was the master regulator of S phase entry. Gene knockout mouse studies of cell cycle regulators revealed that Cdk2 is dispensable for S phase initiation and progression whereby Cdk1 can compensate for the loss of Cdk2. Nevertheless, recent evidence indicates that Cdk2 is involved in cell cycle independent functions such as DNA damage repair. Whether these properties are unique to Cdk2 or also being compensated by other Cdks in the absence of Cdk2 is under extensive investigation. Here we review the emerging new role of Cdk2 in DNA damage repair and also discuss how the loss of Cdk2 impacts the G1/S phase DNA damage checkpoint. PMID- 19445730 TI - Non-typhoidal Salmonella bacteraemia: epidemiology, clinical characteristics and its' association with severe immunosuppression. AB - BACKGROUND: Non-typhoidal Salmonella (NTS) is increasingly recognized as an important pathogen associated with bacteraemia especially in immunosuppressed patients. However, there is limited data specifically describing the clinical characteristics and outcome amongst the immunosuppressed patients. METHODS: A total of 56,707 blood culture samples and 5,450 stool samples were received by the microbiology laboratory at a tertiary referral hospital in Malaysia, during a 4-year study period. Out of these samples, 55 non-duplicate NTS isolates were identified from blood and 121 from stool. A retrospective analysis of the 55 patients with NTS bacteraemia was then conducted to determine the predominant NTS serovars causing bacteraemia and its' blood invasive potential, epidemiological data, clinical characteristics and antimicrobial susceptibility. Patients were then grouped as immunosuppressed and non-immunosuppressed to determine the association of severe immunosuppression on clinical features. Data was analyzed using the Statistical Package for Social Sciences (SPSS version 15.0) using the non-parametric Mann-Whitney test, Fisher's exact test or Chi-squared test. The odds ratio (OR) and its 95% confidence intervals (CI) were calculated. The P value < 0.05 (two-tailed) was taken as the level of significance. RESULTS: Out of 55 NTS bacteraemia cases identified, 81.8% (45/55) were community-acquired. Salmonella enterica serovar Enteritidis had the highest blood invasiveness. An extra-intestinal focus of infection was noted in 30.9% (17/55) of the patients, most commonly involving the lungs and soft tissue. 90.9% (50/55) of the patients had an underlying disease and 65.5% (36/55) of the patients had severe clinical immunosuppressive condition with malignancy and HIV being the most common. Immunosuppressed patients had higher mortality (P = 0.04), presented more commonly with primary bacteraemia (P = 0.023), leukopenia (P = 0.001) and opportunistic infections (P = 0.01). In contrast, atherosclerotic conditions (P = 0.015), mycotic aneurysms (0.037) and gastroenteritis (P = 0.03), were significantly more common in the non-immunosuppressed patients. The non immunosuppressed group also had a higher proportion of older patients (>50 years) with a significantly higher median age (64 versus 36.5 years; p = 0.005). CONCLUSION: Patients with severe clinical immunosuppression had higher mortality, presented more commonly with primary bacteraemia, leukopenia and opportunistic infections and absence of gastroenteritis. Early identification and prompt medical treatment can be life saving because of the high mortality and morbidity associated with this disease especially in the immunosuppressed patients. PMID- 19445731 TI - Mosaicism for combined tetrasomy of chromosomes 8 and 18 in a dysmorphic child: a result of failed tetraploidy correction? AB - BACKGROUND: Mosaic whole-chromosome tetrasomy has not previously been described as a cause of fetal malformations. CASE PRESENTATION: In a markedly dysmorphic child with heart malformations and developmental delay, CGH analysis of newborn blood DNA suggested a 50% dose increase of chromosomes 8 and 18, despite a normal standard karyotype investigation. Subsequent FISH analysis revealed leukocytes with four chromosomes 8 and four chromosomes 18. The child's phenotype had resemblance to both mosaic trisomy 8 and mosaic trisomy 18. The double tetrasomy was caused by mitotic malsegregation of all four chromatids of both chromosome pairs. A possible origin of such an error is incomplete correction of a tetraploid state resulting from failed cytokinesis or mitotic slippage during early embryonic development. CONCLUSION: This unique case suggests that embryonic cells may have a mechanism for tetraploidy correction that involves mitotic pairing of homologous chromosomes. PMID- 19445732 TI - GarlicESTdb: an online database and mining tool for garlic EST sequences. AB - BACKGROUND: Allium sativum., commonly known as garlic, is a species in the onion genus (Allium), which is a large and diverse one containing over 1,250 species. Its close relatives include chives, onion, leek and shallot. Garlic has been used throughout recorded history for culinary, medicinal use and health benefits. Currently, the interest in garlic is highly increasing due to nutritional and pharmaceutical value including high blood pressure and cholesterol, atherosclerosis and cancer. For all that, there are no comprehensive databases available for Expressed Sequence Tags(EST) of garlic for gene discovery and future efforts of genome annotation. That is why we developed a new garlic database and applications to enable comprehensive analysis of garlic gene expression. DESCRIPTION: GarlicESTdb is an integrated database and mining tool for large-scale garlic (Allium sativum) EST sequencing. A total of 21,595 ESTs collected from an in-house cDNA library were used to construct the database. The analysis pipeline is an automated system written in JAVA and consists of the following components: automatic preprocessing of EST reads, assembly of raw sequences, annotation of the assembled sequences, storage of the analyzed information into MySQL databases, and graphic display of all processed data. A web application was implemented with the latest J2EE (Java 2 Platform Enterprise Edition) software technology (JSP/EJB/JavaServlet) for browsing and querying the database, for creation of dynamic web pages on the client side, and for mapping annotated enzymes to KEGG pathways, the AJAX framework was also used partially. The online resources, such as putative annotation, single nucleotide polymorphisms (SNP) and tandem repeat data sets, can be searched by text, explored on the website, searched using BLAST, and downloaded. To archive more significant BLAST results, a curation system was introduced with which biologists can easily edit best-hit annotation information for others to view. The GarlicESTdb web application is freely available at http://garlicdb.kribb.re.kr. CONCLUSION: GarlicESTdb is the first incorporated online information database of EST sequences isolated from garlic that can be freely accessed and downloaded. It has many useful features for interactive mining of EST contigs and datasets from each library, including curation of annotated information, expression profiling, information retrieval, and summary of statistics of functional annotation. Consequently, the development of GarlicESTdb will provide a crucial contribution to biologists for data-mining and more efficient experimental studies. PMID- 19445733 TI - High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas. AB - BACKGROUND: The diagnosis of benign renal oncocytomas (RO) and chromophobe renal cell carcinomas (RCC) based on their morphology remains uncertain in several cases. METHODS: We have applied Affymetrix GeneChip Mapping 250 K NspI high density oligoarrays to identify small genomic alterations, which may occur beyond the specific losses of entire chromosomes, and also Affymetrix GeneChip HG-U133 Plus2.0 oligoarrays for gene expression profiling. RESULTS: By analysing of DNA extracted from 30 chRCCs and 42 ROs, we have confirmed the high specificity of monosomies of chromosomes 1, 2, 6, 10, 13, 17 and 21 in 70-93% of the chRCCs, while ROs displayed loss of chromosome 1 and 14 in 24% and 5% of the cases, respectively. We demonstrated that chromosomal gene expression biases might correlate with chromosomal abnormalities found in chromophobe RCCs and ROs. The vast majority genes downregulated in chromophobe RCC were mapped to chromosomes 2, 6, 10, 13 and 17. However, most of the genes overexpressed in chromophobe RCCs were located to chromosomes without any copy number changes indicating a transcriptional regulation as a main event. CONCLUSION: The SNP-array analysis failed to detect recurrent small deletions, which may mark loci of genes involved in the tumor development. However, we have identified loss of chromosome 2, 10, 13, 17 and 21 as discriminating alteration between chromophobe RCCs and ROs. Therefore, detection of these chromosomal changes can be used for the accurate diagnosis in routine histology. PMID- 19445734 TI - HIV: treating Pneumocystis pneumonia (PCP). AB - INTRODUCTION: Pneumocystis pneumonia (PCP) is a common AIDS-defining opportunistic illness in people with HIV infection, but its incidence has fallen with use of prophylactic treatment. Without treatment, PCP is likely to be fatal in people with AIDS, so placebo-controlled studies would be considered unethical. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line antipneumocystis treatments for Pneumocystis pneumonia in people infected with HIV? What are the effects of adjuvant corticosteroids in people receiving first-line antipneumocystis treatments for Pneumocystis pneumonia in people infected with HIV? What are the effects of treatments for Pneumocystis pneumonia in people infected with HIV who have not responded to first-line antipneumocystis treatment? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adjuvant corticosteroids, aerosolised or intravenous pentamidine, atovaquone, clindamycin-primaquone, treatment after failure of first-line treatment, trimethoprim-dapsone, and trimethoprim sulfamethoxazole (TMP-SMX, co-trimoxazole). PMID- 19445735 TI - Opioids in people with cancer-related pain. AB - INTRODUCTION: Up to 80% of people with cancer experience pain at some time during their illness, and most will need opioid analgesics. This review assesses how different opioid analgesics compare, in terms of both pain control and adverse effects, in people with cancer. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: what are the effects of opioids in treating cancer-related pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: codeine, dihydrocodeine, transdermal fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. PMID- 19445736 TI - Carbon monoxide poisoning (acute). AB - INTRODUCTION: Carbon monoxide is an odourless, colourless gas, and poisoning causes hypoxia, cell damage, and death. Exposure to carbon monoxide is measured either directly from blood samples and expressed as a percentage of carboxyhaemoglobin, or indirectly using the carbon monoxide in expired breath. Carboxyhaemoglobin percentage is the most frequently used biomarker of carbon monoxide exposure. Although the diagnosis of carbon monoxide poisoning can be confirmed by detecting elevated levels of carboxyhaemoglobin in the blood, the presence of clinical signs and symptoms after known exposure to carbon monoxide should not be ignored. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of oxygen treatments for acute carbon monoxide poisoning? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: 100% hyperbaric oxygen, oxygen 28%, and oxygen 100% by non-re-breather mask. PMID- 19445737 TI - Bronchitis (acute). AB - INTRODUCTION: Acute bronchitis, with transient inflammation of the trachea and major bronchi, affects over 40/1000 adults a year in the UK. The causes are usually considered to be infective, but only around half of people have identifiable pathogens. The role of smoking or of environmental tobacco smoke inhalation in predisposing to acute bronchitis is unclear. A third of people may have longer-term symptoms or recurrence. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute bronchitis in people without chronic respiratory disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (amoxicillin [with or without clavulanic acid], cephalosporins, or macrolides), antihistamines, antitussives, beta(2) agonists (inhaled or oral), cephalosporins, expectorants, and analgesics. PMID- 19445738 TI - Community-acquired pneumonia. AB - INTRODUCTION: In the northern hemisphere about 12/1000 people a year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. Mortality ranges from about 5-35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent community-acquired pneumonia? What are the effects of treatments for community-acquired pneumonia in outpatient settings, in people admitted to hospital, and in people receiving intensive care? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (oral, intravenous), different combinations, and prompt administration of antibiotics in intensive-care settings, early mobilisation, influenza vaccine, and pneumococcal vaccine. PMID- 19445739 TI - Halitosis. AB - INTRODUCTION: Halitosis can be caused by oral disease, or by respiratory tract conditions such as sinusitis, tonsillitis, and bronchiectasis, but an estimated 40% of affected individuals have no underlying organic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with physiological halitosis? We searched: Medline, Embase, The Cochrane Library and other important databases up to July 2008 (BMJ Clinical evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found five systematic reviews, RCTs or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: artificial saliva; cleaning, brushing or scraping the tongue; diet modification; regular or single use of mouthwash; sugar-free chewing gums; and zinc toothpastes. PMID- 19445740 TI - HIV infection. AB - INTRODUCTION: Infection with the human immunodeficiency virus (HIV) usually leads to 8-10 years of asymptomatic infection before immune function deteriorates and AIDS develops. Without treatment, about 50% of infected people will die of AIDS over 10 years. With treatment, prognosis depends on age, CD4 cell count, and initial viral load. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions? What are the effects of different antiretroviral drug treatment regimens in HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 17 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: combination treatments containing either CCR5 inhibitors or fusion inhibitors; early diagnosis and treatment of sexually transmitted diseases (STDs); early and delayed antiretroviral treatment using triple antiretroviral regimens; non nucleoside reverse transcriptase inhibitor (NNRTI) based triple regimens; nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor-based triple regimens (standard, and boosted); post-exposure prophylaxis in healthcare workers; and presumptive mass treatment of sexually transmitted diseases (STDs). PMID- 19445742 TI - Ocular herpes simplex. AB - INTRODUCTION: Ocular infection with herpes simplex virus (HSV) is usually acquired early in life, with 50% of people from higher and 80% from lower socioeconomic groups in the USA having antibodies by the age of 30 years. Attacks usually resolve spontaneously within 1-2 weeks, but 50% of people will experience a recurrence within 10 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with epithelial keratitis? What are the effects of treatments in people with stomal keratitis? What are the effects of interventions to prevent recurrence of ocular herpes simplex? What are the effects of interventions to prevent recurrence of ocular herpes simplex in people with corneal grafts? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found seven systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding oral aciclovir to topical corticosteroids plus topical antiviral treatment; adding topical corticosteroids to topical antiviral treatment; antiviral agents (topical); debridement; interferons (topical); and oral aciclovir. PMID- 19445741 TI - Recurrent cystitis in non-pregnant women. AB - INTRODUCTION: Cystitis is a bacterial infection of the lower urinary tract which causes pain when passing urine, and causes urgency, haematuria, and suprapubic pain not associated with passing urine. Recurrent cystitis is usually defined as three episodes of urinary tract infection in the previous 12 months, or two episodes in the previous 6 months. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: Which interventions prevent further recurrence of cystitis in women experiencing at least two infections per year? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: continuous antibiotic prophylaxis (trimethoprim, co-trimoxazole, nitrofurantoin, cefaclor, or a quinolone or cephalexin); continuous prophylaxis with methenamine hippurate; cranberry juice and cranberry products; oestrogen (topical) in postmenopausal women; passing urine after intercourse; postcoital antibiotic prophylaxis; single-dose self-administered antibiotic. PMID- 19445743 TI - Diabetes: glycaemic control in type 1. AB - INTRODUCTION: Type 1 diabetes occurs when destruction of the pancreatic islet beta cells, usually attributable to an autoimmune process, causes the pancreas to produces too little insulin or none at all. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of intensive treatment programmes and educational interventions in adults and adolescents with type 1 diabetes? What are the effects of different insulin regimens on glycaemic control in adults and adolescents with type 1 diabetes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2006 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: different frequencies of insulin administration (continuous subcutaneous insulin infusion compared with multiple daily subcutaneous insulin injections); different frequencies of blood glucose self-monitoring; educational interventions; and intensive treatment programmes. PMID- 19445744 TI - Inguinal hernia. AB - INTRODUCTION: The main risk factors for inguinal hernia are male sex and increasing age. Complications of inguinal hernia include strangulation, intestinal obstruction, and infarction. Recurrence can occur after surgery. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of elective treatments for primary unilateral, primary bilateral, and recurrent inguinal hernia in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: expectant management, open mesh repair, open suture repair, totally extraperitoneal (TEP) laparoscopic repair, and transabdominal preperitoneal (TAPP) laparoscopic repair. PMID- 19445745 TI - Ventricular tachyarrhythmias (out-of-hospital cardiac arrests). AB - INTRODUCTION: Pulseless ventricular tachycardia and ventricular fibrillation are the main causes of sudden cardiac death, but other ventricular tachyarrhythmias can occur without haemodynamic compromise. Ventricular arrhythmias occur mainly as a result of myocardial ischaemia or cardiomyopathies, so risk factors are those of cardiovascular disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antiarrhythmic drug treatments and defibrillation for use in out-of-hospital cardiac arrest associated with shock-resistant ventricular tachycardia or ventricular fibrillation? What are the effects of antiarrhythmic drug treatments for use in out-of-hospital cardiac arrest associated with shock-resistant ventricular tachycardia or ventricular fibrillation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 11 systematic reviews and RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: bretylium, lidocaine, amiodarone, procainamide, and defibrillation. PMID- 19445746 TI - Lung cancer. AB - INTRODUCTION: Lung cancer is the leading cause of cancer deaths in both men and women, with 80-90% of cases caused by smoking. Small cell lung cancer accounts for 20% of all cases, and is usually treated with chemotherapy. Adenocarcinoma is the main non-small cell pathology, and is treated initially with surgery. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for resectable and unresectable non-small cell lung cancer? What are the effects of treatments for small cell lung cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 86 systematic reviews and RCTs. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: chemotherapy (postoperative or preoperative, dose intensification), continuous hyperfractionated accelerated radiotherapy (CHART), different single-agent chemotherapy regimens, first-line palliative chemotherapy (single or multiple agents), first-line platinum (or non-platinum)-based chemotherapy, molecular targeted therapy, non-CHART hyperfractionated radiotherapy, palliative care, prophylactic cranial irradiation, second-line chemotherapy (with single or multiple agents), second-line molecular-targeted therapy (with gefitinib or erlotinib), second-line palliative chemotherapy, and thoracic irradiation (with or without chemotherapy). PMID- 19445747 TI - Tubal ectopic pregnancy. AB - INTRODUCTION: Approximately 1/100 pregnancies are ectopic, with the conceptus usually implanting in the fallopian tube. Some ectopic pregnancies resolve spontaneously, but others continue to grow and lead to rupture of the tube. Risks are higher in women with damage to the fallopian tubes due to pelvic infections, surgery, or previous ectopic pregnancy. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What treatments improve outcomes in women with unruptured tubal ectopic pregnancy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). The authors also separately searched Medline and Pubmed up to May 2008 in addition to the Clinical Evidence systematic search to support the comments and clinical guide sections. RESULTS: We found 47 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: salpingotomy, salpingectomy, systemic methotrexate, systemic methotrexate following salpingotomy, and expectant management. PMID- 19445748 TI - Schizophrenia (maintenance treatment). AB - INTRODUCTION: One in a hundred people will develop schizophrenia; about 75% of people have relapses and continued disability, and a third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (demotivation, self-neglect, and reduced emotion) have not been consistently improved by any treatment. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: Which interventions reduce relapse; and improve adherence rates? Which interventions are effective in people resistant to standard antipsychotic drugs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: behavioural therapy, clozapine, cognitive behavioural therapy (CBT), compliance therapy, continuation of antipsychotic drugs (reduce relapse rates), first-generation antipsychotic drugs in treatment resistant people, multiple-session family interventions, psychoeducational interventions, second-generation antipsychotic drugs in treatment-resistant people, and social-skills training. PMID- 19445749 TI - Tuberculosis (HIV-negative people). AB - INTRODUCTION: About a third of the world's population has latent tuberculosis. In 2004, over 14 million people had active tuberculosis. Approximately 1.7 million people died from the infection. Over 80% of new cases diagnosed in 2004 were in people in Africa, South-East Asia, and Western Pacific regions. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing tuberculosis? What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing multidrug-resistant tuberculosis? What are the effects of different drug regimens in people with newly diagnosed pulmonary tuberculosis without HIV infection? What are the effects of different drug regimens in people with multidrug-resistant tuberculosis without HIV infection? What are the effects of low-level laser therapy in people with tuberculosis without HIV infection? Which interventions improve adherence to treatment in people with tuberculosis without HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding pyrazinamide in chemotherapy regimens lasting up to 6 months; adding rifampicin to isoniazid regimens; benefits of different regimens; chemotherapy for less than 6 months; daily chemotherapy; direct observation treatment; intermittent chemotherapy for 6 months or longer; isoniazid; low-level laser therapy for pulmonary tuberculosis; regimens containing quinolones; rifampicin plus isoniazid; substituting rifampicin with ethambutol in the continuous phase; and support mechanisms for directly observed treatment. PMID- 19445750 TI - Stress incontinence. AB - INTRODUCTION: Stress incontinence, involving involuntary leaking of urine on effort, exertion, sneezing, or coughing, affects 17-45% of adult women. Risk factors include pregnancy (especially with vaginal delivery), smoking, and obesity. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-surgical treatments and surgical treatments for women with stress incontinence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 97 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adrenoceptor agonists, anterior vaginal repair, laparoscopic colposuspension, needle suspension, oestrogen supplements, pelvic floor electrical stimulation, pelvic floor muscle exercises, retropubic colposuspension, selective serotonin reuptake inhibitors (duloxetine), suburethral slings, tension-free vaginal tape, transobturator foramen procedures, and vaginal cones. PMID- 19445751 TI - Sickle cell disease. AB - INTRODUCTION: Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises, and increases the risk of stroke, organ damage, bacterial infections, and complications of blood transfusion. In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1-2% of babies are born with the disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmaceutical and non-pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease? What are the effects of pharmaceutical and non-pharmaceutical interventions to treat pain in people with sickle cell crisis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, antibiotic prophylaxis in children under 5 years of age, aspirin, avoidance of cold environment, blood transfusion, codeine, corticosteroid (with narcotic analgesics), diflunisal, hydration, hydroxyurea, ibuprofen, ketorolac, limiting physical exercise, malaria chemoprophylaxis, morphine (controlled-release oral after initial intravenous bolus, repeated intravenous doses), oxygen, paracetamol, patient-controlled analgesia, penicillin prophylaxis in children over 5 years of age, piracetam, pneumococcal vaccines, rehydration, and zinc sulphate. PMID- 19445752 TI - Candidiasis (oropharyngeal). AB - INTRODUCTION: Candida is present in the mouths of up to 60% of healthy people, but overt infection is associated with immunosuppression, diabetes, broad spectrum antibiotics, and corticosteroid use. In most people, untreated candidiasis persists for months or years unless associated risk factors are treated or eliminated. In neonates, spontaneous cure of oropharyngeal candidiasis usually occurs after 3-8 weeks. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent and treat oropharyngeal candidiasis in: adults having treatment causing immunosuppression; infants and children; people with diabetes; people with dentures; and people with HIV infection? Which treatments reduce the risk of acquiring resistance to antifungal drugs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 46 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antifungals (absorbed or partially absorbed, and topical absorbed/partially absorbed/non-absorbed [e.g. amphotericin B, fluconazole, itraconazole, miconazole, and nystatin]) used for intermittent or continuous prophylaxis or therapy, and denture hygiene. PMID- 19445754 TI - Herniated lumbar disc. AB - INTRODUCTION: Herniated lumbar disc is a displacement of disc material (nucleus pulposus or annulus fibrosis) beyond the intervertebral disc space. The highest prevalence is among people aged 30-50 years, with a male to female ratio of 2:1. There is little evidence to suggest that drug treatments are effective in treating herniated disc. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, non-drug treatments, and surgery for herniated lumbar disc? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics, antidepressants, bed rest, corticosteroids (epidural injections), cytokine inhibitors (infliximab), discectomy (automated percutaneous, laser, microdisectomy, standard), exercise therapy, heat, ice, massage, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), percutaneous disc decompression, spinal manipulation, and traction. PMID- 19445753 TI - Trigeminal neuralgia. AB - INTRODUCTION: Trigeminal neuralgia is a sudden, unilateral, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Pain occurs in paroxysms which last from a few seconds to 2 minutes. The frequency of the paroxysms ranges from a few to hundreds of attacks a day. Periods of remission can last for months to years, but tend to shorten over time. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with trigeminal neuralgia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: ablative neurosurgical techniques to the Gasserian ganglion, baclofen, carbamazepine, clonazepam, cryotherapy of peripheral nerves, gabapentin, lamotrigine, microvascular decompression, nerve block, oxcarbazepine, peripheral acupuncture, phenytoin, proparacaine eye drops, sodium valproate, stereotactic radiosurgery, tizanidine, and topiramate. PMID- 19445755 TI - Leg cramps. AB - INTRODUCTION: Involuntary, localised leg cramps are common and typically affect the calf muscles at night. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for idiopathic leg cramps? What are the effects of treatments for leg cramps in pregnancy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: analgesics, anti-epileptic drugs, calcium salts, compression hosiery, magnesium salts, multivitamin and mineral supplements, quinine alone or with theophylline, sodium chloride, and stretching exercises. PMID- 19445756 TI - Bunions. AB - INTRODUCTION: Bunions are prominent and often inflamed metatarsal heads and overlying bursae, usually associated with hallux valgus where the great toe moves towards the second toe. Hallux valgus is found in at least 2% of children aged 9 10 years, and almost half of adults, with greater prevalence in women. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of conservative treatments, surgery, and postoperative care for bunions? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: arthrodesis (Lapidus procedure); bone fixation (absorbable pin fixation, screw fixation plus early weight-bearing, standard fixation, suture fixation plus delayed weight-bearing, percutaneous Kirschner-wire fixation); chevron osteotomy plus adductor tenotomy; distal metatarsal osteotomy; early weight-bearing; Keller's arthroplasty; Keller Lelievre arthroplasty; night splints; orthoses (including antipronatory orthoses in children); phalangeal (Akin) osteotomy plus distal chevron osteotomy; proximal osteotomy, and slipper casts. PMID- 19445757 TI - Brain metastases. AB - INTRODUCTION: Metastases to the central nervous system may occur with tumours of any primary origin. Brain (cerebral) metastases may be either single or multiple, with or without disseminated disease elsewhere. Brain metastases may present with focal or generalised symptoms, although up to a third of patients may be asymptomatic. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions for managing brain metastases in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare Regulatory Agency (MHRA). RESULTS: We identified 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: corticosteroids; cytotoxic chemotherapy (systemic); radiation sensitisers plus whole-brain radiotherapy (external beam); surgery; radiosurgery; surgery plus radiosurgery; surgery plus radiosurgery plus whole-brain radiotherapy (external beam); surgery plus whole-brain radiotherapy (external beam); whole-brain radiotherapy (external beam); and whole-brain radiotherapy plus radiosurgery. PMID- 19445758 TI - Anorexia nervosa. AB - INTRODUCTION: Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and up to 0.7% of this age group may be affected. While most people with anorexia nervosa recover completely or partially, about 5% die of the condition, and 20% develop a chronic eating disorder. Young women with anorexia nervosa are at increased risk of bone fractures later in life. METHODS AND OUTCOMES: We conducted a systematic review which aimed to answer the following clinical questions: What are the effects of treatments for anorexia nervosa? What are the effects of interventions to prevent or treat complications of anorexia nervosa? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anxiolytic drugs, cyproheptadine, inpatient/outpatient treatment setting, oestrogen treatment, psychotherapy, refeeding, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants. PMID- 19445759 TI - Influenza. AB - INTRODUCTION: During the autumn-winter months (influenza seasons), influenza circulates more frequently, causing a greater proportion of influenza-like illness, and sometimes serious seasonal epidemics. The incidence of infection depends on the underlying immunity of the population. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of vaccines to prevent influenza? What are the effects of antiviral chemoprophylaxis of influenza? What are the effects of antiviral medications to treat influenza? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: vaccines, amantadine, oseltamivir, zanamivir, rimantadine. PMID- 19445761 TI - Thromboembolism. AB - INTRODUCTION: DVT or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5-15% of people with untreated DVT may die from pulmonary embolism. Risk factors for deep vein thrombosis include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for: proximal deep vein thrombosis; isolated calf deep vein thrombosis; and pulmonary embolism? What are the effects of computerised decision support on oral anticoagulation management? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation, compression stockings, low molecular weight heparin (short and long term, once or twice daily, home treatment), oral anticoagulants (short and long term, high intensity, abrupt discontinuation, computerised decision support), prolonged duration of anticoagulation, thrombolysis, vena cava filters, and warfarin. PMID- 19445760 TI - Croup. AB - INTRODUCTION: Croup leads to signs of upper airway obstruction, and must be differentiated from acute epiglottitis, bacterial tracheitis, or an inhaled foreign body. Croup affects about 3% of children a year, usually between the ages of 6 months and 3 years, and 75% of infections are caused by Parainfluenza virus. Symptoms usually resolve within 48 hours, but severe infection can, rarely, lead to pneumonia, and to respiratory failure and arrest. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in children with: mild croup; moderate to severe croup; and impending respiratory failure because of severe croup? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, corticosteroids, dexamethasone (intramuscular, oral, single-dose oral, route of administration), heliox, humidification, intermittent positive pressure breathing, L-adrenaline, nebulised adrenaline (epinephrine), nebulised budesonide, nebulised short-acting beta(2) agonists, oral decongestants, oral prednisolone, oxygen, and sedatives. PMID- 19445762 TI - Intimate partner violence towards women. AB - INTRODUCTION: Between 10-69% of women may have been physically or sexually assaulted by a partner at some stage, with assault rates against men reported at about a quarter of the rate against women. In at least half of people studied, the problem lasts for 5 years or more. Women reporting intimate partner violence (IPV) are more likely than other women to complain of poor physical or mental health, and of disability. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions initiated by healthcare professionals aimed at female victims of intimate partner violence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). RESULTS: We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: advocacy; career counselling plus critical consciousness awareness; cognitive behavioural counselling; cognitive trauma therapy; counselling; nurse support and guidance; peer support groups; safety planning; and shelters. PMID- 19445763 TI - Nausea and vomiting in people with cancer and other chronic diseases. AB - INTRODUCTION: Nausea and vomiting occur in 40-70% of people with cancer, and are also common in other chronic conditions such as hepatitis C and inflammatory bowel disease. Nausea and vomiting become more common as disease progresses. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for nausea and vomiting occurring either as a result of the disease or its treatment, in adults with cancer? What are the effects of treatments for nausea and vomiting occurring either as a result of the disease or its treatment, in adults with chronic diseases other than cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found nine systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: 5HT(3) antagonists, antihistamines, antimuscarinics, atypical antipsychotics, benzodiazepines, butyrophenones, cannabinoids, corticosteroids, haloperidol, metoclopramide, NK1 antagonists, phenothiazines, prokinetics, 5HT(3) antagonists plus corticosteroids, and venting gastrostomy. PMID- 19445764 TI - Varicocele. AB - INTRODUCTION: Varicocele is estimated to affect 10-15% of men and adolescent boys. It usually occurs only on the left side, and is often asymptomatic. There is little evidence that varicocele reduces male fertility, although it is found in 12% of male partners of couples presenting with infertility, and in 25% of men with abnormal semen analysis. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in men with varicocele? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: embolisation, expectant management, sclerotherapy, and surgical ligation. PMID- 19445766 TI - Head lice. AB - INTRODUCTION: Head lice can only be diagnosed by finding live lice, as eggs take 7 days to hatch and may appear viable for weeks after death of the egg. Infestation may be more likely in school children, with risks increased in children with more siblings, longer hair, and of lower socioeconomic group. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for head lice? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: dimeticone, herbal and essential oils, insecticide combinations, lindane, malathion, mechanical removal by combing ('bug busting'), oral trimethoprim-sulfamethoxazone (co-trimoxazole, TMP-SMX), permethrin, phenothrin, and pyrethrum. PMID- 19445767 TI - PCOS. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is diagnosed in up to 10% of women attending gynaecology clinics, but the prevalence in the population as a whole is unclear. PCOS has been associated with hirsutism, infertility, acne, weight gain, type 2 diabetes, cardiovascular disease (CVD), and endometrial hyperplasia. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: finasteride, flutamide, metformin, spironolactone, cyproterone acetate-ethinylestradiol (co-cyprindiol), interventions to achieve weight loss, ketoconazole, and mechanical hair removal. PMID- 19445765 TI - Psoriasis (chronic plaque). AB - INTRODUCTION: Psoriasis affects 1-3% of the population, in some people causing changes to the nails and joints in addition to skin lesions. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of systemic drug treatments, topical drug treatments, and non-drug treatments (other than ultraviolet light) for chronic plaque psoriasis? What are the effects of ultraviolet light treatments for chronic plaque psoriasis? What are the effects of combined treatment with drugs plus ultraviolet light on chronic plaque psoriasis? What are the effects of combined systemic plus topical drug treatments for chronic plaque psoriasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 122 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, adding calcipotriol (topical) to psoralen plus ultraviolet light A or ultraviolet light B, adding oral retinoids to psoralen plus ultraviolet A (PUVA), alefacept, balneotherapy, ciclosporin, dithranol, T cell-targeted therapies, cytokine blocking agents, emollients (alone or plus ultraviolet light B), etanercept, fish oil supplementation, fumaric acid derivatives, Goeckerman treatment, heliotherapy, infliximab, Ingram regimen, keratolytics (salicylic acid, urea), leflunomide, methotrexate, oral pimecrolimus, phototherapy plus balneotherapy, psoralen plus ultraviolet A, psychotherapy, oral retinoids (alone or with ultraviolet light B), systemic drug treatments plus topical vitamin D derivatives, tars, tazarotene, topical corticosteroids (alone or plus oral retinoids), topical Vitamin D derivatives, ultraviolet light A, and ultraviolet light B. PMID- 19445769 TI - Epilepsy. AB - INTRODUCTION: About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the benefits and risks of starting anti epileptic drug treatment following a single seizure? What are the effects of monotherapy in newly diagnosed partial epilepsy, and in newly diagnosed generalised epilepsy (tonic clonic type)? What are the effects of additional treatments in people with drug-resistant partial epilepsy? Which people in remission from seizures are at risk of relapse on withdrawal of drug treatment? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 59 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: addition of second-line drugs (gabapentin, levetiracetam, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin, or zonisamide), amygdalohippocampectomy, anti-epileptic drug withdrawal for people in remission, anti-epileptic drugs after a single seizure, biofeedback, carbamazepine, cognitive behavioural therapy (CBT), educational programmes, family counselling, hemispherectomy, lesionectomy, phenobarbital, phenytoin, relaxation therapy (alone or plus behavioural modification therapy), sodium valproate, temporal lobectomy, topiramate, vagus nerve stimulation as adjunctive therapy for partial seizures, and yoga. PMID- 19445768 TI - Postnatal depression. AB - INTRODUCTION: The differentiation between postnatal depression and other types of depression is often unclear, but there are treatment issues in nursing mothers that do not apply in other situations. Overall, the prevalence of depression in postpartum women is the same as the prevalence in women generally, at about 12 13%. Suicide is a major cause of maternal mortality in resource-rich countries, but rates are lower in women postpartum than in women who have not had a baby. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, and of non drug treatments, for postnatal depression? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: group cognitive behavioural therapy, hormones, individual cognitive behavioural therapy (CBT), infant massage by mother, interpersonal psychotherapy, light therapy, mother-infant interaction coaching, non-directive counselling, other antidepressants, physical exercise, psychodynamic therapy, psychoeducation with partner, selective serotonin reuptake inhibitors (SSRIs), St John's Wort, telephone-based peer support. PMID- 19445770 TI - Depression in children and adolescents. AB - INTRODUCTION: Depression may affect 2-8% of children and adolescents, with a peak incidence around puberty. It may be self-limiting, but about 40% of affected children experience a recurrent attack, a third of affected children will make a suicide attempt, and 3-4% will die from suicide. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological, psychological, combination, and complementary treatments for depression in children and adolescents? What are the effects of treatments for refractory depression in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: citalopram, cognitive behavioural therapy (CBT) (individual or group, to prevent relapse), escitalopram, electroconvulsive therapy, family therapy, fluoxetine (alone or with cognitive therapy or CBT), fluvoxamine, group therapeutic support (other than CBT), guided self-help, individual psychodynamic psychotherapy, interpersonal therapy, lithium, mirtazapine, monoamine oxidase inhibitors (MAOIs), omega-3 polyunsaturated fatty acids, paroxetine, sertraline (alone or with CBT), St John's Wort (Hypericum perforatum), tricyclic antidepressants, and venlafaxine. PMID- 19445771 TI - Dengue haemorrhagic fever or dengue shock syndrome in children. AB - INTRODUCTION: Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. Up to 5% of people with dengue haemorrhagic fever die of the infection, depending on availability of appropriate supportive care. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of supportive treatments for dengue haemorrhagic fever or dengue shock syndrome in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 13 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding blood component transfusion to standard intravenous fluids; adding carbazochrome sodium sulfonate, corticosteroids, or intravenous immunoglobulin to standard intravenous fluids; adding recombinant-activated factor VII to blood component transfusion; colloids; crystalloids; and intravenous fluids. PMID- 19445772 TI - Ovarian cancer (advanced). AB - INTRODUCTION: Ovarian cancer is the fourth most common cause of cancer deaths in the UK. The 5-year relative survival rate in the UK at diagnosis for women aged 15-39 years is nearly 70%. In comparison, it is only 12% for women diagnosed aged over 80 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical treatments for ovarian cancer that is advanced at first presentation? What are the effects of platinum-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of taxane-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of intraperitoneal chemotherapy for ovarian cancer that is advanced at first presentation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding taxanes to platinum-based chemotherapy, carboplatin plus a taxane, cisplatin plus a taxane, combination or single-agent platinum-based chemotherapy, docetaxel, intravenous and intraperitoneal chemotherapy, interval debulking, paclitaxel, primary surgery, and second-look surgery. PMID- 19445773 TI - Diabetic nephropathy. AB - INTRODUCTION: Up to a third of people with type 1 or 2 diabetes will develop microalbuminuria or macroalbuminuria after 20 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with type 1 diabetes and early nephropathy? What are the effects of treatments in people with type 1 diabetes and late nephropathy? What are the effects of treatments in people with type 2 diabetes and early nephropathy? What are the effects of treatments in people with type 2 diabetes and late nephropathy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, captopril, glycaemic control, protein restriction, and tight control of blood pressure. PMID- 19445774 TI - Diabetes: foot ulcers and amputations. AB - INTRODUCTION: Diabetic foot ulceration is full-thickness penetration of the dermis of the foot in a person with diabetes. Severity is classified using the Wagner system, which grades it from 1 to 5. The annual incidence of ulcers among people with diabetes is 2.5-10.7% in resource-rich countries, and the annual incidence of amputation for any reason is 0.25-1.8%. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent foot ulcers and amputations in people with diabetes? What are the effects of treatments in people with diabetes with foot ulceration? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 41 systematic reviews and RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: debridement, human cultured dermis, human skin equivalent, patient education, pressure off-loading with felted foam or pressure relief half-shoe, pressure off-loading with total-contact or non-removable casts, screening and referral to foot care clinics, systemic hyperbaric oxygen for non infected ulcers, systemic hyperbaric oxygen in infected ulcers, therapeutic footwear, topical growth factors, and wound dressings. PMID- 19445775 TI - Haemorrhoids. AB - INTRODUCTION: Haemorrhoids are cushions of submucosal vascular tissue located in the anal canal starting just distal to the dentate line. Incidence is difficult to ascertain as many people with the condition will never consult with a medical practitioner, although one study found 10 million people in the USA complaining of the disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for haemorrhoidal disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 44 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: closed haemorrhoidectomy, haemorrhoidal artery ligation, infrared coagulation/photocoagulation, injection sclerotherapy, open excisional (Milligan-Morgan/diathermy) haemorrhoidectomy, radiofrequency ablation, rubber band ligation, and stapled haemorrhoidectomy. PMID- 19445776 TI - Migraine headache in children. AB - INTRODUCTION: Diagnosis of migraine headache in children can be difficult as it depends on subjective symptoms; diagnostic criteria are broader than in adults. Migraine occurs in 3-10% of children and increases with age up to puberty. Migraine spontaneously remits after puberty in half of children, but if it begins during adolescence it may be more likely to persist throughout adulthood. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute attacks, and of prophylaxis for migraine headache in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: for acute symptom relief (antiemetics, codeine phosphate, non-steroidal anti inflammatory drugs [NSAIDs], paracetamol, and 5HT1 antagonists [such as triptans]) and for prophylaxis (beta-blockers, dietary manipulation, pizotifen, progressive muscle relaxation, stress management, thermal biofeedback, and topiramate). PMID- 19445777 TI - Blood sampling in infants (reducing pain and morbidity). AB - INTRODUCTION: Preterm or ill neonates may undergo 1-21 heel punctures or venepunctures per day. These punctures are likely to be painful. Heel punctures comprise 61-87% and venepunctures comprise 8-13% of the invasive procedures performed on ill infants. Analgesics are rarely given specifically for blood sampling procedures, but 5-19% of infants receive analgesia for other indications. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to reduce pain-related distress and morbidity during venepuncture in preterm or term babies aged under 12 months in a neonatal unit? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: oral sweet solutions, pacifiers, and topical anaesthetics (lidocaine-prilocaine cream, tetracaine). PMID- 19445778 TI - Acute coronary syndrome (unstable angina and non-ST elevation MI). AB - INTRODUCTION: In people with acute coronary syndrome (ACS) the incidence of serious adverse outcomes (such as death, acute myocardial infarction [MI], or refractory angina requiring emergency revascularisation) is 5-10% within the first 7 days and about 15% at 30 days. Between 5-14% of people with acute coronary syndrome die in the year after diagnosis, with about half of these deaths occurring within 4 weeks of diagnosis. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: antiplatelet; antithrombin; anti-ischaemic; lipid-lowering; and invasive treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 32 systematic reviews, RCTs, or observational studies that met our inclusion criteria. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin, beta-blockers, calcium channel blockers, clopidogrel, direct thrombin inhibitors, glycoprotein IIb/IIIa inhibitors (oral or intravenous), heparin (low molecular weight, unfractionated), nitrates, routine early cardiac catheterisation and revascularisation, statins, and warfarin. PMID- 19445779 TI - Myocardial infarction (ST-elevation). AB - INTRODUCTION: About a quarter of people having an acute myocardial infarction (MI) in the USA will die of it, half of them within 1 hour of the onset of symptoms. Cardiogenic shock develops in over 5% of people surviving the first hour after an acute MI, with a mortality of 50-80% in the first 48 hours. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: Which treatments improve outcomes in acute MI? Which treatments improve outcomes for cardiogenic shock after MI? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 50 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin-converting enzyme (ACE) inhibitors, aspirin, beta-blockers, calcium channel blockers, early cardiac surgery, early invasive cardiac revascularisation, glycoprotein IIb/IIIa inhibitors, intra-aortic balloon counterpulsation, nitrates (with or without thrombolysis), positive inotropes, primary percutaneous transluminal coronary angioplasty (PTCA), pulmonary artery catheterisation, thrombolysis (with or without low molecular weight heparin, with or without unfractionated heparin), vasodilators, and ventricular assistance devices and cardiac transplantation. PMID- 19445780 TI - Jet lag. AB - INTRODUCTION: Jet lag affects most air travellers crossing five or more time zones; it tends to be worse on eastward than on westward flights. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to prevent or minimise jet lag? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found five systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: hypnotics, melatonin, and lifestyle and environmental adaptations. PMID- 19445781 TI - Fungal toenail infections. AB - INTRODUCTION: Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people seen by dermatologists, but are less common in the general population, affecting 3-5% of people. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral treatments for fungal toenail infections? What are the effects of topical treatments for fungal toenail infections? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: amorolfine, butenafine, ciclopirox, fluconazole, griseofulvin, itraconazole, ketoconazole, mechanical debridement, terbinafine, and tioconazole. PMID- 19445782 TI - Wrinkles. AB - INTRODUCTION: Skin disorders associated with photodamage from ultraviolet light include wrinkles, hyperpigmentation, tactile roughness, and telangiectasia, and are more common in people with white compared with other skin types. Wrinkles are also associated with aging, hormonal status, smoking, and intercurrent disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to prevent and treat skin wrinkles? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: carbon dioxide laser, chemical peel, dermabrasion, facelifts, glycolic acid, isotretinoin, lactic acid, natural cartilage polysaccharides (oral or topical), retinyl esters, sunscreens, tazarotene, tretinoin, variable pulse erbium:YAG laser, and vitamin C or E (topical). PMID- 19445784 TI - Postpartum haemorrhage: prevention. AB - INTRODUCTION: Loss of more than 500 mL of blood is usually caused by failure of the uterus to contract fully after delivery of the placenta, and occurs in over 10% of deliveries, with a 1% mortality rate worldwide. Other causes of postpartum haemorrhage include retained placental tissue, lacerations to the genital tract, and coagulation disorders. Uterine atony is more likely in women who have had a general anaesthetic or oxytocin, an overdistended uterus, a prolonged or precipitous labour, or who are of high parity. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of drug and of non-drug interventions to prevent primary postpartum haemorrhage? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: active management of the third stage of labour, carboprost injection, controlled cord traction, ergot compounds (ergometrine/methylergotamine), immediate breastfeeding, misoprostol (oral, rectal, sublingual, or vaginal), oxytocin plus ergometrine combinations, oxytocin, prostaglandin E2 compounds, and uterine massage. PMID- 19445783 TI - Copd. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. The main risk factor for the development and deterioration of COPD is smoking. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of maintenance drug treatment in stable COPD? What are the effects of maintenance drug treatment in stable COPD? What are the effects of non-drug interventions in people with stable COPD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha(1) antitrypsin, antibiotics (prophylactic), anticholinergics (inhaled), beta(2) agonists (inhaled), corticosteroids (oral and inhaled), general physical activity enhancement, inspiratory muscle training, maintaining healthy weight, mucolytics, oxygen treatment (long-term domiciliary treatment), peripheral muscle strength training, psychosocial and pharmacological interventions for smoking cessation, pulmonary rehabilitation, and theophylline. PMID- 19445785 TI - Raynaud's phenomenon (primary). AB - INTRODUCTION: Raynaud's phenomenon is an episodic vasospasm of the peripheral arteries, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia. On rare occasions it can lead to ulceration of the fingers and toes (and in some cases of the ears or nose). This review focuses on primary (idiopathic) Raynaud's phenomenon occurring in the absence of an underlying disease. The prevalence of primary Raynaud's phenomenon varies by sex, country, and exposure to workplace vibration. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for primary Raynaud's phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: amlodipine, diltiazem, exercise, inositol nicotinate, keeping warm, moxisylyte (thymoxamine), naftidrofuryl oxalate, nicardipine, nifedipine, prazosin, and smoking cessation. PMID- 19445786 TI - Deliberate self-harm (and attempted suicide). AB - INTRODUCTION: The lifetime prevalence of deliberate self-harm is about 3-5% of the population in Europe and the USA, and has been increasing. Familial, biological, and psychosocial factors may contribute. Risks are higher in women and young adults, people who are socially isolated or deprived, and people with psychiatric or personality disorders. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for deliberate self-harm in adolescents and adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: cognitive therapy; continuity of care; dialectical behavioural therapy; emergency card; flupentixol depot injection; general practice-based guidelines; hospital admission; intensive outpatient follow-up plus outreach; mianserin; nurse-led case management; oral antipsychotics; paroxetine; problem solving therapy; psychodynamic interpersonal therapy; and telephone contact. PMID- 19445787 TI - Panic disorder. AB - INTRODUCTION: Panic disorder occurs in up to 3% of the adult population at some time, and is associated with other psychiatric and personality disorders, and with drug and alcohol abuse. The risk of suicide and attempted suicide has been found to be higher in people with panic disorder than in people with other psychiatric illness, including depression. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug treatments for panic disorder? What are the effects of drug treatments for panic disorder? What are the effects of combined drug and psychological treatments for panic disorder? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 36 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied relaxation, benzodiazepines, breathing retraining, brief dynamic psychotherapy, buspirone, client-centred therapy, cognitive behavioural therapy (CBT) (alone or plus drug treatments), cognitive restructuring, couple therapy, exposure (external or interoceptive), insight-orientated therapy, monoamine oxidase inhibitors (MAOIs), psychoeducation, selective serotonin reuptake inhibitors (SSRIs), self-help, and tricyclic antidepressants (imipramine). PMID- 19445788 TI - Chronic pancreatitis. AB - INTRODUCTION: Chronic pancreatitis affects 3-9 people in 100,000; 70% of cases are alcohol-induced. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of lifestyle interventions in people with chronic pancreatitis? What are the effects of dietary supplements in people with chronic pancreatitis? What are the effects of drug interventions in people with chronic pancreatitis? What are the effects of nerve blocks for pain relief in people with chronic pancreatitis? What are the effects of different invasive treatments for specific complications of chronic pancreatitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: avoiding alcohol consumption, biliary decompression, calcium supplements, ductal decompression (endoscopic or surgical), low-fat diet, nerve blocks, opioid analgesics, pancreatic enzyme supplements, pseudocyst decompression (endoscopic or surgical), resection using distal pancreatectomy, resection using pancreaticoduodenectomy (Kausch-Whipple or pylorus-preserving), and vitamin/antioxidant supplements. PMID- 19445789 TI - Acute cholecystitis. AB - INTRODUCTION: Of people admitted to hospital for biliary tract disease, 20% have acute cholecystitis. Up to the age of 50 years, acute calculous cholecystitis is three times more common in women than in men, and about 1.5 times more common in women than in men thereafter. About 95% of people with acute cholecystitis have gallstones. Optimal therapy for acute cholecystitis, based on timing and severity of presentation, remains controversial. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute cholecystitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: early cholecystectomy, laparoscopic cholecystectomy, minilaparoscopic cholecystectomy, observation alone, and open cholecystectomy. PMID- 19445790 TI - Gout. AB - INTRODUCTION: Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of treatments to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, corticotrophin (ACTH), non-steroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, xanthine oxidase inhibitors, advice to lose weight, advice to reduce alcohol intake, advice to reduce dietary intake of purines. PMID- 19445791 TI - Low back pain (chronic). AB - INTRODUCTION: Over 70% of people in resource-rich countries develop low back pain (LBP) at some time. But recovery is not always favourable: 82% of non-recent onset patients still experience pain one year later. Many chronic patients who were initially told that their natural history was good spend months or years seeking relief. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments? What are the effects of injection therapy? What are the effects of non-drug treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 74 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture, analgesics, antidepressants, back schools, behavioural therapy, electromyographic biofeedback, exercise, injections (epidural steroid injections, facet joint injections, local injections), intensive multidisciplinary treatment programmes, lumbar supports, massage, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulative therapy, traction, and transcutaneous electrical nerve stimulation (TENS). PMID- 19445792 TI - Low back pain (acute). AB - INTRODUCTION: Low back pain (LBP) affects about 70% of people in resource-rich countries at some point. Acute low back pain is usually perceived as self limiting; however, one year later, as many as 33% of people still have moderate intensity pain and 15% have severe pain. It has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may also increase in severity and duration over time. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for low back pain? What are the effects of local injections for low back pain? What are the effects of non-drug treatments for low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti inflammatory drugs (NSAIDs), spinal manipulation (in the short term), temperature treatments (short wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation (TENS). PMID- 19445793 TI - ADHD in children and adolescents. AB - INTRODUCTION: Prevalence estimates of attention deficit hyperactivity disorder (ADHD) vary according to the diagnostic criteria used and the population sampled. DSM-IV prevalence estimates among school children in the US are 3-5%, but other estimates vary from 1.7% to 16.0%. No objective test exists to confirm the diagnosis of ADHD, which remains a clinical diagnosis. Other conditions frequently co-exist with ADHD. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological treatments for ADHD in children and adolescents? What are the effects of psychological treatments for ADHD in children and adolescents? What are the effects of combination treatments for ADHD in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: atomoxetine, bupropion, clonidine, dexamfetamine sulphate, homeopathy, methylphenidate, modafinil, omega 3-polyunsaturated fatty acids, and psychological/behavioural treatment (either alone or in combination with a drug treatment). PMID- 19445794 TI - GORD in children. AB - INTRODUCTION: Gastro-oesophageal regurgitation is considered a problem if it is frequent, persistent, and associated with other symptoms such as increased crying, discomfort with regurgitation, and frequent back arching. A cross sectional survey of parents of 948 infants attending 19 primary care paediatric practices found that regurgitation of at least one episode a day was reported in 51% of infants aged 0-3 months. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatment for symptomatic gastro-oesophageal reflux? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 27 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: domperidone, feed thickeners in infants, H(2) antagonists, head elevated sleep positioning, left lateral or prone sleep positioning, metoclopramide, proton pump inhibitors, sodium alginate, surgery, soy formula with added fibre, and weight loss. PMID- 19445795 TI - Angina (chronic stable). AB - INTRODUCTION: Stable angina is usually caused by coronary atherosclerosis, and affects up to 16% of men and 10% of women aged 65-74 years in the UK. Risk factors include hypertension, elevated serum cholesterol levels, smoking, physical inactivity, and overweight. People with angina are at increased risk of other cardiovascular events and mortality compared with people without angina. Among people not thought to need coronary artery revascularisation, annual mortality is 1-2% and the annual non-fatal myocardial infarction (MI) rate is 2 3%. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are effects of long-term drug treatment for stable angina? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found nine systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the long-term effectiveness and safety of the following interventions: beta-blockers, calcium channel blockers, long-acting nitrates, potassium channel openers, combinations of these anti-anginal drug treatments and the use of these anti-anginal drug treatment as an adjunct to existing therapies. PMID- 19445796 TI - Postoperative pulmonary infections. AB - INTRODUCTION: Postoperative pulmonary infections are associated with cough, phlegm, shortness of breath, chest pain, temperature above 38 degrees C, and pulse rate above 100 a minute. Up to half of people may have asymptomatic chest signs after surgery, and up to a quarter develop symptomatic disease. The main risk factor is the type of surgery, with higher risks associated with surgery to the chest, abdomen, and head and neck compared with other operations. Other risk factors include age over 50 years, chronic obstructive pulmonary disease (COPD), smoking, hypoalbuminemia, and being functionally dependent. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to prevent postoperative pulmonary infections? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 17 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: advice to stop smoking preoperatively, anaesthesia, lung expansion techniques, and postoperative nasogastric decompression. PMID- 19445797 TI - Acute renal failure. AB - INTRODUCTION: Acute renal failure is characterised by abrupt and sustained decline in glomerular filtration rate, which leads to accumulation of urea and other chemicals in the blood. The term acute kidney injury has been recently introduced to encompass a wide spectrum of acute alterations in kidney function from very mild to severe. Acute renal failure/acute kidney injury is classified according to the RIFLE criteria where a change from baseline serum creatinine or urine output determines the level of renal dysfunction. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent acute renal failure in people at high risk? What are the effects of treatments for critically ill people with acute renal failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 77 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: albumin supplementation plus loop diuretics (intravenous), aminoglycosides, aminophylline, amphotericin B, calcium channel blockers, contrast media, dialysis membranes, dopamine, fenoldopam, loop diuretics, mannitol, N-acetylcysteine, natriuretic peptides, renal replacement therapy, sodium bicarbonate-based fluids, sodium chloride-based fluids, and theophylline. PMID- 19445798 TI - Venous leg ulcers. AB - INTRODUCTION: Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of standard treatments, adjuvant treatments, and organisational interventions for venous leg ulcers? What are the effects of interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 80 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: compression bandages and stockings, cultured allogenic (single or bilayer) skin replacement, debriding agents, dressings (cellulose, collagen, film, foam, hyaluronic acid-derived, semi-occlusive alginate), hydrocolloid (occlusive) dressings in the presence of compression, intermittent pneumatic compression, intravenous prostaglandin E1, larval therapy, laser treatment (low level), leg ulcer clinics, multilayer elastic system, multilayer elastomeric (or non-elastomeric) high-compression regimens or bandages, oral treatments (aspirin, flavonoids, pentoxifylline, rutosides, stanozolol, sulodexide, thromboxane alpha(2) antagonists, zinc), peri-ulcer injection of granulocyte-macrophage colony-stimulating factor, short-stretch bandages, single-layer non-elastic system, skin grafting, superficial vein surgery, systemic mesoglycan, therapeutic ultrasound, self-help (advice to elevate leg, advice to keep leg active, advice to modify diet, advice to stop smoking, advice to reduce weight), and topical treatments (antimicrobial agents, autologous platelet lysate, calcitonin gene related peptide plus vasoactive intestinal polypeptide, freeze-dried keratinocyte lysate, mesoglycan, negative-pressure recombinant keratinocyte growth factor, platelet-derived growth factor). PMID- 19445799 TI - Perineal care. AB - INTRODUCTION: Over 85% of women having a vaginal birth suffer some perineal trauma. Spontaneous tears requiring suturing are estimated to occur in at least a third of women in the UK and USA, with anal sphincter tears in 0.5% to 7% of women. Perineal trauma can lead to long-term physical and psychological problems. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of intrapartum surgical and non-surgical interventions on rates of perineal trauma? What are the effects of different methods and materials for primary repair of first- and second-degree tears and episiotomies? What are the effects of different methods and materials for primary repair of obstetric anal sphincter injuries (third- and fourth-degree tears)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: active pushing, spontaneous pushing, and sustained breath-holding (Valsalva) method of pushing; continuous support during labour; conventional suturing; different methods and materials for primary repair of obstetric anal sphincter injuries; episiotomies (midline and mediolateral incisions); epidural analgesia; forceps; methods of delivery ("hands-on" method, "hands poised"); water births; non-suturing of muscle and skin (or perineal skin alone); passive descent in the second stage of labour; positions (supine or lithotomy positions, upright position during delivery); restrictive or routine use of episiotomy; sutures (absorbable synthetic sutures, catgut sutures, continuous sutures, interrupted sutures); and vacuum extraction. PMID- 19445800 TI - Dystonia. AB - INTRODUCTION: Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or all of the body. It is more common in women, and some types of dystonia are more common in people of European Ashkenazi Jewish descent. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, surgical treatments, and physical treatments for focal, and for generalised dystonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 13 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acetylcholine receptor inhibitors, acupuncture, anticholinergic drugs, anticonvulsants, atypical antipsychotic drugs, benzodiazepines, biofeedback, botulinum toxin, chiropractic manipulation, deep brain stimulation of thalamus and globus pallidus, dopaminergic agonists and antagonists, gamma aminobutyric acid (GABA) inhibitors, microvascular decompression, myectomy, occupational therapy, osteopathy, pallidotomy, physiotherapy, selective peripheral denervation, serotonergic agonists and antagonists, speech therapy, and thalamotomy. PMID- 19445801 TI - Raynaud's phenomenon (secondary). AB - INTRODUCTION: Raynaud's phenomenon is episodic vasospasm of the peripheral vessels, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia, and, rarely, ulceration of the fingers and toes. It presents as episodic colour changes of the digits, usually in response to cold exposure or stress. The classic triphasic colour change is white (ischaemia), then blue (deoxygenation), then red (reperfusion). Raynaud's phenomenon can be primary (idiopathic) or secondary to several different conditions and causes. This review deals with secondary Raynaud's phenomenon. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of self-help measures for secondary Raynaud's phenomenon? What are the effects of drug treatments for secondary Raynaud's phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha blockers; angiotensin-converting enzyme (ACE) inhibitors; angiotensin II receptor antagonists; antithrombotics/inhibitors of platelet aggregation; biofeedback; calcium channel blockers; endothelin-1 receptor anatagonists; glyceryl trinitrate (transdermal); hand exercises; inositol nicotinate; moxisylyte; nafitidrofuryl oxylate; phosphodiesterase inhibitors; prostaglandins (oral, intravenous); relaxation therapy; serotonin reuptake inhibitors SRIs; smoking cessation; and warming hands and feet. PMID- 19445802 TI - Menorrhagia. AB - INTRODUCTION: Menorrhagia limits normal activities, and causes anaemia in two thirds of women with objective menorrhagia (loss of 80 mL blood per cycle). Prostaglandin disorders may be associated with idiopathic menorrhagia, and with heavy bleeding due to fibroids, adenomyosis, or use of intrauterine devices (IUDs). Fibroids have been found in 10% of women with menorrhagia overall, and in 40% of women with severe menorrhagia; but half of women having a hysterectomy for menorrhagia are found to have a normal uterus. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments for menorrhagia? What are the effects of surgical treatments for menorrhagia? What are the effects of endometrial thinning before endometrial destruction in treating menorrhagia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 39 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following medical interventions: combined pill, danazol, etamsylate, gonadorelin analogues, intrauterine progesterone, non-steroidal inflammatory drugs (NSAIDs), progestogens, and the following surgical interventions: dilatation and curretage, endometrial destruction, and hysterectomy. PMID- 19445803 TI - Stomach cancer. AB - INTRODUCTION: Stomach cancer is usually an adenocarcinoma arising in the stomach, and includes tumours arising at or just below the gastro-oesophageal junction (type II and III junctional tumours). The annual incidence varies among countries and by sex, with about 80 cases a year per 100,000 in Japanese men, 30/100,000 in Japanese women, 18/100,000 in British men, and 10/100,000 in British women. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of radical versus conservative surgical resection? What are the effects of adjuvant chemotherapy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adjuvant chemoradiotherapy, adjuvant chemotherapy, lymphadenectomy (radical, conservative), removal of adjacent organs, and subtotal gastrectomy for resectable distal tumours. PMID- 19445804 TI - Stroke prevention. AB - INTRODUCTION: People with a history of stroke or transient ischaemic attack are at high risk of all vascular events, such as myocardial infarction (MI), but are at particular risk of subsequent stroke (about 10% in the first year and about 5% each year thereafter). METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in people with previous stroke or transient ischaemic attack? What are the effects of preventive anticoagulant and antiplatelet treatments in people with atrial fibrillation and either with or without previous stroke or transient ischaemic attack? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2006 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 120 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: alternative antiplatelet regimens to aspirin, anticoagulation (oral dosing, or in those with sinus rhythm), aspirin (high-dose, or low-dose aspirin), blood pressure reduction, carotid and vertebral percutaneous transluminal angioplasty, carotid endarterectomy (in people: with asymptomatic but severe carotid artery stenosis; with less than 30% symptomatic carotid artery stenosis; with moderate [30-49%] symptomatic carotid artery stenosis; with moderately severe [50-69%] symptomatic carotid artery stenosis; with severe [more than 70%] symptomatic carotid artery stenosis; or with symptomatic near occlusion of the carotid artery), cholesterol reduction, vitamin B suppliments (including folate), or different blood pressure-lowering regimens. PMID- 19445805 TI - Stroke management. AB - INTRODUCTION: Stroke is the third most common cause of death in most resource rich countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of surgical treatment for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 42 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), neuroprotective agents (calcium channel antagonists, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists, tirilazad), specialised stroke care, systemic anticoagulation (heparinoids, low or specific thrombin inhibitors, molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis. PMID- 19445806 TI - Malignant melanoma (metastatic). AB - INTRODUCTION: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide. PMID- 19445807 TI - Scabies. AB - INTRODUCTION: Scabies is a common public health problem, with an estimated prevalence of 300 million cases worldwide, the majority in resource-poor countries. In industrialised countries, it is most common in institutionalised communities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of topical treatments for scabies? What are the effects of systemic treatments for scabies? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found two systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: benzyl benzoate (topical), crotamiton (topical), lindane (topical), malathion (topical), ivermectin (oral), permethrin (topical), and sulphur compounds (topical). PMID- 19445808 TI - Pre-eclampsia, eclampsia, and hypertension. AB - INTRODUCTION: Pre-eclampsia (raised blood pressure and proteinuria) complicates 2 8% of pregnancies, and raises morbidity and mortality in the mother and child. Pre-eclampsia is more common in women with multiple pregnancy and in those who have conditions associates with microvascular disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in women at risk of pre-eclampsia? What are the effects of interventions in women who develop mild moderate hypertension during pregnancy? What are the effects of interventions in women who develop severe pre-eclampsia or very high blood pressure during pregnancy? What is the best choice of anticonvulsant for women with eclampsia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants, antihypertensive drugs, antioxidants, antiplatelet drugs, atenolol, bed rest, hospital admission or day care, calcium supplementation, choice of analgesia during labour, early delivery (interventionist care), evening primrose oil, fish oil, glyceryl trinitrate, magnesium supplementation, plasma volume expansion, and salt restriction. PMID- 19445809 TI - Neck pain. AB - INTRODUCTION: Non-specific neck pain has a postural or mechanical basis and affects about two thirds of people at some stage, especially in middle age. Acute neck pain resolves within days or weeks, but may become chronic in about 10% of people. Whiplash injuries follow sudden acceleration-deceleration of the neck, such as in road traffic or sporting accidents. Up to 40% of people continue to report symptoms 15 years after the accident, although this varies between countries. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for people with non-specific neck pain without severe neurological deficit? What are the effects of treatments for acute whiplash injury? What are the effects of treatments for chronic whiplash injury? What are the effects of treatments for neck pain with radiculopathy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 91 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of the evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, biofeedback, drug treatments (analgesics, antidepressants, epidural steroid injections, muscle relaxants, non steroidal anti-inflammatory drugs [NSAIDs]), early mobilisation, early return to normal activity, exercise, heat or cold, manipulation (alone or plus exercise), mobilisation, multimodal treatment, patient education, percutaneous radiofrequency neurotomy, physical treatments, postural techniques (yoga, pilates, Alexander technique), pulsed electromagnetic field (PEMF) treatment, soft collars and special pillows, spray and stretch, surgery, traction, and transcutaneous electrical nerve stimulation (TENS). PMID- 19445811 TI - Alcohol misuse. AB - INTRODUCTION: Alcohol use is a leading cause of mortality and morbidity internationally, and is ranked by the World Health Organization (WHO) as one of the top five risk factors for disease burden. Without treatment, approximately 16% of hazardous or harmful alcohol users will progress to more dependent patterns of alcohol consumption. This review covers interventions in hazardous or harmful but not dependent alcohol users. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions in hazardous or harmful drinkers in the primary-care setting? What are the effects of interventions in hazardous or harmful drinkers in the emergency-department setting? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2006 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 13 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions in primary care and in emergency departments: brief intervention (single- or multiple-session), universal screening plus brief interventions, and targeted screening plus brief interventions. PMID- 19445810 TI - Chronic fatigue syndrome. AB - INTRODUCTION: Chronic fatigue syndrome (CFS) affects between 0.006% and 3% of the population depending on the criteria of definition used, with women being at higher risk than men. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic fatigue syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antidepressants, cognitive behavioural therapy (CBT), corticosteroids, dietary supplements, evening primrose oil, galantamine, graded exercise therapy, homeopathy, immunotherapy, intramuscular magnesium, oral nicotinamide adenine dinucleotide, and prolonged rest. PMID- 19445812 TI - Cataract. AB - INTRODUCTION: Cataract accounts for over 47% of blindness worldwide, causing blindness in about 17.3 million people in 1990. Surgery for cataract in people with glaucoma may affect glaucoma control. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgery for age-related cataract without other ocular comorbidity? What are the effects of treatment for age-related cataract in people with glaucoma? What are the effects of surgical treatments for age-related cataract in people with diabetic retinopathy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: cataract surgery alone; cataract surgery with non-concomitant glaucoma surgery; concomitant cataract and glaucoma surgery; diabetic retinopathy treatment with cataract surgery; intracapsular extraction; manual (large or small) incision extracapsular extraction; and phaco extracapsular extraction. PMID- 19445814 TI - Indications for fetal echocardiography high referral, low yield? AB - An excellent imaging tool in the prenatal diagnosis and ongoing evaluation of congenital heart defects, fetal echocardiography is indicated in a selected population at increased risk compared with the general population. For certain "soft markers" of fetal congenital heart defects, ambiguity in the indications for fetal echo may result in a high referral rate, but low yield of congenital heart disease. Here, we critically examine 4 conditions, 2 maternal and 2 fetal: maternal gestational diabetes, advanced maternal age, isolated echogenic focus, and single umbilical artery. This critical review reveals that more prospective population-based studies with higher power and minimal bias need to be performed to establish the absolute risk of congenital heart defects in a selected population compared with that of the general population. Nonetheless, our analysis indicates that the absolute risk of congenital heart defects associated with each of these markers is low. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to define which patients should be referred for fetal echocardiography based on known risks, distinguish between relative and absolute risks for fetal congenital heart disease, and summarize fetal anomaly risks for women with altered glucose metabolism. PMID- 19445813 TI - Management of Bartholin duct cysts and abscesses: a systematic review. AB - OBJECTIVE: To review systematically the literature, published in English, on recurrence and healing after treatment of Bartholin duct cysts and abscesses. DATA SOURCES: We searched PubMed, EMBASE, CINAHL, LILACS, Web-of-science, the Cochrane database, and POPLINE from 1982 until May 2008. We searched the internet, hand-searched reference lists, and contacted experts and authors of relevant papers to detect all published and unpublished studies. METHODS OF STUDY SELECTION: We included any study with at least 10 participants, addressing either frequency of recurrence or healing time after treatment of Bartholin duct cyst or abscess. We followed MOOSE (meta-analysis of observational studies in epidemiology) guidelines. Of 532 articles identified, 24 studies (5 controlled trials, 2 cohort studies, and 17 case series) met all inclusion criteria. Study size ranged between 14 and 200 patients. TABULATION, INTEGRATION, AND RESULTS: The interventions included: (1) Silver nitrate gland ablation, (2) cyst or abscess fenestration, ablation, or excision using carbon dioxide (CO(2)) laser, (3) marsupialization, (4) needle aspiration with or without alcohol sclerotherapy, (5) fistulization using a Word catheter, Foley catheter, or Jacobi ring, (6) gland excision, and (7) incision and drainage followed by primary suture closure. The reported frequency of recurrence varied from 0% to 38%. There was no recurrence after marsupialization in available studies. Recurrence after other treatments varied, and was most common after aspiration alone. Healing generally occurred in 2 weeks or less. CONCLUSION: There are multiple treatments for Bartholin duct cysts and abscesses. A review of the literature failed to identify a best treatment approach. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to identify seven different treatments for Bartholin duct cysts or abscesses, contrast treatment choice complications and recurrence risks for the different options for treatment of Bartholin duct cysts or abscesses, and point out the limited quality and quantity of data upon which to choose best practices. PMID- 19445815 TI - Manipulative therapy for pregnancy and related conditions: a systematic review. AB - OBJECTIVE: The objective of this review is to evaluate the evidence on the effects of Spinal Manipulative Therapy (SMT) on back pain and other related symptoms during pregnancy. DATA SOURCES: A literature search was conducted using Pubmed, Manual, Alternative and Natural Therapy Index System, Cumulated Index to Nursing and Allied Health, Index to Chiropractic Literature, the Cochrane Library, and Google Scholar. In addition hand searches and reference tracking were also performed, and the citation list was assessed for comprehensiveness by content experts. METHODS OF STUDY SELECTION: This review was limited to peer reviewed manuscripts published in English from 1966 until September 2008. The initial search strategy yielded 140 citations of which 12 studies were reviewed for quality. TABULATION, INTEGRATION, AND RESULTS: The methodological quality of the included studies was assessed independently using quality checklists of the Scottish Intercollegiate Guidelines Network and Council on Chiropractic Guidelines and Practice Parameters. The review indicates that the use of SMT during pregnancy to reduce back pain and other related symptoms is supported by limited evidence. CONCLUSION: Overall, this body of evidence is best described as emergent. However, since effective treatments for pregnancy-related back pain are limited, clinicians may want to consider SMT as a treatment option, if no contraindications are present. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to describe the concepts of spinal manipulative therapy and types of symptoms for which it might be considered in pregnancy, explain the quality of available research on the use of spinal manipulative therapy, and plan to discuss this therapy with interested pregnant patients. PMID- 19445816 TI - Association between trans-fatty acids in erythrocytes and pro-atherogenic lipid profiles among Canadian Inuit of Nunavik: possible influences of sex and age. AB - Dietary exposure to trans-fatty acids (TFA) is likely to be high among Canadian Inuit; yet no data are available on the physiological effects of TFA in this population. The purpose of the present study was to assess the association between TFA and plasma lipid profiles in Inuit men and women living in Nunavik (Quebec, Canada). In a cross-sectional, population-based survey, a total of 795 Nunavik Inuit eligible participants gave a blood sample. Exposure to TFA was assessed by their relative proportion in erythrocyte membrane. We performed multiple regression analysis using plasma lipids or their linear combinations as the dependent variables and TFA as the main predictor, adjusting for potential confounders. The associations varied markedly between the sexes and according to age. In men (n 357, aged 36.3 (sd 14.3) years, TFA 1.24 (sd 0.54) %), TFA tended to be negatively associated with HDL-cholesterol (HDL-C), apoA1 and LDL particle size, and positively associated with non-HDL-C, LDL-cholesterol (LDL-C), apoB100, the apoB100:apoA1 ratio and the ratios of total cholesterol (TC), LDL-C and TAG to HDL-C. No such trends were observed in women (n 438, aged 37.0 (sd 14.1) years, TFA 1.16 (sd 0.54) %), except for HDL-C and apoA1 in women aged 50 years and more. These results suggest that TFA could raise the risk of CHD in Inuit men at least through their physiological effects on plasma lipids. The differential associations reported in pre- and postmenopausal women need to be reproduced in other populations and in experimental studies addressing the influence of sex hormones in response to dietary fats. PMID- 19445817 TI - Obesity and chronic disease: always offender or often just accomplice? AB - Over a decade ago, the finding of a form of low-grade systemic inflammation ('metaflammation') associated with obesity, insulin resistance and chronic disease proffered a causal explanation for the latter. However, recent work has shown that metaflammation is also associated with several modern lifestyle related and environmental inducers, with or without obesity. Here, we present accumulating data to show a link between metaflammation and a number of non microbial environmental and lifestyle stimulants, both with and without obesity. This implies that obesity may often be an accomplice to, as much as an offender in, major metabolic disease. The real (albeit distal) cause of such a disease appears to lie in aspects of the modern techno-industrial environment driving unhealthy lifestyle behaviours. If true, this suggests that while individual weight loss may be a component of chronic disease management, it may be neither 'necessary' nor 'sufficient' to reduce the problem at a population level. Greater multidisciplinary and policy input is needed to modify the economic and political drivers of the modern, obesogenic environment. PMID- 19445818 TI - In utero and postnatal exposure to a high-protein or high-carbohydrate diet leads to differences in adipose tissue mRNA expression and blood metabolites in kittens. AB - The objective of the present study was to measure the differences in body composition, adipose tissue gene expression, blood metabolite and hormone concentrations, and insulin sensitivity in kittens exposed to high-protein (HP) or high-carbohydrate (HC) nutrition in utero and through the growth period. Eight dams were randomised onto two test diets, and fed the diets throughout gestation and lactation. Male offspring were evaluated for 9 months. Kittens were weaned at 2 months of age onto the same treatment diet as the dam and were allowed to consume diets ad libitum. The HC diet contained 34.3 % crude protein (CP), 19.2 % fat and 30.8 % digestible carbohydrate, while the HP diet contained 52.9 % CP, 23.5 % fat and 10.8 % digestible carbohydrate. Blood samples were collected at 6 months after birth. Body composition was determined at 2 and 8 months of age and an intravenous glucose tolerance test, neutering and adipose tissue biopsy conducted at 8 months of age. Physical activity was quantified at 6 and 9 months. Energy intake, DM intake and body weight were not different between groups. At 2 months, blood TAG were greater (P < 0.05) in kittens fed the HP diet. At 8 months, blood leptin was higher (P < 0.05) in kittens fed the HC diet, while chemokine receptor 5, hormone-sensitive lipase, uncoupling protein 2, leptin and insulin receptor mRNA were greater (P < 0.05) in kittens fed the HP diet. The present results demonstrate some of the changes in blood metabolites and hormones, physical activity and mRNA abundance that occur with feeding high protein levels to kittens. PMID- 19445819 TI - The effects of a low-sodium base-producing diet including red meat compared with a high-carbohydrate, low-fat diet on bone turnover markers in women aged 45-75 years. AB - A randomised, parallel-design dietary intervention study was conducted in women (aged 45-75 years) with prehypertension or stage 1 hypertension. The aim was to compare the effects on bone turnover of a low-Na base-producing (LNAB) Dietary Approaches to Stop Hypertension (DASH)-type diet (including six serves lean red meat/week) with a high-carbohydrate low-fat (HCLF) diet with a higher acid load (both >800 mg dietary Ca/d). Fasting serum bone markers (baseline and week 14) and 24 h urinary electrolyte excretion (baseline, weeks 4, 8, 12 and 14) were measured. After the intervention period, the LNAB group (n 46) had a fall of 26 (sem 6) % (P < 0.0001) in urinary Na, an increase in K excretion (6.8 (sem 3.6) mmol/d; P = 0.07) and, compared with the HCLF group (n 49), a greater reduction in urinary Ca excretion by 0.7 (sem 0.3) mmol/d. Serum 25-hydroxyvitamin D, intact parathyroid hormone and osteocalcin did not change, and both groups had a similar increase of 23 (sem 5) % (P < 0.0001) in C-terminal telopeptide of type I collagen. The HCLF group had an 11 (sem 4) % increase (P = 0.003) in N-terminal propeptide, type I procollagen, which could indicate an increased rate of bone turnover. The fall in urinary Ca with the lower-Na lower-acid load diet is likely to have long-term beneficial effects on bone. As bone resorption was not different between the two dietary patterns with relatively high Ca intake, the effect on bone health of a dietary pattern with a lower acid load warrants further study on a lower Ca intake. PMID- 19445820 TI - Growth and nutrient intake among very-low-birth-weight infants fed fortified human milk during hospitalisation. AB - Postnatal growth failure in preterm infants is due to interactions between genetic and environmental factors, which are not fully understood. We assessed dietary supply of nutrients in very-low-birth-weight (VLBW, < 1500 g) infants fed fortified human milk, and examined the association between nutrient intake, medical factors and growth during hospitalisation lasting on average 70 d. We studied 127 VLBW infants during the early neonatal period. Data were obtained from medical records on nutrient intake, growth and growth-related factors. Extra uterine growth restriction was defined as body weight < 10th percentile of the predicted value at discharge. Using logistic regression, we evaluated nutrient intake and other relevant factors associated with extra-uterine growth restriction in the subgroup of VLBW infants with adequate weight for gestational age at birth. The proportion of growth restriction was 33 % at birth and increased to 58 % at discharge from hospital. Recommended values for energy intake (>500 kJ/kg per d) and intra-uterine growth rate (15 g/kg per d) were not met, neither in the period from birth to 28 weeks post-conceptional age (PCA), nor from 37 weeks PCA to discharge. Factors negatively associated with growth restriction were energy intake (Ptrend = 0.002), non-Caucasian ethnicity (P = 0.04) and weight/predicted birth weight at birth (Ptrend = 0.004). Extra-uterine growth restriction is common in VLBW infants fed primarily fortified human milk. Currently recommended energy and nutrient intake for growing preterm infants was not achieved. Reduced energy supply and non-Caucasian ethnicity were risk factors for growth restriction at discharge from hospital. PMID- 19445821 TI - Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. AB - Diet influences the composition of the gut microbiota and host's health, particularly in patients suffering from food-related diseases. Coeliac disease (CD) is a permanent intolerance to cereal gluten proteins and the only therapy for the patients is to adhere to a life-long gluten-free diet (GFD). In the present preliminary study, the effects of a GFD on the composition and immune function of the gut microbiota were analysed in ten healthy subjects (mean age 30.3 years) over 1 month. Faecal microbiota was analysed by fluorescence in situ hybridisation (FISH) and quantitative PCR (qPCR). The ability of faecal bacteria to stimulate cytokine production by peripheral blood mononuclear cells (PBMC) was determined by ELISA. No significant differences in dietary intake were found before and after the GFD except for reductions (P = 0.001) in polysaccharides. Bifidobacterium, Clostridium lituseburense and Faecalibacterium prausnitzii proportions decreased (P = 0.007, P = 0.031 and P = 0.009, respectively) as a result of the GFD analysed by FISH. Bifidobacterium, Lactobacillus and Bifidobacterium longum counts decreased (P = 0.020, P = 0.001 and P = 0.017, respectively), while Enterobacteriaceae and Escherichia coli counts increased (P = 0.005 and P = 0.003) after the GFD assessed by qPCR. TNF-alpha, interferon gamma, IL-10 and IL-8 production by PBMC stimulated with faecal samples was also reduced (P = 0.021, P = 0.037, P = 0.002 and P = 0.007, respectively) after the diet. Therefore, the GFD led to reductions in beneficial gut bacteria populations and the ability of faecal samples to stimulate the host's immunity. Thus, the GFD may constitute an environmental variable to be considered in treated CD patients for its possible effects on gut health. PMID- 19445822 TI - Effect of moderate intakes of different tea catechins and caffeine on acute measures of energy metabolism under sedentary conditions. AB - Green tea may stimulate energy metabolism; however, it is unclear if acute effects are caused by specific catechins, caffeine or their combination. The objective of the present study was to examine the separate and combined effects of different catechins and caffeine on energy expenditure (EE) and fat oxidation over a single day. Fifteen healthy, normal-weight males received capsules containing placebo, caffeine alone (150 mg), or caffeine plus a catechin mixture (600 mg) enriched in either epigallocatechin-3-gallate (EGCG), epigallocatechin or a mix of catechins, in a randomised cross-over double-blinded design. On each test day EE, respiratory quotient (RQ) and substrate oxidation were measured under sedentary conditions in a respiratory chamber for 13.5 h. We found no significant treatment effect on EE (P = 0.20) or RQ (P = 0.68). EGCG with caffeine insignificantly raised EE and fat oxidation v. caffeine-only and placebo (EE 5.71 (SE 0.12) v. 5.68 (SE 0.14) v. 5.59 (SE 0.13) MJ/12.5 h, respectively; fat oxidation 84.8 (SE 5.2) v. 80.7 (SE 4.7) v. 76.8 (SE 4.0) g/12.5 h). Catechin/caffeine combinations at these dosages and mode of application had non significant acute effects on EE and fat oxidation. The maximum observed effect on EE of about 2 % could still be meaningful for energy balance over much longer period of exposure. However, higher short-term effects reported in the literature may reflect variations in green tea extracts, added caffeine, or synergies with physical activity. The specific mechanisms and conditions that may underpin observed longer-term benefits of catechin-enriched green tea consumption on body composition remain to be confirmed. PMID- 19445823 TI - Comparison of the activity of human and bovine milk on two cell lines. AB - The activity of human milk on cell growth has been evaluated on two cell lines, MDCK and Caco-2. The proportion of human milk samples that reduced by half the growth of MDCK cells was of 36%. This inhibitory activity was associated with casein and not the whey fraction. Great variability was found in the degree of inhibitory activity depending on the milk sample. The susceptibility of Caco-2 cells to milk inhibitory activity was lower than that of MDCK. Bovine milk did not have any effect on cell growth, either as skimmed milk or as whey or casein. Morphology of cells incubated with active human casein showed abnormal features, such as chromatin condensation, reduced cellular volume and apoptotic bodies, and also fragmented DNA, which are all features of apoptosis. PMID- 19445824 TI - Comparison of the level of residual coagulant activity in different cheese varieties. AB - The coagulant retained in cheese curd is a major contributor to proteolysis during ripening. The objective of this study was to quantify residual coagulant in 9 cheese varieties by measuring its activity on a synthetic heptapeptide (Pro Thr-Glu-Phe-[NO2-Phe]-Arg-Leu) assayed using reversed-phase HPLC. The level of residual coagulant activity was highest in Camembert cheese, probably due to its low pH at whey drainage and the high moisture content of the cheese, followed in order by Feta=Port du Salut=Cheddar>Gouda>Emmental=Parmigiano Reggiano=low moisture part-skim Mozzarella=Mozzarella di Bufala Campana. The high cooking temperature (50-54 degrees C) used during the manufacture of Emmental and Parmigiano Reggiano cheeses and the cooking and stretching step in hot water during the manufacture of Mozzarella cheese may be the reasons for the lowest residual coagulant activity in these cheeses. The level of residual coagulant activity was higher in Feta cheese made from milk concentrated by ultrafiltration than in conventional Feta. PMID- 19445825 TI - Influence of somatic cell counts and breed on physico-chemical and sensory characteristics of hard ewes'-milk cheeses. AB - The aim of the present work was to perform a physico-chemical, descriptive quantitative and consumer-preference analysis of hard ewes'-milk cheeses that had been matured for one year and to determine the correlations between the variables studied. The cheeses were elaborated with milk from three breeds of sheep (Castellana, Churra and Assaf) with different somatic cell counts (lower than 500,000 cells ml-1; between 1,000,000 and 1,500,000 cells ml-1, and more than 2,500,000 cells ml-1). The results show that the cheeses elaborated with milk with high SCC had lower values of dry extract and fat and high values of pH and fat acidity and were described as pungent, granulose and less creamy. Regarding the effect of breed, the cheeses made with milk from the Churra breed had lower values for fat and those made with Assaf breed milk were significantly more rancid. The study of correlations showed that creaminess was positively correlated with the dry extract and total fat content and negatively correlated with ash and fat acidity, indeed grainy texture and pungency had the opposite sign in their correlation with these latter variables. The yellow colour was positively correlated with ash and negatively with protein. Finally, the consumer preferences reveals that the less accepted cheeses showed the higher values for rancidness and pungency and they were less likely to accept the cheeses made with Assaf breed milk. PMID- 19445826 TI - Conjugated linoleic acid (CLA) and fatty acid composition of milk, curd and Grana Padano cheese in conventional and organic farming systems. AB - CLA levels and fatty acid composition were measured to compare the fat composition in organic bulk milk, destined to the production of Grana Padano cheese, with those produced by conventional system. The curds and Grana Padano cheeses were also analysed to evaluate the effects of the production technology on the CLA content. All analysed organic samples were characterized by higher annual means of CLA, vaccenic acid (TVA) and linolenic acid (LNA) in comparison with conventional samples (with P<0.05). Nevertheless, no particular effect of the production technology was seen on the CLA content. The animal diet appears to be the factor which has the highest effect on the CLA concentration in milk and milk products and an organic diet based on fresh or dried forage, that is rich in CLA precursory fatty acids, may improve the yield of fatty acids with beneficial effects on health. PMID- 19445827 TI - Electronic Nose analysis of milk from cows grazing on two different Alpine vegetation types. AB - The nutritional distinctiveness of pasture-fed dairy products is mainly influenced by the transfer of specific chemical compounds from the grass to the milk and by their effect on rumen microflora and animal metabolism. Thus, the pasture-fed origin has to be objectively proven, using fast and reproducible analytical methods applied to finished products, in order to protect consumers against potential frauds. In this work, Electronic Nose patterns of Alpine milks produced by cows grazing Trifolium alpinum and Festuca nigrescens pasture types have been examined, in order to test the potential use of this device for routine control analyses of the botanical origin of milk and dairy products. The data have been treated with different multivariate analyses (MANOVA, LDA) and chemometrics (MPLS). The results allow a very good classification of the milks, according to the two treatments. Such results demonstrate that this device could be successfully applied to PDO dairy products food chain as a tool for the determination of their dietary origin. PMID- 19445828 TI - Effect of high-pressure homogenisation on rheological properties of rennet induced skim milk and standardised milk gels. AB - The effects of high-pressure homogenisation (HPH) in the pressure range 100-300 MPa on the gel formation and rheological properties of rennet-induced skim milk (0.08%, fat, w/w) and standardised milk (3.60% fat, w/w) gels at pH 6.60 were studied. The average casein micelle size in skim milk was significantly reduced and the gel formation time decreased when skim milk was subjected to the pressures of 200 and 300 MPa. The storage modulus of rennet-induced skim milk gels at 2700 s after rennet addition was higher for samples homogenised at higher pressures, which contained smaller casein particles. HPH had little effect on the large deformation properties of rennet-induced skim milk gels. The gel formation time of renneted standardised milk was significantly reduced as a result of HPH, while the storage modulus of rennet-induced milk gels 2700 s after rennet addition increased with increasing homogenising pressure. The apparent fracture stress was slightly higher for standardised milk gels formed from HPH-treated milk, whereas the apparent strain at fracture was lower, than that of unhomogenised milk. In conclusion, HPH treatment influenced gel formation processes of skim milk and its small-deformation rheological properties, mainly through modification of casein micelles. HPH also significantly affected the gel formation process of standardised milk gels and its rheological properties as a result of an increase in volume fraction of aggregating particles, while the particle size was of lesser importance. PMID- 19445829 TI - Cell population, viability, and some key immunomodulatory molecules in different milk somatic cell samples in dairy cows. AB - Immune cells in the milk are most important in combating pathogens that invade the mammary gland. This study investigated the immune competence and viability of somatic milk cells that are already resident in milk and udders free of infection. Cells were studied in freshly removed milk to simulate conditions in the udder. Effects of incubation, cell preparation, and immunological stimulation with 0.5 mug/ml lipopolysaccharide (LPS) from Escherichia coli were analysed. Viability and differential counts of milk cells between high and low somatic cell count (SCC) quarters, and cisternal and alveolar milk with and without LPS stimulation were compared. Incubation and preparation of cells caused a cell loss which further increased with time independently of SCC and milk fraction. The viability of these cells was stable until 3 h post incubation and decreased until 6 h. Cell populations differed between both investigations, but did not change during the course of the experiment. mRNA expression of immune and apoptosis factors of the cells, measured by qPCR, did not change substantially: mRNA expression of caspase 3, Toll like receptor 4, and GM-CSF did not change, whereas the expression of the death receptor Fas/APO-1 (CD95), lactoferrin and lysozyme was decreased at 6 h. Cyclooxygenase-2 and TNF-alpha mRNA expression were decreased after 6 h of LPS treatment. In comparison with other studies in vivo or in vitro (in cell culture), in this study where cells are studied ex vivo (removed from the udder but kept in their natural environment, the milk) resident milk cells seem to be more vulnerable, less viable, less able to respond to stimulation, and thus less immune competent compared with cells that have freshly migrated from blood into milk after pathogen stimulation. The cell viability and differential cell count differed between high- and low-SCC milk and between cisternal and alveolar milk depending on the individual cow. In conclusion, the results support the view that for a most effective defence against invading pathogens the mammary gland is reliant on the recruitment of fresh immune cells from the blood. PMID- 19445830 TI - Long-term effects on heifer performance of an enhanced-growth feeding programme applied during the preweaning period. AB - Sixty female dairy calves (body weight, BW, 43.2+/-0.58 kg and age 9.8+/-0.61 d) were arranged in two groups to compare the short-term and long-term effects of an enhanced-growth feeding programme (EF) with those of a conventional-growth feeding programme (CF). After 1 week of adaptation to a milk replacer (MR), CF calves were fed 4 l/d of MR (25% crude protein, CP; 19.2% ether extract) at 12% dry matter (DM) from days 1 to 27 and 2 l/d at 12% DM from days 28 to 34, and the EF calves were offered the same MR at 18% DM: 4 l/d from days 1 to 6, 6 l/d from days 7 to 13, 7 l/d from days 14 to 20, 6 l/d from days 21 to 27 and 3 l/d from day 28 to weaning at day 34 of the study (50 d of age). Individual calf starter (20.7% CP) intake was recorded daily from the beginning until day 41 of study (57 d of age). Then, calves were placed in groups of six and they received a total mixed ration (TMR) containing 18.5% CP until day 56 d of study (72 d of age). Then, heifers were moved to larger pens and were fed the same TMR in both treatments at each subsequent stage of growth throughout the study. Calves were weighed weekly until day 56 of study and before every pen change (days 94, 149, 200, 387 of study). When heifers were 400 d old and weighed >380 kg, they were moved to a breeding pen where oestruses were checked three times a day. Heifers were inseminated 12 h after the detection of oestrus. One month before calving, heifers were returned to their original farm and milk yield at 305 days in milk was recorded from 28 cows. Starter intake was greater (P<0.001) in CF than in EF calves (0.79 v. 0.29+/-0.043 kg/d, respectively) during the preweaning period, but TMR consumption was similar in both treatments from days 42 to 56 of study. BW of EF calves was greater (P<0.01) than that of CF calves at weaning (76.4 v. 71.6+/-1.10 kg, respectively), but BW was not different at day 387 of study (405 d of age) (406.3 v. 401.3+/-4.05 kg, respectively). There were numerical differences in age at first breeding, fertility at first artificial insemination, age at pregnancy, and milk yield but some of these differences might have reached statistical significance with more replication. PMID- 19445831 TI - Administration of a live culture of Lactococcus lactis DPC 3147 into the bovine mammary gland stimulates the local host immune response, particularly IL-1beta and IL-8 gene expression. AB - Mastitis is one of the most costly diseases to the dairy farming industry. Conventional antibiotic therapy is often unsatisfactory for successful treatment of mastitis and alternative treatments are continually under investigation. We have previously demonstrated, in two separate field trials, that a probiotic culture, Lactococcus lactis DPC 3147, was comparable to antibiotic therapy to treat bovine mastitis. To understand the mode of action of this therapeutic, we looked at the detailed immune response of the host to delivery of this live strain directly into the mammary gland of six healthy dairy cows. All animals elicited signs of udder inflammation 7 h post infusion. At this time, clots were visible in the milk of all animals in the investigation. The most pronounced increase in immune gene expression was observed in Interleukin (IL)-1beta and IL 8, with highest expression corresponding to peaks in somatic cell count. Infusion with a live culture of a Lc. lactis leads to a rapid and considerable innate immune response. PMID- 19445832 TI - Prediction of total quarter milk somatic cell counts based on foremilk sampling. AB - Determination of somatic cell count (SCC) is used worldwide in dairy practice to describe the hygienic status of the milk and the udder health of cows. When SCC is tested on a quarter level to detect single quarters with high SCC levels of cows for practical reasons, mostly foremilk samples after prestimulation (i.e. cleaning of the udder) are used. However, SCC is usually different in different milk fractions. Therefore, the goal of this study was the investigation of the use of foremilk samples for the estimation of total quarter SCC. A total of 378 milkings in 19 dairy cows were performed with a special milking device to drain quarter milk separately. Foremilk samples were taken after udder stimulation and before cluster attachment. SCC was measured in foremilk samples and in total quarter milk. Total quarter milk SCC could not be predicted precisely from foremilk SCC measurements. At relatively high foremilk SCC levels (>300 x 10(3) cells/ml) foremilk SCC were higher than total quarter milk. At around (50-300) x 10(3) cells/ml foremilk and total quarter SCC did not differ considerably. Most interestingly, if foremilk SCC was lower than 50 x 10(3) cells/ml the total quarter SCC was higher than foremilk SCC. In addition, individual cows showed dramatic variations in foremilk SCC that were not very well related to total quarter milk SCC. In conclusion, foremilk samples are useful to detect high quarter milk SCC to recognize possibly infected quarters, only if precise cell counts are not required. However, foremilk samples can be deceptive if very low cell numbers are to be detected. PMID- 19445839 TI - Real-time PCR analysis of the heat-shock response of Acidithiobacillus ferrooxidans ATCC 23270. AB - As one of the most important bioleaching bacterial species, Acidithiobacillus ferrooxidans is subjected to different kinds of environmental stress such as temperature changes, presence of some toxic heavy metals or pH changes, which normally take place in bioleaching operations and may affect the activity of the bacteria. To obtain further knowledge of the protective mechanisms employed by A. ferrooxidans in response to elevated growth temperature, temporal gene expression profiles were examined in cells subjected to heat stress by using real-time PCR. The majority of predicted genes, including those encoding chaperones and heat shock proteins, were significantly up-regulated (P < 0.05 and the fold change >or= 2.0) over a 25-min period after upshift to the heatshock temperature (from 30 to 42 degrees C) and then decrease to readjust their transcript levels to a new steady state at 42 degrees C. Finally, based on the gene expression data and computational analysis, a putative regulatory site having T-T-T-T-T-T-n-n in the 35 region and n-T-A-T-n-A-T-C in the -10 region with average 19 base pairs separating the two elements was predicted upstream of a number of heat-inducible genes. PMID- 19445840 TI - The effects of hypo- and hyperthyroidism on nuclear, cytosolic, endoplasmic and mitochondrial fractions of sialoglycoproteins in rabbit hepatocytes. AB - Enhanced sialylation of glycoproteins occurs during hypo- and hyperthyroidism. The role of sialic acid (SA) in cell membranes is well-standing, but its role in intracellular structures is still under analysis. We wanted to evaluate the influence of thyroid hormones on the sialylation ratio of intracellular proteins presented in cytosolic, mitochondrial, endoplasmic and nuclear fractions of rabbit hepatocytes. Twenty-one New Zealand male rabbits were divided into three groups. Hypothyroidism (N = 7) or hyperthyroidism (N = 7) was induced by adding propylthiouracyl (2 mg/l) or L-thyroxine (12 mg/l), respectively, to the drinking water for four weeks. Results were compared with healthy (euthyroid) control animals (N = 7). After isolation of intracellular fractions, standard SDS-PAGE electrophoresis and transfer onto nitrocellulose membrane were performed. Identification of SA residue was carried out with digoxigenin- labelled lectins: Sambucus nigra agglutinin (SNA) and Maackia amurensis agglutinin (MAA). We noticed significantly higher level of SNA than MAA linkage sialoglycoproteins in all evaluated fractions. The sialylation ratio was significantly lower (P < 0.05) in the nuclear fraction in case of hyperthyroidism (detected with both agglutinins). In contrast to the nuclear fraction the content of SNA-detected sialoglycoproteins was significantly reduced in mitochondrial fraction of hyperthyroid hepatocytes (P < 0.05). Non-significant augmentation of MAA-detected sialoglycoproteins was observed in the mitochondrial fractions in both hypo- and hyperthyroidism. The fluctuations of sialoglycoproteins in endoplasmic fraction were not significant. Our work showed that the subcellular structures are rich in SA residues. Differing effects of thyroid hormones on sialylation ratio suggest an important role for hypo- and hyperthyroidism in sialoglycoprotein metabolism. PMID- 19445841 TI - Angiotensin II receptor blockage prevents diabetes-induced oxidative damage in rat heart. AB - Current findings suggest a role for the angiotensin II (Ang II) signalling pathway in generation of reactive oxygen species and diabetes-induced cardiac complications. In this study we aimed to investigate the effect of angiotensin II type 1 (AT1) receptor blockage on some antioxidant enzymes such as glucose- 6 phosphate dehydrogenase (G6PD), 6-phoshogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), and catalase (CAT) in the heart of streptozotocin (STZ) induced diabetic rats. The effect of AT1 receptor blocker, candesartan-cilexetil (5 mg/kg/day for 4 weeks) was studied. Diabetes caused hyperglycaemia (4-fold of control) with significant increases in G6PD, 6PGD, GR, GSH-PX, CAT and no effect on GST in heart tissues as compared to normal control rats. Treatment of STZ induced diabetic rats with candesartan-cilexetil had significant beneficial effects on these parameters without any side effect on control rats. These results suggest that Ang II can take part in induction of oxidative stress in diabetic rat heart and that blockage of its activity by AT1 receptor blocker is potentially protective against diabetes-induced cellular damage. PMID- 19445842 TI - Efficient human growth hormone gene expression in the milk of non-transgenic goats. AB - Heterogenous expression of recombinant proteins in milk of livestock at a large scale is very labour-intensive to be achieved with current transgenic animals, and usually seen as time-consuming, expensive and technically most challenging. Here we describe a convenient system for transient production of recombinant human growth hormone and its extensive use in recombinant protein production for therapeutic purposes. In this study, an adenoviral vector containing the GFP gene and hGH gene was constructed for direct infusion into the epithelium of mammary glands of goats via the teat canal during the period of natural lactation. Western-blot analysis of milk samples obtained from all of the viral-treated founders indicated that the recombinant hGH (rhGH) was secreted into the milk of the goats. The concentrations of rhGH in milk ranged from 0.6 to 2.4 mg/ml and lasted for more than 10 days during lactation. These data suggest that it is possible to produce larger amounts of recombinant human growth hormone in the milk of livestock animals by using replication-defective adenoviruses. PMID- 19445844 TI - Mesenchymal progenitor cells in red and yellow bone marrow. AB - Marrow cavities in all bones of newborn mammals contain haematopoietic tissue and stromal microenvironment that support haematopoiesis (haematopoietic microenvironment), known as red bone marrow (BM). From the early postnatal period onwards, the haematopoietic microenvironment, mainly in tubular bones of the extremities, is replaced by mesenchymal cells that accumulate lipid drops, known as yellow BM, whereas haematopoietic tissue gradually disappears. We analysed the ability of mesenchymal cell progenitors in red and yellow BM to produce bone and haematopoietic microenvironment in vivo after transplantation into normal or haematopoietically deficient (irradiated and old) recipients. We found that (1) normal substitution of red with yellow BM results from a gradual loss of mesenchymal stem cells (MSCs) capable of developing bone and haematopoietic microenvironment; (2) the mesenchymal cell population in tubular bones still containing active haematopoietic tissue gradually becomes depleted of MSCs, starting from a young age; (3) haematopoietic microenvironment is incapable of self-maintenance and its renewal depends on the presence of precursor cells; (4) the mesenchymal cell population remaining in areas with yellow BM contains cells able to develop functionally active haematopoietic microenvironment in conditions of haematopoietic insufficiency. Our data also indicate the possible existence of bi-potential stromal precursor cells producing either bone in normal, or bone together with active haematopoietic microenvironment in irradiated or old recipients. This study opens a spectrum of opportunities for the extension of haematopoietic territories by substituting the fat contents of BM cavities with haematopoietic tissue, thereby improving haematopoiesis compromised by cytotoxic treatments, irradiation, ageing, etc. PMID- 19445843 TI - Synergy of serum and cerebrospinal fluid antibodies against axonal cytoskeletal proteins in patients with different neurological diseases. AB - Autoantibodies against different axonal cytoskeletal proteins [the light (NFL) and medium (NFM) subunit of neurofilament and tubulin (TUB)] in serum and cerebrospinal fluid may be generated in response to the release of cytoskeleton from damaged neurons. We studied the relationships among these autoantibodies. Paired cerebrospinal fluid (CSF) and serum samples were obtained from 47 multiple sclerosis (MS) patients, 14 patients with neurodegenerative diseases, 21 patients with various neurological diseases and 16 normal control subjects. Levels of antibodies against NFL, NFM and TUB were related to each other in CSF in all groups, whereas close association of anti-cytoskeletal antibodies in serum was found in the MS group only. A concordant spectrum of anti-cytoskeletal antibodies is present in serum of MS patients, unlike in other neurological patients. The synergy between the spectrum of anti-cytoskeletal antibodies in serum and CSF might be one of the immunological features typical for the MS patients. PMID- 19445845 TI - [Benchmarking between Internal Medicine services]. PMID- 19445846 TI - [Lung cancer: how does it appear in our hospital?]. AB - INTRODUCTION: Lung cancer is the most frequently diagnosed tumor in industrialized countries and that which causes the largest number of deaths. The aim of this study is to know the relevant clinical and epidemiological characteristics of lung cancer in the Health Care Area of Salamanca. PATIENTS AND METHODS: A cross-sectional descriptive epidemiological study conducted in 140 patients, in the Rapid Diagnosis of Lung Cancer Pneumology Department of the University Hospital of Salamanca. RESULTS: The percentage of men diagnosed is greater than for to women: 126 (90%) were men and 14 (10%) women. Ninety percent had had an active contact with the tobacco. The percentage of men who were ex smokers is greater than that of those who smoke, there being a rate of packages per year in both groups at the time of diagnosis. Women continue to be mostly non smokers, although there is a progressive increase of active smokers. The most frequent clinical manifestation on diagnosis is chest pain (36.4%), 46.4% of the patients having symptoms of the constitutional syndrome. The most frequent histological type among men is squamous cell carcinoma (35.7%), and among women adenocarcinoma (50%), the significant relationship (p < 0.05) between the histological stain and the principal risk factor, that is tobacco, standing out. CONCLUSIONS: The known tobacco-lung cancer relationship, corroborated in this study, makes it necessary to have a more effective fight against tobacco to reduce the incidence of lung cancer. It is also necessary to develop multidisciplinary protocols that help early diagnosis and make it possible to increase the percentage of curative treatments. PMID- 19445847 TI - [Evaluation of cardiovascular risk in the longitudinal phase of the Mediterranean study]. AB - INTRODUCTION AND OBJECTIVES: There is little information on cardiovascular longitudinal studies. In Spanish patients with hypertension (AHT)) and/or hypercholesterolemia (HC), with poor initial control of blood pressure (BP) and/or total cholesterol (TC), incidence rate (IR), cumulative incidence (CI), relative risks (RR), survival curves (SC), therapeutic compliance (TC) were quantified and the Framingham-Anderson scale (FAS) was adjusted to our patients. PATIENTS AND METHODS: A total of 6,893 primary prevention patients with AHT and/or with HC were included in primary prevention, with an average of 1.22 years of follow-up. A total of 480 physicians participated. Incidence rate (IR), cumulative incidence (CIN), relative risks (RR), survival curves (SC) by Kaplan Meier method, and therapeutic compliance (TCOM) by Haynes-Sackett self-reported questionnaire were calculated. The Framingham-Anderson scale (FAS) was validated with Pearson's correlation coefficient (r) and intraclass correlation index (ICI). RESULTS: CIN was 1.59% (1.31-1.90); the IR 1,321.6 cardiovascular events/ 100,000 patients/year (1,026.6-1,598.8). RRs with statistical significance were: age (p = 0.03). Blood pressure at the end of the study (p = 0.02), coronary background (p = 0.00), left ventricular hypertrophy (LVH) (p = 0.00), microalbuminuria (p = 0.02), CT >/= 250 mg/dl (p = 0.01), fasting glycemia (Gb) >/= 126 mg/dl (p = 0.00), creatinine >/= 1.2 mg/dl at the beginning (p = 0.00) and at the end of the study (p = 0.00), and poor compliance in HC patients (p = 0.00). SC have statistical significance (p < 0.05) for AHT background, fasting glucose >/= 126 mg/dl, target organ damage, and high cardiovascular risk with FAS scale. The adjusted FAS formula for global cardiovascular risk was (0.415 x FAS Risk%) + 0.517%, r = 0.9962 (p = 0.00) and ICI = 0.9969 (p < 0.0001). CONCLUSIONS: The equation for the FAS scale was adjusted for Spanish AHT/HC patients. Prognostic factors and SC were calculated. Benefit between TC and decrease of CVR in HC patients was quantified. PMID- 19445848 TI - [Chronic eosinophilic pneumonia in the province of Soria (1995-2004). A review of literature]. AB - INTRODUCTION: Chronic eosinophilic pneumonia (NEC) is a rare disease that has a subacute or chronic course. Symptoms include shortness of breath, coughing, weight loss and fever. The eosinophilia is characteristic. Radiologically, peripheral alveolar infiltrates with predominance in the upper lobes are found. Treatment is based on corticosteroids for 6-8 months. MATERIAL AND METHODS: We performed a retrospective analysis on the incident cases of NEC in the health care area of Soria during the period of 1995 to 2004, considering their clinical features, diagnosis and treatment. RESULTS: A total of 5 cases of NEC were diagnosed in our center. Average age of patients was 57 years. Every case showed symptoms of the disease for months before diagnosis, the most frequent being fever, cough and fatigue. Peripheral eosinophilia was higher than 6% in all the cases. Recurrences occurred in two patients. CONCLUSIONS: NEC is a rare disease that requires the finding of either peripheral or pulmonary eosinophilia for its diagnosis. A typical symptom with alveolar infiltrates observed on a chest X-ray and peripheral eosinophilia suggests a NEC diagnosis, although this must be confirmed by the bronchoalveolar lavage (LBA) a lung biopsy may be necessary. Treatment must be maintained for at least 6 months. Relapses are frequent. PMID- 19445849 TI - [Contribution of the patent foramen ovale to the etiopathogeny of the irritable bowel syndrome]. AB - A higher prevalence of cardiac right-to-left shunt through a patent foramen ovale (PFO) has been recently reported in the irritable bowel syndrome (IBS). At the same time, signs of ischemia in medullary cerebral microcirculation and the presence of excess sympathetic activity in peripheral circulation have been identified, both related with change in pain perception and autonomic dysfunction characteristic of IBS. Considering these findings together, the possible etiopathogenic role of PFO in the development of IBS can be proposed, because the paradoxical embolism characteristic of PFO could damage the cerebral and intestinal microcirculation, and that injury would be also amplified by the percentage of venous blood that shunts the pulmonary filter, producing an alteration in the metabolism of serotonin, pro-inflammatory bradykinins or neurotensin, substances with a proven etiopathogenic relationship with IBS. PMID- 19445850 TI - [Chest x-ray with alveolointerstitial pattern in patients with type 1 diabetes mellitus and fever]. PMID- 19445851 TI - [Hip pain having uncommon etiology]. PMID- 19445852 TI - [Aortitis in patients with unknown origin fever]. PMID- 19445853 TI - [Woman with hypotension and acute kidney failure]. PMID- 19445854 TI - [Adrenal carcinoma. Presentation of one case and a review of the literature]. PMID- 19445855 TI - [Determination of serum myoglobin and troponin T for early diagnosis of acute myocardial infarction]. PMID- 19445856 TI - [Alopecia as adverse reaction of mesalazine]. PMID- 19445857 TI - [Prevalence of anemia in heart failure: a practical approach]. PMID- 19445858 TI - [Benign recurrent lymphocytic meningitis from herpes simplex virus type 2]. PMID- 19445859 TI - Inhaled steroids for young children with recurrent wheezing: friend or foe? PMID- 19445860 TI - Effect of inhaled fluticasone on lung function in infants with recurrent wheezing: a randomised controlled trial. AB - BACKGROUND: Inhaled corticosteroids are used to treat infants with troublesome asthma-like symptoms but their effect on the lung function of these young patients is controversial. MATERIAL AND METHODS: Forty-four infants with recurrent wheezing (more than 3 episodes) and family history of asthma completed this randomised, parallel, double-blind, controlled trial to compare the effect on lung function (main endpoint) of once-daily inhaled fluticasone (375 microg) versus placebo for 3 months. Pulmonary function was measured while infants were asymptomatic, using the raised volume rapid thoracic compression technique (spirometry-like), and values were converted to z-scores. RESULTS: The fluticasone group showed a significant increase in forced flows, (p < 0.001), a lower number of physician diagnosed wheezing episodes (p < 0.002), and a significant decrease in the parent-reported number of wheezing episodes per month (p < 0.03), as compared to placebo. One third of parents in the placebo group reported a clinical improvement in their infants. There was no significant difference in morning plasma cortisol between groups at entry or discharge. CONCLUSIONS: We conclude that once-daily treatment with 375 microg fluticasone increased forced flows and controlled symptoms in infants with recurrent wheezing without altering plasma cortisol levels. The spirometry-like technique is a useful tool to objectively assess the efficacy of anti-asthma medications in infants with repeated troublesome asthma-like symptoms. PMID- 19445861 TI - Single oral dose of dexamethasone in outpatients with bronchiolitis: a placebo controlled trial. AB - BACKGROUND AND OBJECTIVE: The management of bronchiolitis is still controversial and to the best of our knowledge, no clinical trial with oral corticosteroids in outpatients has been carried out in developing countries. The objective was to compare the efficacy of a single dose of oral dexamethasone in infants with moderate to severe bronchiolitis presenting to an emergency department. MATERIAL AND METHODS: A randomised, double-blind, placebo-controlled trial was conducted in Paraguay. At baseline, respiratory distress assessment instrument (RDAI), heart and respiratory rates, and transcutaneous haemoglobin oxygen saturation (SpO(2)) were recorded. Children received either a single dose of dexamethasone (0.5 mg/kg) or placebo; and then both groups received two nebulisations with adrenaline. Respiratory status was recorded again after the 1st and 4th hours. The primary outcome was RDAI improvement at the 4th hour; and the secondary was the hospital admission rate. RESULTS: During 5 months, 80 (33.3 %) out of 240 infants who consulted with acute respiratory illness fulfilled the inclusion criteria. During the trial 15 were excluded, therefore, 65 infants (33 in the dexamethasone vs. 32 in the placebo group) finished the study. Baseline characteristics and respiratory status were similar between groups. There were no differences in RDAI, heart and respiratory rate and SpO(2) between groups after the 1st and 4th hours. The hospitalisation rate was similar between groups (21 % vs. 25 %, p = 0.9, respectively), independently of the virus identified. CONCLUSIONS: Infants with moderate-severe bronchiolitis who were treated with a single dose of dexamethasone did not significantly alter the rate of hospitalisation or respiratory status. PMID- 19445862 TI - Protophormia terraenovae. A new allergenic species in amateur fishermen of Caceres, Spain. AB - BACKGROUND: Asticot maggot (Blowfly, Calliphoridae family) is the most important live bait used for angling in our country. Prevalence of allergy to live fish bait in occupationally exposed workers has been described. The purpose of this study was to determine the prevalence of asticot allergy in amateur fishermen and the identification of marketed asticot species in Caceres, Spain. MATERIALS AND METHODS: Seventy-two randomised selected patients (Angler's Society of Caceres) completed a questionnaire about fishing habits and allergic symptoms related with live bait handling. Skin prick test (SPT) with local asticot and common earthworm extracts were performed. Serum IgE levels to imported species (Protophormia terraenovae, Calliphora vomitoria, Lucilia sericata, Lumbricus terrestris) were measured. Local asticot and common earthworm samples were obtained for taxonomic identification. Data were analysed using the SPSS 12.0 software. RESULTS: Five patients (7 %) reported allergic symptoms caused by asticot maggots. All of them were positive for SPT to asticot and specific IgE to P. terraenovae. Sensitisation to P. terraenovae was found in 40 patients (58.8 %). No associated factors for asticot allergy were observed. Larvae and adult flies of local asticot samples were identified as P. terraenovae. CONCLUSIONS: Commercially available asticot, in Caceres, is composed by P. terraenovae larvae (Diptera. Calliphoridae). A 7 % prevalence of P. terraenovae allergy in amateur fishermen of Caceres was obtained. The allergenic potential of P. terraenovae seems to be greater than that of other blowflies and L. terrestris. The SPT with P. terraenovae extract is a very sensitive and specific technique in the diagnosis of live bait allergy in fishermen. PMID- 19445863 TI - Skin prick test reactivity to common aeroallergens among allergic rhinitis patients in Iran. AB - BACKGROUND: Allergic rhinitis is the most common allergic disease with negative impacts on patients' quality of life. The prevalence and pattern of sensitisation vary between different countries and populations. Identification of the most prevalent aeroallergens in each area has a very important role in diagnosis and treatment of allergic rhinitis. Iran is a fairly large country with different geo climatic conditions and there are no data about the most prevalent aeroallergen in Mashhad City, which is the second largest city in Iran, with a semiarid climate. The aim of this study was to evaluate the prevalence of positive skin test to various common aeroallergens among allergic rhinitis patients in the city of Mashhad. MATERIALS AND METHODS: Skin prick tests were performed with 27 common regional aeroallergens including grass, weed, tree, mite and mould in 311 patients with allergic rhinitis. RESULTS: The overall rate of sensitisation to any allergen was 81 %. 76 % of patients were poly-sensitised and weed and grass were the most prevalent allergens (77 % and 62 % respectively). Salsola Kali and mould were the most and the least prevalent individual allergens (72.5 % and 6.5 % respectively). Mean total IgE in patients with positive skin prick test was significantly higher than in patients without any positive skin prick test (308 vs 128 IU/mL, P = 0.016). 97 % of atopic patients were sensitised to Salsola kali and or Fraxinus americana. CONCLUSIONS: Our work showed the importance of weeds, especially the Amaranthaceae and Chenopodiaceae families. Diagnosis of pollen allergy can be simplified by using a combination of a few common aeroallergens. PMID- 19445864 TI - Cough affects quality of life in asthmatic children aged 8-14 more than other asthma symptoms. AB - BACKGROUND: Asthma may influence children's health-related quality of life (QoL) differently by various symptoms, at different severity. The primary aim of this study was to evaluate the QoL in children with asthma and describe the impact of each asthma symptom on the child's well-being at different severity levels. MATERIAL AND METHODS: Two hundred randomly selected children and one of their parents who consulted an outpatient asthma clinic, participated in the study. Qol was assessed with DISABKIDS-Smiley measure for children aged 4-7 years and with DISABKIDS DCGM-37 and Asthma Module for children 8-14 year old. RESULTS: Most of the children suffered from mild or moderate persistent asthma. Children with uncontrolled asthma stated lower QoL compared to partly controlled or controlled in both age groups (p < 0.05 in all domains). Cough appeared to affect QoL of 8 14 year olds more than other symptoms, especially in girls. In younger children, sex (boys, p = 0.039), age (p = 0.045), proxy sex (father, p = 0.048), frequency of doctor visits (4-6 months, p = 0.001), use of beta-2 agonists (p = 0.007) and father's smoking habits (p = 0.015) were associated with the QoL of coughing children but no correlation between cough and QoL was detected. In the 8-14 year age group coughers reported lower QoL compared to their counterparts; moreover, cough was found to affect QoL more than other symptoms (p < 0.05 in all domains). CONCLUSIONS: Cough has a direct effect on asthmatic children's QoL but there is still an obvious need for research to reveal all the determinats of this effect. PMID- 19445865 TI - The role of allergic sensitisation in childhood eczema: an epidemiologist's perspective. PMID- 19445866 TI - Design and debugging databases for statistical analysis. AB - Any form of data analysis requires the prior creation of a database to house the study information collected in one format or other (questionnaire, clinical history, etc.). The design of such databases should be optimised to allow adequate statistical analysis without the drawing of wrong conclusions. In addition, prior to analysis, debugging or filtering of the variables is required in order to avoid doubling the effort made in extracting the results. The present study offers a series of suggestions for database design and debugging, to ensure that the later statistical analyses are based on the revised data. PMID- 19445867 TI - Diagnosing immune-mediated reactions to drugs. AB - Drug allergy is a type B adverse drug reaction, which is unpredictable and difficult to prevent or manage. In patients who have a previous history of drug allergy it must be confirmed by laboratorial diagnosis. However, the diagnostic test remains a major problem in clinical practice. Skin testing is validated for some drugs, such as penicillin, but not for others. Provocation test is a confirmatory test but bears the risk of severe reactions. Lymphocyte transformation test is a reliable test but is considered as a research tool. This review addresses the most recent published literature regarding the techniques which have already been developed as well as the new tests that can be promising alternatives for diagnosis of drug allergy. PMID- 19445868 TI - Successful desensitisation to ceftriaxone in a patient with doxycicline resistant Lyme disease. PMID- 19445869 TI - Exanthematic reaction to pseudoephedrine. PMID- 19445870 TI - Snail allergy without house dust mites sensitisation. PMID- 19445871 TI - [Needs and demands in dermocosmetics]. PMID- 19445872 TI - [Evidence-based dermatology: a synopsis]. AB - The aim of evidence-based medicine is to support clinical decision making by providing tools for systematically locating, appraising, and applying the best information currently available to improve patient outcomes. This article summarizes the basic steps for practicing evidence-based medicine in the management of cutaneous diseases. Special emphasis is placed on the following 4 major steps in the process: asking a clinical question taking into consideration 4 elements; finding the evidence; critically appraising the evidence; and integrating the new information into clinical expertise and judgment, in order to make the best decision in each clinical setting. PMID- 19445873 TI - [Dermatitis Caused by Hair Dye (Quinone Produced by the Action of Aqueous Hydrogen Peroxide on p-Phenylenediamine Hydrochloride), by Juan de Azua]. AB - In the first issue of Actas Dermo-Sifiliograficas, Juan de Azua published a magnificent article on contact dermatitis caused by hair dyes, which reflects his profound knowledge of allergy and how the skin responds to chemical stimuli. It gives a brilliant description of irritative and allergic dermatitis, although without naming the allergic form explicitly. Of note is how he is concerned about the composition of <>; so much so that he contacted the local laboratory to determine their chemical composition and how they work. It is a delight to study the case histories and treatments administered to these 15 patients. During the months of treatment, he reports trying different officinal formulas that, although unknown to most of today's dermatologists, nevertheless managed to cure the patients in the end. PMID- 19445874 TI - [Reactions to infliximab infusions in dermatologic patients: consensus statement and treatment protocol. Working Group of the Grupo Espanol de Psoriasis de la Academia Espanola de Dermatologia y Venereologia ]. AB - Infliximab is a chimeric monoclonal antibody that binds to and blocks tumor necrosis factor alpha and is the most effective biologic agent approved for the treatment of moderate-to-severe psoriasis. It is administered by intravenous infusion, usually in day hospitals on an outpatient basis. The main problem with the administration of infliximab is the possibility of infusion reactions, which may be immediate or delayed; these reactions are related to the immunogenicity of this monoclonal antibody, leading to the production of anti-infliximab antibodies. Infusion reactions to infliximab are not usually anaphylactic (ie, they are not mediated by immunoglobulin E), and re-exposure of the patient using specific protocols to prevent and treat these reactions is therefore possible. The extensive experience in the use of infliximab for the treatment of rheumatic conditions and chronic inflammatory bowel disease has made it possible to develop infusion reaction management protocols; these can be applied to dermatologic patients, who constitute a growing proportion of patients treated with intravenous biological agents. The aim of this review is to draw up a consensus protocol for the treatment of infusion reactions in dermatologic patients treated with infliximab. PMID- 19445876 TI - [Epidemiology of pemphigus in the Hospital Universitario Virgen Macarena, Seville, Spain, 2005-2006]. AB - BACKGROUND: Pemphigus is a serious, potentially fatal chronic autoimmune bullous disease with cutaneous and mucosal manifestations. Early diagnosis and treatment are essential. MATERIAL AND METHODS: We performed a retrospective cohort study that included patients diagnosed with pemphigus in the dermatology department of Hospital Universitario Virgen Macarena, Seville, Spain, in 2005 and 2006. We reviewed demographic, clinical, and therapeutic data. RESULTS AND CONCLUSIONS: Twenty-three patients, the majority women, were included in the study. Clinical onset usually occurred between 30 and 60 years of age. The most common variant was pemphigus vulgaris (79 %), and the sites most frequently affected were the oral mucosa, trunk, and scalp. Oral corticosteroids were the initial treatment of choice in all patients, and azathioprine and mycophenolate mofetil were given as adjuvant therapy. Complete remission was induced in 8.68 % of patients and partial remission in 91.32 %. The main complications were infections, osteopenia and osteoporosis, and cataracts. PMID- 19445875 TI - [Prolonged complete clinical remission in patients with severe pemphigus vulgaris after cycles of intravenous cyclophosphamide]. AB - BACKGROUND: Corticosteroids are the systemic treatment of choice in patients with pemphigus vulgaris, but chronic administration is associated with side effects. Intravenous treatment with cyclophosphamide can improve the clinical signs of pemphigus vulgaris. MATERIAL AND METHODS: We prospectively studied 8 patients diagnosed with pemphigus vulgaris. Six of these had mucocutaneous pemphigus vulgaris and 2 had mucosal pemphigus vulgaris. Treatment consisted of 10 cycles of cyclophosphamide at a dose of 10-15 mg/kg separated by 15 days, while maintaining the initial corticosteroid and immunosuppressant dose. Clinical efficacy was assessed and the anti-epidermal intercellular substance (EIS) and anti-desmoglein (DSG) 3 and 1 antibody titers were monitored (by indirect immunofluorescence and enzyme-linked immunosorbent assay, respectively). RESULTS: All patients with pemphigus vulgaris responded excellently to treatment. Five of the 8 patients achieved complete remission of pemphigus lesions after 10 cycles of cyclophosphamide. In the other 3 patients, the skin lesions disappeared a few weeks after the last cycle of cyclophosphamide. A substantial reduction in immuno suppressant dose was possible in all patients. Furthermore, an improved immunologic response was observed in all cases after cyclophosphamide treatment, with decreased anti-DSG1 and anti-DSG3 antibody titers and well as decreased circulating anti-EIS antibody titers. During the mean 15.1 month follow-up (range, 1-25 months), no new lesions appeared and no side effects of cyclophosphamide therapy were reported. CONCLUSIONS: Fortnightly cycles of intravenous cyclophosphamide may be a useful therapeutic option in patients with severe pemphigus vulgaris. A reduction of corticosteroid dose was possible with this therapeutic approach and the cumulative cyclophosphamide dose was lower than with daily oral administration. Our findings also show that the therapeutic approach induces clinical and immunologic remission in most patients. PMID- 19445877 TI - [Cutaneous granular cell tumor: a clinical and pathologic analysis of 34 cases]. AB - BACKGROUND: Granular cell tumor (GCT), also known as Abrikossoff tumor, is an uncommon benign neoplasm, probably of neural origin derived from Schwann cells. It presents clinically as a solitary asymptomatic nodule and its pathogenesis has been the subject of much debate in the literature. OBJECTIVES: We aimed to analyze the clinical, histologic, and immunohistochemical characteristics associated with this tumor and to determine whether these findings correspond to those reported to date in the literature. METHODS: In this retrospective study of 34 patients with histologic diagnosis of GCT, we analyzed clinical characteristics (site, age, sex, duration, and suspected diagnosis), histological findings (border, cell atypia and mitoses, involvement of adnexal structures, pseudoepitheliomatous hyperplasia, and presence of the recently described pustulo ovoid bodies), and immunohistochemical findings (S-100 staining in 16 randomly selected cases). RESULTS: In total, 58.82 % were men and 41.18 % were women, and the mean age was 31.74 years. The most common site was the oral cavity (61.76 %). The most frequently suspected clinical diagnosis was fibroma (17.65 %). The lesion was poorly defined and diffuse in 85.29 %. Pseudoepitheliomatous hyperplasia was present in 58.82 %. Nuclear atypia was found in 29.41 % and mitoses in 20.59 %. One case was considered malignant (2.94 %) and 2 atypical (5.88 %). Pustulo-ovoid bodies were present in 47.06 % of the cases and S-100 staining was positive in all cases analyzed. CONCLUSIONS: Our series confirms the characteristics described previously for GCT, except for certain peculiarities, and supports the presence of pustulo-ovoid bodies as an additional histologic finding for diagnosis of this tumor. PMID- 19445878 TI - [Dermoscopic features of eccrine poroma]. AB - Eccrine poroma is a benign adnexal neoplasm that clinically may mimic malignant skin tumors such as squamous cell carcinoma and amelanotic melanoma. The dermoscopic features of pigmented and nonpigmented eccrine poroma have recently been described. We present 2 cases of eccrine poroma, with their dermoscopic features. The lesions were characterized by multiple red lacunes and a polymorphous vascular pattern in both cases. Dermoscopy can improve the clinical diagnosis of this benign adnexal skin tumor. PMID- 19445879 TI - [Proliferative cutaneous epithelioid angiomatous nodule]. AB - The cutaneous epithelioid angiomatous nodule is an uncommon benign vascular proliferation that has only recently been described. Clinically, it usually presents as a solitary, fast-growing, small reddish papulous or nodular lesion on the trunk or limbs of adults. Histopathologic study reveals a proliferation of epithelioid cells and predominantly solid, well delimited, unilobular growth in the superficial dermis. Well defined vessels are often found permeating the lesion, which also shows a certain degree of inflammatory infiltration. The cells contain abundant pink cytoplasm, often with vacuoles, and vesicular nuclei with prominent nucleoli. The morphology of these cells is relatively uniform, without atypia or pleomorphism, although mitoses are not uncommon. We report 2 new cases of cutaneous epithelioid angiomatous nodules, the first in a 28-year-old pregnant woman and the second in a 27-year-old man. In both cases, the usual characteristics of this entity were present, but with the peculiarity of a high mitotic index. We discuss the differential diagnosis of cutaneous epithelioid angiomatous nodules with other vascular proliferations that exhibit epithelioid cytology. PMID- 19445880 TI - [Methotrexate-associated lymphoproliferative disorder presenting as oral ulcers in a patient with rheumatoid arthritis]. AB - Methotrexate-associated lymphoproliferative disorders are a heterogeneous group of lymphoid proliferations or lymphomas that develop in patients with autoimmune diseases treated using methotrexate. These lymphoproliferative disorders are often associated with Epstein-Barr virus infection and occasionally regress after the withdrawal of methotrexate therapy. The lymphoproliferative disorder in this case was diffuse large B-cell lymphoma, unusually presenting as oral ulcers in a 79-year-old woman on treatment with methotrexate for longstanding rheumatoid arthritis. Latent membrane protein 1 positivity was detected by immunohistochemistry and Epstein-Barr-virus encoded small RNA positivity by chromogenic in situ hybridization. Clonality was confirmed by immunohistochemistry (kappa light-chain restriction), polymerase chain reaction (monoclonal immunoglobulin H gene rearrangement), and capillary electrophoresis (GeneScan). Staging procedures were negative. Withdrawal of methotrexate therapy led to complete remission within 6 weeks, and the patient is alive and disease free 18 months after the diagnosis was made. The oral cavity is not often involved in the initial presentation of methotrexate-associated lymphoproliferative disorders, and presentation with intraoral ulcers is very rare. We have performed a review of the literature on methotrexate-associated lymphoproliferative disorders presenting as ulcers in the oral cavity. PMID- 19445881 TI - [Multiple acrokeratotic papules]. PMID- 19445882 TI - [Asymptomatic facial papules]. PMID- 19445883 TI - [Merkel cell carcinoma of the breast]. PMID- 19445884 TI - [Moluscum contagiosum over a tattoo]. PMID- 19445885 TI - [Burning mouth syndrome and alpha-lipoic acid]. PMID- 19445886 TI - [Blaschkoid, zosteriform linear lichen sclerosus et atrophicus]. PMID- 19445887 TI - [Hyperkeratosis lenticularis perstans, or Flegel disease, with palmoplantar involvement]. PMID- 19445888 TI - [Verrucous carcinoma of the face: a report of 2 cases]. PMID- 19445894 TI - Modeling the spatio-temporal network that drives patterning in the vertebrate central nervous system. AB - In this review, we discuss the gene regulatory network underlying the patterning of the ventral neural tube during vertebrate embryogenesis. The neural tube is partitioned into domains of distinct cell fates by inductive signals along both anterior-posterior and dorsal-ventral axes. A defining feature of the dorsal ventral patterning is the graded distribution of Sonic hedgehog (Shh), which acts as a morphogen to specify several classes of ventral neurons in a concentration dependent fashion. These inductive signals translate into patterned expressions of transcription factors that define different neural progenitor subtypes. Progenitor boundaries are sharpened by repressive interactions between these transcription factors. The progenitor-expressed transcription factors induce another set of transcription factors that are thought to contribute to neural identities in post-mitotic neural precursors. Thus, the gene regulatory network of the ventral neural tube patterning is characterized by hierarchical expression [inductive signal-->progenitor specifying factors (mitotic)--> precursor specifying factors (post mitotic)--> differentiated neural markers] and cross repression between progenitor-expressed regulatory factors. Although a number of transcriptional regulators have been identified at each hierarchical level, their precise regulatory relationships are not clear. Here we discuss approaches aimed at clarifying and extending our understanding of the formation and propagation of this network. PMID- 19445889 TI - Functional impairment of PRRSV-specific peripheral CD3+CD8high cells. AB - The replication of porcine reproductive and respiratory syndrome virus (PRRSV) in lungs and lymphoid tissues of PRRSV-infected pigs is already strongly reduced before the appearance of neutralizing antibodies, indicating that other immune mechanisms are involved in eliminating PRRSV at those sites. This study aimed to determine whether PRRSV Lelystad virus (LV)-specific cytotoxic T-lymphocytes (CTL) can efficiently eliminate PRRSV-infected alveolar macrophages. Therefore, CTL assays were performed with PRRSV-infected alveolar macrophages as target cells and autologous peripheral blood mononuclear cells (PBMC) from PRRSV infected pigs as a source of PRRSV-specific CTL. PBMC of 3 PRRSV-infected pigs were used either directly in CTL assays, or following restimulation in vitro. CTL assays with pseudorabies virus (PRV) Begonia-infected alveolar macrophages and autologous PBMC, from 2 PRV Begonia-inoculated pigs, were performed for validation of the assays. In freshly isolated PBMC, derived from PRRSV-infected pigs, CTL activity towards PRRSV-infected macrophages was not detected until the end of the experiment (56 days post infection-dpi). Restimulating the PBMC with PRRSV in vitro resulted in proliferation of CD3+CD8high cells starting from 14 dpi. Although CD+CD8high cells are generally considered to be CTL, CTL activity was not detected in PRRSV-restimulated PBMC of the 3 pigs until 49 dpi. A weak PRRSV-specific CTL activity was observed only at 56 dpi in PRRSV-restimulated PBMC of one pig. In contrast, a clear CTL activity was observed in PRV Begonia restimulated PBMC, derived from PRV Begonia-infected pigs, starting from 21 dpi. This study indicates that PBMC of PRRSV-infected pigs contain proliferating CD3+CD8high cells upon restimulation in vitro, but these PBMC fail to exert CTL activity towards PRRSV-infected alveolar macrophages. PMID- 19445895 TI - Nutritional stress of adult female tsetse flies (Diptera: Glossinidae) affects the susceptibility of their offspring to trypanosomal infections. AB - The epidemiology of tsetse-transmitted trypanosomiasis depends, among other factors, on the proportion of infected flies in a tsetse population. A wide range of intrinsic and extrinsic factors seem to determine the ability of a tsetse fly to become infected and to transmit the parasite. In this paper, we investigated the effect of nutritional stress of reproducing female Glossina morsitans morsitans on the susceptibility of their offspring to trypanosomal infections. Adult female flies that were nutritionally stressed by feeding only once a week, produced pupae with a significant lower weight and offspring with a significant lower fat content as well as a lower baseline immune peptide gene expression. Moreover, infection experiments showed that the emerging teneral flies were significantly more susceptible to a Trypanosoma congolense or Trypanosoma brucei brucei infection than flies emerging from non-starved adult females. These findings suggest that in the field, substantial nutritional stress of adult tsetse flies, as is often experienced during the hot dry season, can increase significantly the vectorial capacity of the emerging teneral flies and thus result in an increased infection rate of the tsetse population. PMID- 19445896 TI - Electrostatics of the FeS clusters in respiratory complex I. AB - Respiratory complex I couples the transfer of electrons from NADH to ubiquinone and the translocation of protons across the mitochondrial membrane. A detailed understanding of the midpoint reduction potentials (E(m)) of each redox center and the factors which influence those potentials are critical in the elucidation of the mechanism of electron transfer in this enzyme. We present accurate electrostatic interaction energies for the iron-sulfur (FeS) clusters of complex I to facilitate the development of models and the interpretation of experiments in connection to electron transfer (ET) in this enzyme. To calculate redox titration curves for the FeS clusters it is necessary to include interactions between clusters, which in turn can be used to refine E(m) values and validate spectroscopic assignments of each cluster. Calculated titration curves for clusters N4, N5, and N6a are discussed. Furthermore, we present some initial findings on the electrostatics of the redox centers of complex I under the influence of externally applied membrane potentials. A means of determining the location of the FeS cofactors within the holo-complex based on electrostatic arguments is proposed. A simple electrostatic model of the protein/membrane system is examined to illustrate the viability of our hypothesis. PMID- 19445897 TI - Role of FOXA in mitochondrial citrate carrier gene expression and insulin secretion. AB - In this study, we have investigated the transcriptional role of the FOXA site present in the promoter of the mitochondrial citrate carrier (CIC) gene. We have shown that wild-type (but not mutated) CIC FOXA site cloned in front of the luciferase promoter confers transcriptional activation of the gene reporter, particularly in cells overexpressing FOXA1. We have also demonstrated that overexpression and silencing of FOXA increases and reduces CIC transcript and protein levels, respectively. In addition, FOXA1 silencing in INS-1 cells decreases not only CIC mRNA and protein but also the amount of citrate in the cytosol and glucose-stimulated insulin secretion. These results show that FOXA plays a role in the transcriptional regulation of CIC and in insulin secretion. PMID- 19445898 TI - Ginsenoside Rh2 induces ligand-independent Fas activation via lipid raft disruption. AB - Lipid rafts are plasma membrane platforms mediating signal transduction pathways for cellular proliferation, differentiation and apoptosis. Here, we show that membrane fluidity was increased in HeLa cells following treatment with ginsenoside Rh2 (Rh2), as determined by cell staining with carboxy-laurdan (C laurdan), a two-photon dye designed for measuring membrane hydrophobicity. In the presence of Rh2, caveolin-1 appeared in non-raft fractions after sucrose gradient ultracentrifugation. In addition, caveolin-1 and GM1, lipid raft landmarkers, were internalized within cells after exposure to Rh2, indicating that Rh2 might disrupt lipid rafts. Since cholesterol overloading, which fortifies lipid rafts, prevented an increase in Rh2-induced membrane fluidity, caveolin-1 internalization and apoptosis, lipid rafts appear to be essential for Rh2-induced apoptosis. Moreover, Rh2-induced Fas oligomerization was abolished following cholesterol overloading, and Rh2-induced apoptosis was inhibited following treatment with siRNA for Fas. This result suggests that Rh2 is a novel lipid raft disruptor leading to Fas oligomerization and apoptosis. PMID- 19445899 TI - Implication of human OCT4 transactivation domains for self-regulatory transcription. AB - OCT4 plays a crucial role in pluripotency and self-renewal of embryonic stem cells. OCT4 is also expressed in testicular germ cell tumors (GCTs), suggesting the important function of OCT4 as an oncogenic factor in GCTs. To understand the molecular mechanism of human OCT4 (hOCT4) in tumorigenesis as well as stemness, we identified hOCT4 transactivation domains in human embryonic carcinoma cells. Context analyses of heterologous GAL4 and natural hOCT4 revealed that each N terminal domain or C-terminal domain independently stimulated transcriptional activity, and that both domains are required for synergistic transactivation by deletion mapping analysis. Dose-dependent overexpression of exogenous hOCT4 significantly decreased the transcriptional activity of the hOCT4 promoter. This inhibition was reversed by the removal of one or both domains. These results suggest that the inhibitory effect of hOCT4 is mediated by transactivation domains, and that the self-regulation of hOCT4 may be mediated via a negative feedback loop in pluripotent cells. PMID- 19445900 TI - The inhibition of TNF-alpha-induced NF-kappaB activation by marine natural products. AB - The deregulated activation of NF-kappaB is associated with cancer development and inflammatory diseases. With an aim to find new NF-kappaB inhibitors, we purified and characterized compounds from extracts of the Fijian sponge Rhabdastrella globostellata, the crinoid Comanthus parvicirrus, the soft corals Sarcophyton sp. nov. and Sinularia sp., and the gorgonian Subergorgia sp. after an initial screening of 266 extracts from different marine origins. Results obtained show that selected purified compounds had a cytotoxic effect on the human leukaemia cell line K562, inhibited both TNF-alpha-induced NF-kappaB-DNA binding as well as TNF-alpha-induced IkappaBalpha degradation and nuclear translocation of p50/p65. Furthermore, we observed the inhibition of NF-kappaB activation induced by an overexpression of IKKbeta. Interestingly, natural products inhibited IKKbeta kinase as well as the 26S proteasome proteolytic activity. PMID- 19445901 TI - A novel delta-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells. AB - In this study, we investigated the anti-tumor activity of KBH-A42 [N-hydroxy-3-(2 oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a novel synthetic histone deacetylase (HDAC) inhibitor. KBH-A42 inhibited a variety of HDAC isoforms in enzyme assays and suppressed growth of various cancer cell lines. Among the cell lines examined, colon cancer cells, including SW620, SW480 and HCT-15, were the cell types most sensitive to KBH-A42. KBH-A42 inhibition of cancer cell growth was comparable to or stronger than that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor approved by the FDA to treat cutaneous T cell lymphomas. In SW620 cells, KBH-A42 increased the acetylation of histones, mediated cell cycle arrest (G1 arrest at low doses and G2 arrest at high doses), and induced apoptosis. The cell cycle arrest and apoptosis induced by KBH-A42 might be mediated through up-regulation of p21(Waf1) and activation of caspases, respectively. In addition, KBH-A42 inhibited SW620 tumor growth in a human tumor xenograft model. Taken together, our results indicate that KBH-A42 exerts an anti-tumor activity in vitro and in vivo and is a promising therapeutic candidate to treat human cancers. PMID- 19445902 TI - Effects of CYP2D6 status on harmaline metabolism, pharmacokinetics and pharmacodynamics, and a pharmacogenetics-based pharmacokinetic model. AB - Harmaline is a beta-carboline alkaloid showing neuroprotective and neurotoxic properties. Our recent studies have revealed an important role for cytochrome P450 2D6 (CYP2D6) in harmaline O-demethylation. This study, therefore, aimed to delineate the effects of CYP2D6 phenotype/genotype on harmaline metabolism, pharmacokinetics (PK) and pharmacodynamics (PD), and to develop a pharmacogenetics mechanism-based compartmental PK model. In vitro kinetic studies on metabolite formation in human CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) hepatocytes indicated that harmaline O-demethylase activity (V(max)/K(m)) was about 9-fold higher in EM hepatocytes. Substrate depletion showed mono-exponential decay trait, and estimated in vitro harmaline clearance (CL(int), microL/min/10(6)cells) was significantly lower in PM hepatocytes (28.5) than EM hepatocytes (71.1). In vivo studies in CYP2D6-humanized and wild-type mouse models showed that wild-type mice were subjected to higher and longer exposure to harmaline (5 and 15mg/kg; i.v. and i.p.), and more severe hypothermic responses. The PK/PD data were nicely described by our pharmacogenetics-based PK model involving the clearance of drug by CYP2D6 (CL(CYP2D6)) and other mechanisms (CL(other)), and an indirect response PD model, respectively. Wild-type mice were also more sensitive to harmaline in marble-burying tests, as manifested by significantly lower ED(50) and steeper Hill slope. These findings suggest that distinct CYP2D6 status may cause considerable variations in harmaline metabolism, PK and PD. In addition, the pharmacogenetics-based PK model may be extended to define PK difference caused by other polymorphic drug-metabolizing enzyme in different populations. PMID- 19445903 TI - The development of glucose intolerance after focal cerebral ischemia participates in subsequent neuronal damage. AB - Hyperglycemia is a known exacerbating factor in ischemic stroke; however, most information is limited to pre-ischemic hyperglycemia, while little is known about post-ischemic hyperglycemia. In addition, it has been clinically reported that hyperglycemia can develop after stroke, but the detailed mechanisms underlying this are unknown. Here, we focused on the relationship between post-ischemic hyperglycemia and the development of neuronal damage. In particular, we investigated the time course of alterations in fasting blood glucose levels (FBG) and the development of neuronal damage, including neuronal death (the development of infarction), behavioral abnormality and memory disturbance, using middle cerebral artery occlusion (MCAO) model mice. The neuronal death was observed from 6 h, reaching a maximum on day 3 and was gradually aggravated up to day 5 after MCAO. Interestingly, 12 h and 1 day after MCAO, FBG was significantly increased and insulin sensitivity and insulin secretory capacity were decreased on 1 day after MCAO. In addition, we found that the basal plasma insulin levels were significantly higher and adiponectin levels were significantly lower on day 1 in the MCAO group compared with the sham group. These results indicate that the development of glucose intolerance was observed on day 1. Importantly, the neuronal damage observed on day 3 was completely suppressed by continuous administration of insulin during the first 48 h after MCAO. These results suggest that the post-ischemic hyperglycemia in the early phase of ischemic stress may be involved in the development of neuronal damage. PMID- 19445904 TI - Involvement of glyceraldehyde-3-phosphate dehydrogenase in rotenone-induced cell apoptosis: relevance to protein misfolding and aggregation. AB - The hallmarks of Parkinson's disease (PD) are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intracellular inclusion bodies in surviving neurons. Although the specific etiology and pathogenesis of sporadic PD remains unknown, neuronal death was proven to be associated with mitochondrial dysfunction and protein misfolding. However, molecular links between mitochondrial dysfunction and protein misfolding remains obscure. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a classical glycolytic enzyme, is responsible for carbohydrate metabolism under normal circumstances. When translocated to the nucleus, GAPDH promotes neuron apoptosis in several neurodegenerative disorders. But it seems that GAPDH translocation is not the sole mechanism responsible for neuronal apoptosis. We found that rotenone, a common mitochondrial complex I inhibitor used to produce experimental parkinsonism, cannot only induce GAPDH translocation but also trigger intermolecular disulfide bonding and result in the formation of intracytoplasmic aggregates of GAPDH. This suggests a link between mitochondrial dysfunction and protein misfolding, and sheds light on the pathophysiology of Lewy body formation in Parkinson's disease. PMID- 19445905 TI - Alteration of the glycocalyx of two blood-brain barrier mimicking cell lines is inducible by glioma conditioned media. AB - Recent studies showed that glioma conditioned medium is able to induce blood brain barrier properties in in vitro models. In this regard, it was investigated whether glioma conditioned medium can also influence the lectin-binding capacity of blood-brain barrier in vitro models. For the presented study cell lines PBMEC/C1-2 and ECV304 were chosen because it was previously shown that glioma conditioned medium was able to induce specific blood-brain barrier properties in these cell lines. Six different plant lectins (WGA, STL, LCA, UEA-I, DBA, PNA) with distinct sugar specificities were applied in order to elucidate the glycosylation patterns of cell line PBMEC/C1-2 and ECV304. Lectin-binding studies were carried out with monolayers as well as with single cells. In the case of PBMEC/C1-2 monolayers, results showed a significant increase of the binding of lectins WGA, STL, UEA-I, DBA and PNA after application of 25 pmol lectin when cultured in media containing soluble factors derived from glioma cell line C6, whereas the binding capacity for LCA remained similar. For ECV304 monolayers, a significant decrease of WGA, STL and LCA was observable, whereas UEA-I binding increased in comparison to cells grown in the corresponding basal growth medium without soluble C6 factors. Single cell studies showed less significant, but similar changes in the lectin-interactions with the cell surfaces. In conclusion, it was shown that soluble factors derived from glioma cell line C6 can modulate the "glycocalyx" of blood-brain barrier mimicking cell lines. PMID- 19445906 TI - Impaired glial buffering hampers antidromic conduction of CA1 neurons during hypoxia. AB - Increased potassium conductance during hypoxia causes membrane hyperpolarization and a resultant increase in extracellular potassium concentration ([K(+)](o)). In addition, glial buffering of [K(+)](o) is the key mechanism for clearing excess K(+) and is important for neuronal function and survival. Here, we studied the effect of glial buffering of [K(+)](o) on neural impulse conduction during hypoxia using a potassium-selective electrode and evoked potential recording in rat hippocampal slices. The increase in [K(+)](o) during hypoxia was modest and there were no significant differences between the layers. The [K(+)](o) during hypoxia was significantly elevated by addition of barium (1 mM), especially in the stratum pyramidale and stratum oriens. Although synaptic transmission was depressed during hypoxia, the presynaptic volley and antidromic population spike mostly remained unchanged. With the addition of barium, antidromic conduction was more profoundly affected than the presynaptic volley. When presynaptic inhibition was precluded by including a selective A1 adenosine receptor blocker to restore synaptic transmission, blockade of the antidromic conduction became more evident compared with the blockade of other recorded field potentials. These findings are compatible with regional differences in the increase of [K(+)](o) and suggest that glial buffering of high [K(+)](o) is important in antidromic conduction during hypoxia. PMID- 19445907 TI - Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. AB - BACKGROUND: Oxidative and cytotoxic damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Curcumin is proved to elicit a vanity of biological effects through its antioxidant and anti inflammatory properties. But the mechanisms underlying are poorly understood. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. This study evaluated the time course expression regularity of Nrf2, HO-1 and the curcumin's role in cerebral ischemia and its potential mechanism. METHODS: Male, Sprague Dawley rats were subjected to permanent focal cerebral ischemia by right MCA occlusion. Experiment 1 was used to evaluate the expression of Nrf2 and HO-1 in the cerebral ischemia, 6 time points was included. Experiment 2 was used to detect curcumin's neuroprotection in cerebral ischemia. At 24 h neurological deficit was evaluated using a modified six point scale; brain water content was measured; infarct size was analysed with 2, 3, 5-triphenyltetrazolium chloride (TTC). Immunohistochemistry, RT-PCR, Western blot, and confocal microscope were used to analyse the expression of Nrf2 and HO-1. RESULTS: Compared with sham operated, Nrf2 and HO-1 were upregulated at gene and protein level in ischemic brain, beginning at 3 h and peaking at 24 h after MCAO (P<0.05). Curcumin high dose (100 mg/kg) upregulated Nrf2 and HO-1 in MCAO-affected brain tissue and reduced infarct volume (P<0.05), brain water content (P<0.05) and behavioral deficits (P<0.05) caused by MCAO. CONCLUSIONS: Nrf2 and HO-1 were induced at the early stage after MCAO. Curcumin protected the brain from damage caused by MCAO, this effect may be through upregulation of the transcription factor Nrf2 expression. Nrf2 may be one of the strategic targets for cerebral ischemic therapies. PMID- 19445908 TI - PDE9A, PDE10A, and PDE11A expression in rat trigeminovascular pain signalling system. AB - Activation of the trigeminovascular pain signalling system, including cerebral arteries, meninges, trigeminal ganglion, and brain stem, is involved in migraine. Furthermore, stimulation of cyclic nucleotide (cAMP and cGMP) production as well as inhibition of phosphodiesterases (PDEs) induces headache and migraine. In order to investigate the possible role of PDE in the pain pathway of migraine, expression of the most recently discovered PDE subtypes (9A, 10A and 11A) in cerebral arteries, dura mater, and trigeminal ganglion and nucleus was examined. The presence of mRNA and protein in the middle cerebral artery, basilar artery, meninges, trigeminal ganglion, and spinal trigeminal nucleus of male Sprague Dawley rats were investigated using real-time PCR, Western blot, and immunohistochemistry. The results were compared to two peripheral arteries: aorta and mesenteric artery, as well as neocortex and cerebellar cortex. Real-time PCR and Western blotting showed that PDE9A, PDE10A and PDE11A are expressed in components of the rat trigeminovascular pain signalling system including middle cerebral artery, basilar artery, meninges, trigeminal ganglion and spinal trigeminal nucleus. Aorta and mesenteric artery as well as cerebral neocortex and cerebellar cortex also showed expression of PDE9A, PDE10A and PDE11A. Immunohistochemistry revealed that PDE9A, PDE10A and PDE11A are localised in the cytosol of nerve cell bodies of the trigeminal ganglion. We here present, for the first time, the expression of PDE9A, PDE10A, and PDE11A in the trigeminovascular system. The functional implications are yet unknown, but their localisation indicates that they may have a role in the pain pathway of migraine as well as trigeminal neuralgia and trigeminal autonomic cephalalgias. PMID- 19445909 TI - Estradiol impairs hypothalamic molecular responses to hypoglycemia. AB - In rats and humans estradiol attenuates neuroendocrine responses to hypoglycemia. Since neuroendocrine responses to hypoglycemia are mediated by hypothalamic neurons, we assessed if estradiol attenuates hypoglycemia-induced gene expression in the hypothalamus in female ovariectomized mice. As expected, estradiol implanted ovariectomized mice exhibited increased plasma estradiol, increased uterine weight, decreased body weight, decreased visceral adiposity, and enhanced glucose tolerance with decreased plasma insulin. Estradiol-implanted mice exhibited attenuated hypoglycemia-induced gene expression of both glucose transporter 1 (Glut1) and inhibitor of kappa beta signaling (IkappaB) in the hypothalamus but not in the liver. Estradiol also attenuated hypoglycemia-induced plasma glucagon, pituitary proopiomelanocortin (POMC), and adrenal c-fos, consistent with impaired counterregulatory responses to hypoglycemia. In addition, estradiol inhibited hypothalamic expression of carnitine palmitoyltransferase (CPT1a and CPT1c) and pyruvate dehydrogenase kinase 4 (PDK4), effects that would be expected to enhance the accumulation of long-chain fatty acids and glycolysis. Taken together, these findings suggest hypothalamic mechanisms mediating attenuation of hypoglycemia-induced neuroendocrine responses. PMID- 19445910 TI - Chronic electrical stimulation of the contralesional lateral cerebellar nucleus enhances recovery of motor function after cerebral ischemia in rats. AB - Novel neurorehabilitative strategies are needed to improve motor outcomes following stroke. Based on the disynaptic excitatory projections of the dentatothalamocortical pathway to the motor cortex as well as to anterior and posterior cortical areas, we hypothesize that chronic electrical stimulation of the contralesional dentate (lateral cerebellar) nucleus output can enhance motor recovery after ischemia via augmentation of perilesional cortical excitability. Seventy-five Wistar rats were pre-trained in the Montoya staircase task and subsequently underwent left cerebral ischemia with the 3-vessel occlusion model. All survivors underwent stereotactic right lateral cerebellar nucleus (LCN) implantation of bipolar electrodes. Rats were then randomized to 4 groups: LCN stimulation at 10 pps, 20 pps, 50 pps or sham stimulation, which was delivered for a period of 6 weeks. Performance on the Montoya staircase task was re assessed over the last 4 weeks of the stimulation period. On the right (contralesional) side, motor performance of the groups undergoing sham, 10 pps, 20 pps and 50 pps stimulation was, respectively, 2.5+/-2.7; 2.1+/-2.5; 6.0+/-3.9 (p<0.01) and 4.5+/-3.5 pellets. There was no difference on the left (ipsilesional) side motor performance among the sham or stimulation groups, varying from 15.9+/-6.7 to 17.2+/-2.1 pellets. We conclude that contralesional chronic electrical stimulation of the lateral cerebellar nucleus at 20 pps but not at 10 or 50 pps improves motor recovery in rats following ischemic strokes. This effect is likely to be mediated by increased perilesional cortical excitability via chronic activation of the dentatothalamocortical pathway. PMID- 19445911 TI - A fast modified protocol for random-access ultra-high density whole-genome scan: a tool for personalized genomic medicine, positional mapping, and cytogenetic analysis. AB - BACKGROUND: High density single nucleotide polymorphism (SNP) genotyping array is widely applied on genome-wide association study of common diseases. In these studies, a fixed batch-size of 48 or 96 samples allows high-throughput analysis. To enhance the clinical application of microarray analysis on personalized medicine, we describe a modified PCR purification protocol without batch-size limitation for whole-genome scan using ultra-high density SNP microarray. METHODS: Enzyme-digested PCR products were purified with the use of magnetic beads. Separation of the magnetic particles applies magnetic stand devices instead of vacuum pumps. With no batch-size limitation, we genotyped 17 genomic samples and 3 whole genome amplified samples in order to examine the performance of the modified protocol. RESULTS: Our method is simple and fast, provides sufficient amount and high quality PCR products for subsequent fragmentation and labeling procedures prior to GeneChip hybridization. We show that the purified DNA can be genotyped with good QC call rate of >93% in average similar to standard protocol. With the use of the short protocol, we successfully identified the breakpoint localization of a ring chromosome in a female and located the disease gene in a consanguineous family affected by limb-girdle muscular dystrophy. CONCLUSION: By modifying a single step in the original protocol, we are able to speed up the overall genotyping analysis and change the batch-wise analysis to random-access analysis for ultra-high density whole-genome scan for personalized medicine, positional mapping, and cytogenetic analysis. PMID- 19445912 TI - Does the Macroduct collection system reliably define sweat chloride concentration in subjects with intermediate results? AB - OBJECTIVES: The sweat test remains the current diagnostic gold standard for CF disease. Many CF testing centres have switched from the Gibson and Cooke to the Macroduct. Since the validity and sensitivity of Macroduct has not been tested in patients with intermediate sweat chloride concentrations, we compared both methods simultaneously including subjects expected to have intermediate results. DESIGN AND METHODS: We prospectively evaluated controls, obligate heterozygotes, patients with CF and with an uncertain diagnosis of CF (congenital absence of the vas deferens, pancreatitis and sinopulmonary disease). RESULTS: We assessed 82 subjects (3.7-60.1 years); 14 healthy controls, 7 obligate heterozygotes, 20 CF (15 pancreatic insufficient, 5 pancreatic sufficient), and 41 with unproven diagnosis. Mean test difference was close to 0 (95% CI+/-20 mmol/L) and test values were highly correlated (r=0.93, p < or =0.0001). Discrepancies between the two testing methods occurred in 22% of subjects. CONCLUSION: Sweat chloride measured by Macroduct highly correlates with Gibson and Cooke for concentrations in all ranges, including the intermediate range. This study reveals the limitations of sweat testing for excluding a diagnosis of CF since 38% of subjects had intermediate range results. PMID- 19445913 TI - An episode of increased hemolysis due to a defective pneumatic air tube delivery system. AB - OBJECTIVES: To study an episode of excessive sample hemolysis associated with a recently installed pneumatic tube system from the Accident and Emergency Department. DESIGN AND METHODS: Hemolysis rates in samples delivered with a tube system installed 3-4 months previously were followed up retrospectively and prospectively. The laboratory database was searched over a 3-year period for serum potassium results and the number of hemolyzed samples rejected that had been delivered by pneumatic tube or by hand. RESULTS: Before the tube system was installed, the weekly mean hemolysis rate was 3.3%. After installation, the rate was 10.9% for 12 weeks but then it increased to 54%. After a fault was corrected, values fell to 9.0% and to 7.1% after samples were bubble-wrapped. Other wards served as controls. CONCLUSION: Laboratories should be aware that defects may arise in tube systems that may result in rapid sample deceleration and excessive hemolysis. PMID- 19445914 TI - Concurrent decline of several antioxidants and markers of oxidative stress during combination chemotherapy for small cell lung cancer. AB - OBJECTIVES: To investigate the oxidant effects of adriamycin-containing chemotherapy (CT), we evaluated various antioxidants, total antioxidant capacity (TRAP) and different parameters of oxidative and nitrosative stress during combination CT. DESIGN AND METHODS: Blood samples were obtained from 16 small cell lung cancer patients at baseline and several times during the first, second and sixth CT cycles. RESULTS: There were significant decreases in serum urate and serum proteins during all cycles, serum TRAP during the first two cycles, plasma ascorbic acid and serum TBARS during the first cycle, and serum conjugated dienes and plasma alphatocopherol during the last cycle. The baseline levels of tocopherols increased significantly between the first and sixth CT cycles. Higher levels of baseline plasma thiols were associated with better overall survival (p=0.008). CONCLUSIONS: Adriamycin-containing CT causes significant oxidative stress as implied by reduced levels of protective antioxidants. Long-term CT treatment seems to enhance lipid peroxidation. PMID- 19445915 TI - The timing of emergence of muscle progenitors is controlled by an FGF/ERK/SNAIL1 pathway. AB - In amniotes, the dermomyotome is the source of all skeletal muscles of the trunk and the limbs. Trunk skeletal muscles form in two sequential stages: in the first stage, cells located at the four borders of the epithelial dermomyotome delaminate to generate the primary myotome, composed of post-mitotic, mononucleated myocytes. The epithelio-mesenchymal transition (EMT) of the central dermomyotome initiates the second stage of muscle formation, characterised by a massive entry of mitotic muscle progenitors from the central region of the dermomyotome into the primary myotome. The signals that regulate the timing of the dermomyotome EMT are unknown. Here, we propose that this process is regulated by an FGF signal emanating from the primary myotome, a known source of FGF. The over-expression of FGF results in a precocious EMT of the dermomyotome, while on the contrary, the inhibition of FGF signalling by the electoporation of a dominant-negative form of FGFR4 delays this process. Within the dermomyotome, FGF signalling triggers a MAPK/ERK pathway that leads to the activation of the transcription factor Snail1, a known regulator of EMT in a number of cellular contexts. The activation or the inhibition of the MAPK/ERK pathway and of Snail1 mimics that of FGF signalling and leads to an early or delayed EMT of the dermomyotome, respectively. Altogether, our results indicate that in amniotes, the primary myotome is an organizing center that regulates the timely entry of embryonic muscle progenitors within the muscle masses, thus initiating the growth phase of the trunk skeletal muscles. PMID- 19445916 TI - Maintenance of blastemal proliferation by functionally diverse epidermis in regenerating zebrafish fins. AB - Appendage regeneration in salamanders and fish occurs through formation and maintenance of a mass of progenitor tissue called the blastema. A dedicated epidermis overlays the blastema and is required for its proliferation and patterning, yet this interaction is poorly understood. Here, we identified molecularly and functionally distinct compartments within the basal epidermal layer during zebrafish fin regeneration. Proximal epidermal subtypes express the transcription factor lef1 and the blastemal mitogen shh, while distal subtypes express the Fgf target gene pea3 and wnt5b, an inhibitor of blastemal proliferation. Ectopic overexpression of wnt5b reduced shh expression, while pharmacologic introduction of a Hh pathway agonist partially rescued blastemal proliferation during wnt5b overexpression. Loss- and gain-of-function approaches indicate that Fgf signaling promotes shh expression in proximal epidermis, while Fgf/Ras signaling restricts shh expression from distal epidermis through induction of pea3 expression and maintenance of wnt5b. Thus, the fin wound epidermis spatially confines Hh signaling through the activity of Fgf and Wnt pathways, impacting blastemal proliferation during regenerative outgrowth. PMID- 19445917 TI - Involvement of afferent neurons in the pathogenesis of endotoxin-induced ileus in mice: role of CGRP and TRPV1 receptors. AB - Activation of neuronal reflex pathways by inflammatory mediators is postulated as an important pathogenic mechanism in postoperative ileus. In this study, we investigated the involvement of afferent neurons and more specifically the role of the transient receptor potential vanilloid receptor type 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in endotoxin-induced motility disturbances in mice. Mice were injected with either lipopolysaccharides (LPS) or saline (control) and pre-treated with hexamethonium (blocker of neuronal transmission), capsaicin (neurotoxin), CGRP 8-37 (CGRP antagonist) or BCTC (TRPV1 receptor antagonist). We measured gastric emptying and intestinal transit of Evans blue next to rectal temperature and a global sickness behaviour scale. In vehicle treated mice, LPS significantly delayed gastric emptying, small intestinal transit and rectal temperature while the sickness behaviour scale was increased. Hexamethonium, capsaicin, CGRP8-37 and BCTC all reversed the endotoxin-induced delay in gastric emptying and significantly reduced the delay in intestinal transit without effect on the endotoxin-induced decrease in rectal temperature and increase in sickness behaviour scale. Our findings provide evidence for the involvement of afferent nerves in the pathogenesis of endotoxin-induced motility disturbances in mice mediated via CGRP and TRPV1 receptors. Blockade of CGRP and TRPV1 receptors may offer a novel strategy for the treatment of endotoxin-induced ileus. PMID- 19445918 TI - Zinc prevents indomethacin-induced renal damage in rats by ameliorating oxidative stress and mitochondrial dysfunction. AB - The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs) is limited by their gastrointestinal and renal toxicities. Indomethacin (an NSAID commonly used in toxicity studies) has been shown to induce significant oxidative stress and mitochondrial dysfunction in the rat kidney. The current study was designed to assess the potential of zinc, a known antioxidant, to protect the kidney against these drug-induced effects. Male Wistar rats were pre-treated with zinc sulphate (50 mg/kg) and dosed with indomethacin (20 mg/kg) by oral gavage. Rats were sacrificed 24 h after the dose of indomethacin. Parameters of oxidative stress, mitochondrial function and lipid content of the mitochondrial membranes were measured in the kidneys of these animals. It was found that zinc significantly attenuated indomethacin-induced oxidative stress, mitochondrial dysfunction and changes in the lipids in mitochondrial membranes in the kidney. The content of metallothionein, a cysteine-rich zinc-binding protein, was also determined in the tissue. There was no significant induction of metallothionein in the kidney in zinc-treated animals. Estimation of serum creatinine showed that zinc seemed to hasten functional recovery of the kidney following indomethacin administration. We conclude that pretreatment with zinc is effective in protecting against indomethacin-induced changes in the rat kidney. This protective effect does not appear to be mediated by metallothionein. PMID- 19445919 TI - An orally active motilin receptor antagonist, MA-2029, inhibits motilin-induced gastrointestinal motility, increase in fundic tone, and diarrhea in conscious dogs without affecting gastric emptying. AB - The pharmacological properties of MA-2029, a selective and competitive motilin receptor antagonist, were investigated in conscious dogs after oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the paracetamol absorption test. MA-2029 (0.3-10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by motilin (3 microg/kg, i.v.) in a dose-dependent manner. MA-2029 (0.3-3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though MA 2029 had no effect on basal gastrointestinal motility or basal gastric emptying even at 10 and 30 mg/kg p.o. The inhibitory effect of MA-2029 on motilin-induced gastrointestinal motility corresponded to its plasma concentration. Motilin (0.3 microg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by MA-2029 (1 10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of motilin (3 microg/kg, i.v.) induced diarrhea in 9 of 11 dogs. MA-2029 (1-30 mg/kg, p.o.) reduced the incidence of diarrhea induced by motilin in a dose dependent manner. The results indicate that MA-2029 inhibits hypermotility induced by motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate. MA-2029 may be useful in treating gastrointestinal disorders in which the pathogenesis involves the elevation of circulating motilin. PMID- 19445920 TI - Inhibition of superoxide anion generation by CHS-111 via blockade of the p21 activated kinase, protein kinase B/Akt and protein kinase C signaling pathways in rat neutrophils. AB - In formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils, 2-benzyl-3-(4 hydroxymethylphenyl)indazole (CHS-111) inhibited superoxide anion (O(2)(-)) generation, which was not mediated by scavenging the generated O(2)(-) or by a cytotoxic effect, and attenuated migration. CHS-111 had no effect on the arachidonic acid-induced NADPH oxidase activation or the GTPgammaS-stimulated Rac2 membrane translocation in cell-free systems, whereas it effectively attenuated the membrane recruitment of p40(phox), p47(phox) and p67(phox), phosphorylation of Ser residues in p47(phox), association between p47(phox) and p22(phox), and Rac activation in fMLP-stimulated neutrophils. Moreover, the phosphorylation and membrane recruitment of p21-activated kinase (PAK), PAK kinase activity and the interaction of PAK with p47(phox) were inhibited by CHS 111. CHS-111 effectively reduced Akt kinase activity and the association between Akt and p47(phox), moderately inhibited the membrane recruitment of Akt and phospho-PDK1, and slightly attenuated Akt (Thr308) phosphorylation, whereas it had no effect on Akt (Ser473) phosphorylation or p110gamma membrane translocation. The membrane recruitment of protein kinase C (PKC)-alpha, -betaI, betaII, -delta and -zeta, PKC phosphorylation and PKC kinase activity was attenuated by CHS-111, whereas CHS-111 did not affect the phosphorylation of p38 mitogen-activated protein kinase (MAPK) or downstream MAPK-activated protein kinase-2. Higher concentrations of CHS-111 were required to decrease fMLP stimulated intracellular free Ca(2+) concentration ([Ca(2+)](i)) elevation in the presence but not in the absence of extracellular Ca(2+), and to reduce cellular cyclic AMP but slightly increase cyclic GMP levels. Taken together, these results suggest that CHS-111 inhibits fMLP-stimulated O(2)(-) generation in rat neutrophils through the blockade of PAK, Akt and PKC signaling pathways. PMID- 19445921 TI - Cardioprotective effect of salvianolic acid A on isoproterenol-induced myocardial infarction in rats. AB - The present study was designed to evaluate the cardioprotective potential of salvianolic acid A on isoproterenol-induced myocardial infarction in rats. Hemodynamic parameters and lead II electrocardiograph were monitored and recorded continuously. Cardiac marker enzymes and antioxidative parameters in serum and heart tissues were measured. Assay for mitochondrial respiratory function and histopathological examination of heart tissues were performed. Isoproterenol treated rats showed significant increases in the levels of lactate dehydrogenase, aspartate transaminase, creatine kinase and malondialdehyde and significant decreases in the activities of superoxide dismutase, catalase and glutathione peroxidase in serum and heart. These rats also showed declines in left ventricular systolic pressure, maximum and minimum rate of developed left ventricular pressure, and elevation of left ventricular end-diastolic pressure and ST-segment. In addition, mitochondrial respiratory dysfunction characterized by decreased respiratory control ratio and ADP/O was observed in isoproterenol treated rats. Administration of salvianolic acid A for a period of 8 days significantly attenuated isoproterenol-induced cardiac dysfunction and myocardial injury and improved mitochondrial respiratory function. The protective role of salvianolic acid A against isoproterenol-induced myocardial damage was further confirmed by histopathological examination. The results of our study suggest that salvianolic acid A possessing antioxidant activity has a significant protective effect against isoproterenol-induced myocardial infarction. PMID- 19445922 TI - Dopamine receptors in human peripheral blood lymphocytes: changes in mRNA expression in opioid addiction. AB - Gradual adaptations of the brain to repeated drug exposure may induce addiction. Brain mesolimbic dopaminergic pathway is the site of the effect of addictive drugs. The dopamine receptors in peripheral blood lymphocytes may reflect the status of homologous brain receptors. In the present study, the effects of opioid addiction on mRNA expression of dopamine D(3), D(4) and D(5) receptors in human peripheral blood lymphocytes were investigated, using a real-time PCR method. Four groups each comprising 30 individuals were enrolled in the study: opioid addicted, methadone maintained, long-term abstinent and normal subjects. The results indicated that dopamine D(3) receptor mRNA expression was increased in addicted and methadone maintained subjects by a factor of 1.74 and 1.98, respectively, but no change was observed in the abstinent group. The dopamine D(4) receptor mRNA expression was reduced in abstinent and addicted subjects (but not in the methadone group) and reached 0.44 and 0.53 the amount of the control group, respectively. Expression of dopamine D(5) receptor mRNA showed a significant reduction in abstinent subjects (0.41 the amount of the control group). However, in the addicted and methadone maintained groups, the change of expression level was not statistically significant. It can be concluded that persisting deficiency of dopamine D(4) and D(5) receptors may be a risk factor urging individuals to addiction, and methadone may exert its therapeutic effects through normalizing mRNA expression of these receptors. The dopamine D(3) receptor may have a negative feedback role in addiction; however, we have no explanation for the persisting up-regulation of this receptor in methadone subjects. PMID- 19445923 TI - Intracerebroventricular or intrathecal injection of glycine produces analgesia in thermal nociception and chemical nociception via glycine receptors. AB - The present study was designed to investigate the role of glycine receptors in analgesia induced by injection of glycine in vivo. Glycine was injected intracerebroventricularly or intrathecally and strychnine, a glycine receptor antagonist, was injected intracerebroventricularly or intrathecally before glycine injection. The effects on the pain threshold index in hot-plate test and the writhing times in acetic acid-induced writhing test were observed. The locomotor activity and motor performance (rotarod test) were also observed. The dosages of glycine and strychnine we choose had no effect on locomotor activity or motor performance in conscious mice. Glycine increased the pain threshold index in hot-plate test and decreased the writhing times of the mice. Strychnine antagonized the effects induced by glycine above. These results demonstrated that intracerebroventricular or intrathecal injection of glycine can produce analgesia in thermal nociception and chemical nociception in vivo, which is mediated by glycine receptors. PMID- 19445925 TI - Pharmacological characterization of the bradykinin B2 receptor antagonist MEN16132 in rat in vitro bioassays. AB - The pharmacological profile of the bradykinin B(2) receptor antagonist MEN16132 at the rat B(2) receptor has been investigated and compared with that of icatibant (formerly Hoe 140). Antagonist affinity has been measured through radioligand binding experiments with membranes prepared from uterine and airway tissue. MEN16132 inhibited [(3)H]bradykinin binding with subnanomolar affinity (pK(i) values 10.4 and 10.1 in the uterus and airways, respectively), and was about 3-fold less potent than icatibant (pK(i) values 10.9 and 10.5). Antagonist potency has been estimated towards bradykinin-induced contractility of uterine and urinary bladder smooth muscle preparations. In these assays MEN16132 (pK(B): 9.7 both in uterus and bladder) was about 10-fold more potent than icatibant [pK(B): 8.8 in uterus, and pK(B) 8.0 in urinary bladder, as from Meini, S., Patacchini, R., Giuliani, S., Lazzeri, M., Turini, D., Maggi, C.A., Lecci, A., 2000a. Characterization of bradykinin B(2) receptor antagonists in human and rat urinary bladder. Eur. J. Pharmacol. 388, 177-182]. Washout experiments conducted in the uterine preparation indicated for MEN16132 (100 nM) a slower reversibility than icatibant (300 nM).Altogether present results indicate that MEN16132 displays high affinity and potency also for the rat bradykinin B(2) receptor, and thus is suitable for further investigations in pathophysiological models in this species. PMID- 19445924 TI - Alteration in male reproductive system in experimental cholestasis: roles for opioids and nitric oxide overproduction. AB - Cirrhosis is associated with impairment of the male reproductive system, hypogonadism and feminization. It is important to rule out whether the impairment in the reproductive system exists earlier in the course of cholestatic liver disease to target effective therapies at the best time point. In this study we investigated the role of endogenous opioid and nitric oxide system in alterations of the reproductive system in male rats. We performed sham or bile duct ligation surgery on male Sprague-Dawley rats and treated the animals for seven days with saline, naltrexone, an opioid receptor blocker (20 mg/kg) and N (G)-nitro-L arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (10 mg/kg). We then evaluated the plasma level of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH), sperm count and motility as well as biomarkers of cholestasis and nitric oxide productions. The results showed that following cholestasis, total testosterone level decrease and LH level increase in plasma of cholestatic rats and treatment with L-NAME and naltrexone could improve the plasma level of testosterone. Naltrexone could decrease the elevated level of LH in cholestatic animals. In addition, the weight of seminal vesicles and prostate significantly decreased in cholestasis as compared to the control group and treatment with L-NAME and naltrexone could improve the weights of the two organs in cholestasis. Our results demonstrate for the first time that the male reproductive system is impaired early in cholestasis and that endogenous opioid and nitric oxide system contribute to these impairments in the early course of the disease. PMID- 19445926 TI - The prostanoid EP(2) receptor agonist ONO-AE1-259-01 protects against glutamate induced neurotoxicity in rat retina. AB - Prostaglandin E(2) (PGE(2)) plays an important role in promoting inflammation and neurological disorders. The actions of PGE(2) are mediated by four different G protein-coupled receptors (EP(1), EP(2), EP(3), and EP(4)). The purpose of this study was to determine whether stimulation of prostanoid EP(2) receptors has the potential to prevent the excitotoxic injuries in the retina. For this purpose, we examined the effect of 11,15-O-dimethyl prostaglandin E(2) (ONO-AE1-259-01), a selective prostanoid EP(2) receptor agonist, on N-methyl-D-aspartate (NMDA) induced neurotoxicity in the rat retina. ONO-AE1-259-01 (2 or 20 nmol) together with NMDA (200 nmol) was given intravitreally, and histological evaluation was performed at 1 week after the injection. ONO-AE1-259-01 concentration-dependently prevented NMDA-induced cell loss in ganglion cell layer and reduction in thickness of inner plexiform layer. These results indicate that ONO-AE1-259-01 protects the excitotoxic injuries in the rat retina, and that the prostanoid EP(2) receptor may be a target for neuroprotective intervention in the retinal diseases associated with glutamate-induced excitotoxicity, such as glaucoma and diabetic retinopathy. PMID- 19445927 TI - Pharmacological characterization of the nociceptin/orphanin FQ receptor non peptide antagonist Compound 24. AB - Compound 24, 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl] pyrrolidine-2-carboxamide was recently identified as a nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) ligand. In this study, the in vitro and in vivo pharmacological profiles of Compound 24 were investigated. In vitro studies were performed measuring receptor and [(35)S]GTPgammaS binding and calcium mobilization in cells expressing the recombinant NOP receptor as well as using N/OFQ sensitive tissues. In vivo studies were conducted using the tail withdrawal assay in mice. Compound 24 produced a concentration-dependent displacement of [(3)H]N/OFQ binding to CHO(hNOP) cell membranes showing high affinity (pK(i) 9.62) and selectivity (1000 fold) over classical opioid receptors. Compound 24 antagonized with high potency the following in vitro effects of N/OFQ: stimulation of [(35)S]GTPgammaS binding in CHO(hNOP) cell membranes (pA(2) 9.98), calcium mobilization in CHO(hNOP) cells expressing the Galpha(qi5) chimeric protein (pK(B) 8.73), inhibition of electrically evoked twitches in the mouse (pA(2) 8.44) and rat (pK(B) 8.28) vas deferens, and in the guinea pig ileum (pK(B) 9.12). In electrically stimulated tissues, Compound 24 up to 1 microM did not modify the effects of classical opioid receptor agonists. Finally in vivo, in the mouse tail withdrawal assay, Compound 24 at 10 mg/kg antagonized the pronociceptive and antinociceptive effects of 1 nmol N/OFQ given supraspinally and spinally, respectively. Under the same experimental conditions Compound 24 did not affect the antinociceptive action of 3 nmol endomorphin-1 injected intrathecally. The present study demonstrated that Compound 24 is a pure, competitive, and highly potent non-peptide NOP receptor selective antagonist. PMID- 19445928 TI - Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington's disease like symptoms: possible behavioural, biochemical and cellular alterations. AB - 3-Nitropropionic acid inhibits succinate dehydrogenase, complex II enzyme in the mitochondrial respiratory chain that leads to cellular energy deficit and oxidative stress. Huntington's disease is characterized by abnormal body movements (chorea) and cognitive dysfunctions. Rivastigmine, a well known cholinesterase inhibitor used in the management of Alzheimer's disease in a clinical practice. Recent clinical studies suggest the potential role of rivastigmine in the management of Huntington's disease. The present study has been designed to explore the possible role of rivastigmine against 3 nitropropionic acid induced behavioral, biochemical and cellular alterations. Intraperitoneal administration of 3-nitropropionic acid (10 mg/kg for 14 days) caused significant loss in body weight, motor in coordination (locomotor activity and rota rod performance) and poor memory retention in Morris water maze and elevated plus maze performance tasks as compared to vehicle treated animals. Biochemical analysis revealed significant increase in lipid peroxidation, nitrite concentration and depleted superoxide dismutase, catalase levels and alterations in mitochondrial complex enzymes (I, II, IV and MTT assay) in the different regions (striatum, cortex and hippocampus) of rat brain. Rivastigmine (0.5, 1 and 2 mg/kg, orally) once daily treatment for a period of 14 days significantly improved motor performance and cognitive task in both Morris water maze and elevated plus maze tests. Further, rivastigmine treatment significantly attenuated oxidative damage and improved mitochondrial complexes enzyme activities in different regions (striatum, cortex and hippocampus) of rat brain. The results show that rivastigmine could be used as an effective therapeutic agent in the management of Huntington's disease and related conditions. PMID- 19445929 TI - Suberoylanilide hydroxamic acid promotes cardiomyocyte differentiation of rat mesenchymal stem cells. AB - This study was to investigate the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on cardiomyocyte differentiation of bone marrow mesenchymal stem cells (MSCs) in vitro. Rat MSCs were isolated and induced to differentiate into cardiomyocyte with SAHA or 5-azacytidine (5-aza, a DNA methylation inhibitor) or their combination. Following 7 days of SAHA treatment, the transcriptional expression of the cardiomyocyte-specific genes GATA4, NKx2.5, and Mef2c was dose-dependently increased in the cells with up to 15-fold increase in their mRNA levels over baseline. However, the mRNA levels of these genes were only increased by 2-4 fold in 5-aza-treated cells. After 4 weeks of induction with SAHA, cTnT protein content was substantially increased dose-dependently by up to 8-fold in the cells over the baseline. In contrast, only minimal cTnT protein was found in 5-aza-treated cells. When MSCs were treated with both SAHA and 5-aza, the mRNA levels of GATA4, NKx2.5, and Mef2c and cTnT protein content were the same as those in the cells treated with SAHA alone. These results indicate that SAHA effectively promotes cardiomyocyte differentiation of rat MSCs in vitro. SAHA was a much more potent inducer for cardiac differentiation of MSCs then 5-aza. Our data also indicate that no synergistic or antagonistic effect between SAHA and 5-aza on cardiomyocyte differentiation of MSCs is present, and histone acetylation, not DNA demethylation, may be the dominant mechanism that determines the cardiac differentiation of rat MSCs. PMID- 19445930 TI - Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models. AB - Prostaglandins are widely used to lower intraocular pressure (IOP) as part of the treatment regimen for glaucoma. While FP and EP2 agonists are known to lower IOP, we investigated the ocular hypotensive activity and ocular drug distribution of PF-04475270, a novel EP4 agonist following topical administration in normotensive Beagle dogs. PF-04475270 is a prodrug of CP-734432, which stimulated cAMP formation in HEK293 cells expressing EP4 receptor and beta-lactamase activity in human EP4 expressing CHO cells transfected with a cAMP response element (CRE) with an EC(50) of 1 nM. Prodrug conversion and transcorneal permeability were assessed in rabbit corneal homogenates and a human corneal epithelial cell (cHCE) model. The compound underwent rapid hydrolysis to CP-734432 in corneal homogenates, and exhibited good permeability in the cHCE model. The descending order of ocular exposure to CP-734432 after topical dosing of PF-04475270 in dogs was as follows: cornea > aqueous humor >or= iris/ciliary body. When administered q.d., PF-04475270 lowered IOP effectively in the dog IOP model both after single and multiple days of dosing. A maximum decrease in IOP with PF-04475270 was between 30 and 45% at 24h post-dose relative to that observed with vehicle. In conclusion, PF-04475270 is a novel ocular hypotensive compound which is bioavailable following topical dosing, effectively lowering IOP in dogs. EP4 agonists could be considered as potential targets for lowering IOP for the treatment of glaucoma and ocular hypertension. PMID- 19445931 TI - Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. AB - Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF 3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain. PMID- 19445932 TI - Repeated 4-aminopyridine induced seizures diminish the efficacy of glutamatergic transmission in the neocortex. AB - Systemic administration of the potassium channel blocker 4-aminopyridine (4-AP) elicits acute convulsions. Synchronized tonic-clonic activity develops during the first hour after the treatment. However, subsequent chronic spontaneous seizures do not appear which suggests changes in neuronal excitability. The aim of our present work was to evaluate alterations in the glutamatergic transmission in the somatosensory cortex of rats following daily, brief convulsions elicited by 4-AP treatment. Changes in general neuronal excitability and pharmacological sensitivity of glutamate receptors were tested in ex vivo electrophysiological experiments on brain slices. In parallel studies quantitative changes in subunit composition of glutamate receptors were determined with immunohistoblot technique, together with the analysis of kainate induced Co2+ uptake. The results of our coordinated electrophysiological, receptor-pharmacological and histoblot studies demonstrated that repeated, daily, short convulsions resulted in a significant decrease of the general excitability of the somatosensory cortex together with changes in ionotropic glutamate receptor subunits. The relative inhibitory effect of the AMPA receptor antagonist, however, did not change. The NMDA receptor antagonist exerted somewhat stronger effect in the slices from convulsing animals. 4-AP pretreatment resulted in the attenuation of kainate induced Co2+ uptake, which suggests either reduction in non-NMDA receptors numbers or reduction in their Ca2+ permeability. Repeated seizures decreased GluR1-4 AMPA receptor subunit levels in all cortical layers with a relaitve increase in GluR1 subunits. While the principle NR1 NMDA receptor subunit showed no significant change, the staining density of NR2A subunit increased. These changes in ionotropic glutamate receptors are consistent with reduced excitability at glutamatergic synapses following repeated 4-AP induced seizures. PMID- 19445934 TI - Treatment of intracerebral hemorrhage in rats with 12 h, 3 days and 6 days of selective brain hypothermia. AB - Intracerebral hemorrhage (ICH) is a devastating stroke with no proven treatment to reduce brain injury. In this study we modeled ICH by injecting 100 microL of autologous blood into the striatum of rats. We then tested whether hypothermia would reduce brain injury and improve recovery as has been repeatedly observed for ischemic and traumatic brain damage. Aside from reducing blood-brain barrier disruption, inflammation and edema, hypothermia has not consistently improved behavioral or histological outcome after ICH in animal studies. As this might relate to the choice of cooling method and the duration of hypothermia, we used a system that selectively cooled the injured hemisphere to approximately 32 degrees C (striatum) while the body remained normothermic. Cooling (vs. normothermia) started 1 h after ICH and lasted for 12 h, 3 days or 6 days followed by slow re warming (approximately 1 degrees C/h). Functional impairment was evaluated from 2 to 3 weeks post-ICH at which time brain injury was determined. The ICH caused significant impairment on a neurological deficit scale and in tests of walking (horizontal ladder), skilled reaching (tray task) and spontaneous limb usage (cylinder test). Only the limb use asymmetry deficit was significantly mitigated by hypothermia, and then only by the longest treatment. Lesion volume, which averaged 16.9 mm3, was not affected. These results, in conjunction with earlier studies, suggest that prolonged mild hypothermia will not be a profound neuroprotectant for patients with striatal ICH, but it may nonetheless improve functional recovery in addition to its use for treating cerebral edema. PMID- 19445933 TI - Drp1 levels constitutively regulate mitochondrial dynamics and cell survival in cortical neurons. AB - Mitochondria exist as dynamic networks that are constantly remodeled through the opposing actions of fusion and fission proteins. Changes in the expression of these proteins alter mitochondrial shape and size, and may promote or inhibit the propagation of apoptotic signals. Using mitochondrially targeted EGFP or DsRed2 to identify mitochondria, we observed a short, distinctly tubular mitochondrial morphology in postnatal cortical neurons in culture and in retinal ganglion cells in vivo, whereas longer, highly interconnected mitochondrial networks were detected in cortical astrocytes in vitro and non-neuronal cells in the retina in vivo. Differential expression patterns of fusion and fission proteins, in part, appear to determine these morphological differences as neurons expressed markedly high levels of Drp1 and OPA1 proteins compared to non-neuronal cells. This finding was corroborated using optic tissue samples. Moreover, cortical neurons expressed several splice variants of Drp1 including a neuron-specific isoform which incorporates exon 3. Knockdown or dominant-negative interference of endogenous Drp1 significantly increased mitochondrial length in both neurons and non-neuronal cells, but caused cell death only in cortical neurons. Conversely, depletion of the fusion protein, Mfn2, but not Mfn1, caused extensive mitochondrial fission and cell death. Thus, Drp1 and Mfn2 in normal cortical neurons not only regulate mitochondrial morphology, but are also required for cell survival. The present findings point to unique patterns of Drp1 expression and selective vulnerability to reduced levels of Drp1 expression/activity in neurons, and demonstrate that the regulation of mitochondrial dynamics must be tightly regulated in neurons. PMID- 19445935 TI - A polysialic acid mimetic peptide promotes functional recovery in a mouse model of spinal cord injury. AB - Contrary to lower species that recapitulate some of the developmental programs, in mammals, functional recovery after spinal cord injury is impaired by a non permissive environment and the lack of plasticity of adult neurons. The developmental plasticity associated linear homopolymer of alpha 2,8-linked sialic acid (PolySialic Acid, PSA), represents a permissive determinant that could contribute to recovery. We previously showed that a PSA cyclic mimetic peptide (PR-21) displayed PSA-like biological functions (Torregrossa, P., Buhl, L., Bancila, M., Durbec, P., Schafer, C., Schachner, M., Rougon, G., 2004. Selection of poly-alpha 2,8-sialic acid mimotopes from a random phage peptide library and analysis of their bioactivity. J. Biol. Chem. 279, 30707-30714.). In the present study we investigated the therapeutic potential of PR-21 in young adult mice after dorsal hemisection at the T9 level. We show that PR-21 fulfills several criteria for an in vivo use as it is not toxic, not immunogenic and displays good stability in biological fluids or tissue. Delivery of PR-21 to the lesion site decreased the time of the animals' return to continence, and enhanced motor functions, sensorimotor control and coordination of hindlimbs with forelimbs when compared to a control peptide. At the cellular level, PR-21 increased serotonergic axon density at and caudal to the lesion site, and decreased reactive gliosis in vivo. In an in vitro model of reactive astrocytes, PR-21 increased NCAM expression in strongly GFAP positive cells. Our data point to the unique features of a carbohydrate mimicking peptide, and support the notion that PSA can be considered as an important factor in recovery from spinal cord injury. PMID- 19445936 TI - Optic nerve lesion increases cell proliferation and nestin expression in the adult mouse eye in vivo. AB - In the naive adult rodent eye cell proliferation does not occur. The aim of this in vivo study was to evaluate if quiescent putative progenitor-like cells within the adult mouse eye can be activated by optic nerve (ON) injury. For a comprehensive analysis, three areas were assessed: the ON, the neural retina, and the ciliary body (CB). Two lesion types were performed, i.e. intraorbital ON transection, or ON crush lesion, in order to analyse possible differences in cellular response after injury. This mouse study shows, for the first time that ON lesion up-regulates cell proliferation and nestin expression in the mouse eye as compared to naive controls. Numbers and distribution patterns of BrdU+ cells obtained were similar after both lesion types, suggesting analogous mechanisms of activation. Interestingly, a differential cell proliferative response was observed in the CB. After ON lesion, the absence of BrdU/TUNEL co-labelled cells confirmed that BrdU+ cells were indeed proliferating. Following ON lesion, in the retina approximately 18% of all BrdU+ cells were positive for the neural stem cell/progenitor cell (NSC/PC) marker nestin. The fraction of BrdU+/nestin+ cells in the CB was approximately 26%. Most of the BrdU+/nestin+ cells found in the neural retina were identified as reactive astrocytes and Muller cells. Since reactive glia cells can participate in adult neuro- and gliogenesis this may indicate a potential for regeneration after ON lesion in vivo. PMID- 19445937 TI - High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers. AB - BACKGROUND & AIMS: The long-term prognosis of peptic ulcers associated with neither Helicobacter pylori nor nonsteroidal anti-inflammatory drugs (NSAIDs) is unknown. METHODS: This 7-year prospective cohort study recruited patients with bleeding ulcers from January to December 2000. H pylori-negative idiopathic bleeding ulcers were defined as having tested negative for H pylori, having no exposure to aspirin or analgesics within 4 weeks before endoscopy, and having no other identifiable causative factors. After ulcers healed, patients were divided into 2 groups: patients with prior H pylori-negative idiopathic bleeding ulcers (H pylori-negative idiopathic ulcer cohort; n = 120) and those with H pylori positive, NSAID-negative bleeding ulcers who received eradication therapy (H pylori ulcer cohort; n = 213). Both groups were followed for or=5% in the first year after randomization (HR, 1.25 per category increase in weight, 95% CI, 1.01-1.55). CONCLUSIONS: Insulin resistance, histologic features of fatty liver disease, and weight change were associated with outcomes of chronic hepatitis C. Improvement in these weight-related factors might modify disease progression. PMID- 19445940 TI - Selective blockade of DCAMKL-1 results in tumor growth arrest by a Let-7a MicroRNA-dependent mechanism. AB - BACKGROUND & AIMS: MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. The tumor suppressor miRNA let-7a has been reported to be inhibited posttranscriptionally in embryonic stem cells and in human cancers. Microtubule associated kinase DCAMKL-1 is a putative intestinal stem cell marker that is expressed in Apc(Min/+) adenomas. We investigated the role of DCAMKL-1 on expression of let-7a miRNA and the oncogene c-Myc and in tumorigenesis. METHODS: Human tissue microassay slides were immunostained for DCAMKL-1. HCT116 and SW480 cells were transfected with DCAMKL-1 small interfering RNA (siRNA) (si-DCAMKL-1) and analyzed for DCAMKL-1, c-Myc (using immunoblot and real-time reverse transcription polymerase chain reaction [RT-PCR]), and pri-let-7a miRNA (using real-time RT-PCR) levels. A liposomal preparation of si-DCAMKL-1 was administered into HCT116 xenografts in nude mice, and tumor volumes were measured. A luciferase reporter assay, with a plasmid containing a let-7a-binding site at the 3' untranslated region, was utilized to measure let-7a in cell lines. Cells were isolated from normal mouse intestine using DCAMKL-1 and fluorescence-activated cell sorting (FACS) and subjected to pri-let-7a miRNA analysis. RESULTS: Expression of DCAMKL-1 was increased in human colorectal cancers. siRNA-mediated blockade of DCAMKL-1 resulted in H tumor xenograft growth arrest, increased pri let-7a miRNA, a corresponding decrease in luciferase activity, and decreased expression of the oncogene c-Myc. DCAMKL-1(+) cells isolated by FACS demonstrated a significant decrease in pri-let-7a miRNA, compared with more differentiated cells. CONCLUSIONS: DCAMKL-1 is a negative regulator of let-7a miRNA biogenesis in intestinal stem and colorectal cancer cells; it could represent a novel target for anti-cancer stem cell-based strategies. PMID- 19445939 TI - Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. AB - BACKGROUND & AIMS: Epstein-Barr virus (EBV) has been causally associated with cancer; some gastric carcinomas have a monoclonal EBV genome in every cancer cell, indicating that they arose from a single infected progenitor cell. However, the proportion of EBV-positive gastric carcinomas is uncertain, and the etiologic significance is unknown. METHODS: We conducted a meta-analysis of 70 studies including 15,952 cases of gastric cancer assessed by in situ hybridization for EBV-encoded small RNA. RESULTS: The pooled prevalence estimate of EBV positivity was 8.7% (95% confidence interval [CI]: 7.5%-10.0%) overall, with a 2-fold difference by sex: 11.1% (95% CI: 8.7%-14.1%) of gastric cancer cases in males vs 5.2% (95% CI: 3.6%-7.4%) of cases in females. Tumors arising in the gastric cardia (13.6%) or corpus (13.1%) were more than twice as likely to be EBV positive as those in the antrum (5.2%; P < .01 for both comparisons). EBV prevalence was 4 times higher (35.1%) for tumors in postsurgical gastric stump/remnants. Over 90% of lymphoepithelioma-like carcinomas were EBV positive, but only 15 studies reported any cases of this type; prevalence did not significantly differ between the more common diffuse (9.5%) [corrected] and intestinal (7.6%) [corrected] histologies. EBV prevalence was similar in cases from Asia (8.3%), Europe (9.2%), and the Americas (9.9%). CONCLUSIONS: EBV positive gastric cancers greatly differ from other gastric carcinomas based on sex, anatomic subsite, and surgically disrupted anatomy, indicating that it is a distinct etiologic entity. Epidemiologic studies comparing EBV-positive and negative gastric cancers are warranted to investigate EBV's role in gastric carcinogenesis. PMID- 19445941 TI - Aberrant cell cycle progression and endoreplication in regenerating livers of mice that lack a single E-type cyclin. AB - BACKGROUND & AIMS: E-cyclins control the transition of quiescent cells into the cell cycle. Two E-cyclins, CcnE1 and CcnE2, have been described, but their specific contributions to cell cycle reentry in vivo are poorly understood. Liver regeneration following partial hepatectomy is an excellent in vivo model for the study of cell cycle reentry of quiescent cells. We investigated the relevance of E-cyclins in directing resting hepatocytes into the cell cycle after partial hepatectomy using CcnE1 and CcnE2 knockout mice. METHODS: Partial hepatectomy (70%) was performed in CcnE1 (E1(-/-)) and CcnE2 (E2(-/-)) knockout and wild-type mice. Liver regeneration was monitored by cell cycle markers for G(1)/S phase, S phase, and M phase as well as by determining the liver/body weight ratio after partial hepatectomy. Ploidy of hepatocytes was determined by fluorescence activated cell sorting and fluorescent in situ hybridization. RESULTS: CcnE1 deletion resulted in normal liver regeneration with a slight delay of the G(1)/S phase transition and a defect in endoreplication of otherwise polyploid hepatocytes. Surprisingly, E2(-/-) mice displayed accelerated and sustained DNA synthesis after partial hepatectomy, excessive endoreplication in hepatocytes, and a liver mass that was 45% greater than that of wild-type mice after termination of the regeneration process. CcnE2 depletion induced overexpression of CcnE1 and prolonged cdk2 kinase activity after partial hepatectomy. CONCLUSIONS: CcnE2 has an unexpected role in repressing CcnE1; the phenotype of E2(-/-) mice appears to result from CcnE1 overexpression and cdk2 hyperactivation. CcnE1 and CcnE2 therefore have nonredundant functions for S phase entry and endoreplication during liver regeneration. PMID- 19445943 TI - Direct-to-consumer and physician promotion of tegaserod correlated with physician visits, diagnoses, and prescriptions. AB - BACKGROUND & AIMS: Direct-to-consumer advertisement (DTCA) and physician promotion of drugs can influence patient and physician behaviors. We sought to determine the relationship between promotion of tegaserod and the number of office visits for abdominal pain, constipation, and bloating; diagnoses of irritable bowel syndrome (IBS); and tegaserod prescriptions. METHODS: We used an Integrated Promotional Services database to estimate tegaserod DTCA and promotion expenditures; the National Ambulatory/Hospital Medical Care Surveys (1997-2005) to estimate the number of ambulatory care visits for abdominal pain, constipation, and bloating and diagnoses of IBS; and IMS Health's National Prescription Audit Plus (Fairfield, CT) to estimate the number of prescriptions. We constructed segmented and multivariate regression models to analyze the data. RESULTS: In the 3 months immediately following the start of tegaserod DTCA, there was a significant increase in physician visits (by 1 million; 95% confidence interval [CI], 0.5-1.6 million) and IBS diagnoses (by 397,025; 95% CI, 3909 790,141). Subsequently, the trend of visits and IBS diagnoses was reduced. In multivariate analyses that examined the overall relationship of promotion with visits, diagnoses, and prescriptions, only the relationship between physician promotion and tegaserod prescribing was significant; every $1 million spent on physician promotion resulted in an additional 4108 prescriptions (95% CI, 2526 5691). CONCLUSIONS: The initial DTCA of tegaserod was associated with a significant, immediate increase in physician visits and IBS diagnoses. This trend reversed and, in multivariate models, neither DTCA nor physician promotion correlated with visits or diagnoses. Physician promotion (although not DTCA) correlated with tegaserod prescription volume. PMID- 19445942 TI - Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. AB - BACKGROUND & AIMS: Hedgehog signaling is critical in gastrointestinal patterning. Mice deficient in Hedgehog signaling exhibit abnormalities that mirror deformities seen in the human VACTERL (vertebral, anal, cardiac, tracheal, esophageal, renal, limb) association. However, the direction of Hedgehog signal flow is controversial and the cellular targets of Hedgehog signaling change with time during development. We profiled cellular Hedgehog response patterns from embryonic day 10.5 (E10.5) to adult in murine antrum, pyloric region, small intestine, and colon. METHODS: Hedgehog signaling was profiled using Hedgehog pathway reporter mice and in situ hybridization. Cellular targets were identified by immunostaining. Ihh-overexpressing transgenic animals were generated and analyzed. RESULTS: Hedgehog signaling is strictly paracrine from antrum to colon throughout embryonic and adult life. Novel findings include the following: mesothelial cells of the serosa transduce Hedgehog signals in fetal life; the hindgut epithelium expresses Ptch but not Gli1 at E10.5; the 2 layers of the muscularis externa respond differently to Hedgehog signals; organogenesis of the pyloric sphincter is associated with robust Hedgehog signaling; dramatically different Hedgehog responses characterize stomach and intestine at E16; and after birth, the muscularis mucosa and villus smooth muscle consist primarily of Hedgehog-responsive cells and Hh levels actively modulate villus core smooth muscle. CONCLUSIONS: These studies reveal a previously unrecognized association of paracrine Hedgehog signaling with several gastrointestinal patterning events involving the serosa, pylorus, and villus smooth muscle. The results may have implications for several human anomalies and could potentially expand the spectrum of the human VACTERL association. PMID- 19445944 TI - Time trends in therapies and outcomes for adult inflammatory bowel disease, Northern California, 1998-2005. AB - BACKGROUND & AIMS: The management of inflammatory bowel disease (IBD) has become increasingly complicated, and it is unknown whether poor outcomes (prolonged steroid use, hospitalizations, and surgery) have declined in the general population. METHODS: This multilevel study used computerized clinical data. The study comprised 2892 adults with Crohn's disease (CD) and 5895 with ulcerative colitis (UC) who received care at 16 medical centers within an integrated care organization in Northern California between 1998 and 2005. RESULTS: Time trends included (1) a shift in gastroenterology-related visits from the gastroenterology division to primary care; (2) increased use of IBD-related drugs, except for a 7% decline in use of 5-aminosalicylate in CD and no change in steroid use for CD; (3) for the prevalence of prolonged steroid exposure (120 days of continuous use), a 36% decline for CD with a 27% increase for UC; (4) declines in the hospitalization rates of 33% for CD and 29% for UC; and (5) for the surgery rate, no significant change for CD with a 50% decline for UC. CONCLUSIONS: Declines in prolonged steroid exposure and the hospitalization rate for CD and in the hospitalization and surgery rate for UC are encouraging; however, the increase in prolonged steroid exposure for UC merits concern and further investigation. The variability in care patterns observed in this study suggests lack of standardization of care and the opportunity to identify targets for quality improvement. These findings should stimulate research to quantify the effect of current trends in IBD management. PMID- 19445945 TI - Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. AB - BACKGROUND & AIMS: In severe (Maddrey score >or=32) alcoholic hepatitis (AH), infection is classically viewed as a contraindication for corticosteroids, although specific data are lacking. This study's aims were (1) to evaluate the incidence of infection in patients with severe AH before and after corticosteroid treatment; (2) to determine whether infection contraindicates corticosteroids; and (3) to focus on predictive factors of development of infection. METHODS: At admission, systematic screening of infection consisted of chest x-ray and blood, ascites, and urinary cultures. All patients were treated with prednisolone. Response to steroids was defined using the Lille model. RESULTS: Two hundred forty-six patients with severe AH were prospectively included. Infections at admission were as follows: 63 infections (25.6%) were diagnosed: 28 (44.4%) spontaneous bacterial peritonitis or bacteremia, 8 (12.7%) pulmonary infections, 20 (31.7%) urinary tract infections, and 7 (11.2%) other infections. Patients infected before using corticosteroids had 2-month survival similar to that of others: 70.9% +/- 6.1% vs 71.6% +/- 3.4%, respectively, P = .99. Development of infection after steroids: 57 patients (23.7%) developed infection: 16 (28.1%) spontaneous bacterial peritonitis or bacteremia, 23 (40.3%) pulmonary, 10 (17.5%) urinary tract, and 8 (14.1%) other infections. Infection occurred more frequently in nonresponders than in responders: 42.5% vs 11.1%, respectively, P < .000001. In multivariate analysis, only the Lille model (P = .0002) independently predicted infection upon steroids use. The Lille model (P = .000001) and Model for End-Stage Liver Disease score (P = .006) were independently associated with survival, whereas infection was not (P = .52). CONCLUSIONS: Severe AH is associated with high risk of infection. Infection screening is warranted but should not contraindicate steroids. In terms of mechanisms, nonresponse to steroids is the key factor in development of infection and prediction of survival. PMID- 19445946 TI - 6-Br-5methylindirubin-3'oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: exploitation of GSK-3 for treating leishmaniasis. AB - Indirubins known to target mammalian cyclin-dependent kinases (CDKs) and glycogen synthase kinase (GSK-3) were tested for their antileishmanial activity. 6-Br indirubin-3'-oxime (6-BIO), 6-Br-indirubin-3'acetoxime and 6-Br-5methylindirubin 3'oxime (5-Me-6-BIO) were the most potent inhibitors of Leishmania donovani promastigote and amastigote growth (half maximal inhibitory concentration (IC(50)) values < or =1.2 microM). Since the 6-Br substitution on the indirubin backbone greatly enhances the selectivity for mammalian GSK-3 over CDKs, we identified the leishmanial GSK-3 homologues, a short (LdGSK-3s) and a long one, focusing on LdGSK-3s which is closer to human GSK-3beta, for further studies. Kinase assays showed that 5-Me-6-BIO inhibited LdGSK-3s more potently than CRK3 (the CDK1 homologue in Leishmania), whilst 6-BIO was more selective for CRK3. Promastigotes treated with 5-Me-6-BIO accumulated in the S and G2/M cell-cycle phases and underwent apoptosis-like death. Interestingly, these phenotypes were completely reversed in parasites over-expressing LdGSK-3s. This finding strongly supports that LdGSK-3s is: (i) the intracellular target of 5-Me-6-BIO, and (ii) involved in cell-cycle control and in pathways leading to apoptosis-like death. 6 BIO treatment induced a G2/M arrest, consistent with inhibition of CRK3 and apoptosis-like death. These effects were partially reversed in parasites over expressing LdGSK-3s suggesting that in vivo 6-BIO may also target LdGSK-3s. Molecular docking of 5-Me-6-BIO in CRK3 and 6-BIO in human GSK-3beta and LdGSK-3s active sites predict the existence of functional/structural differences that are sufficient to explain the observed difference in their affinity. In conclusion, LdGSK-3s is validated as a potential drug target in Leishmania and could be exploited for the development of selective indirubin-based leishmanicidals. PMID- 19445947 TI - Functional characterisation of the maternal yolk-associated protein (LsYAP) utilising systemic RNA interference in the salmon louse (Lepeophtheirus salmonis) (Crustacea: Copepoda). AB - The salmon louse (Lepeophtheirus salmonis) is an important pathogen in salmon aquaculture and a serious threat to wild populations of salmon. Knowledge of its basic biological processes such as reproduction is crucial for the control of this parasite and can facilitate development of a vaccine. Here, a novel yolk associated protein, LsYAP, was characterised. Quantitative PCR and in situ analysis demonstrated that transcription of LsYAP takes place in the subcuticular tissue of adult females in the reproductive phase. LsYAP protein is transported and deposited in the developing eggs in the genital segment, where further processing takes place. The sequence characteristics, histological localisation and transcript regulation suggest that LsYAP is a yolk-associated protein. In addition, the use of RNA interference is, to our knowledge, demonstrated for the first time in a copepod. Treatment of adult females with double-stranded RNA led to lethality and deformations of offspring only. This result confirms that the LsYAP protein is produced in adult females but is utilised by the offspring. PMID- 19445948 TI - Impact of municipal effluents and hydrological regime on myxozoan parasite communities of fish. AB - Increased productivity from sewage effluents can enhance species richness locally. Results from a study of spottail shiners (Notropis hudsonius) in 1999 showed that prevalence and the mean number of myxozoan parasite species per host were higher downstream of the wastewater outflow from the Island of Montreal than upstream in the St. Lawrence River, Quebec, Canada. This was attributed to organic enrichment of the sediments which presumably lead to increased densities of oligochaetes, the alternate hosts, downstream of Montreal. Spottail shiners subsequently were collected every August/early September in 2001-2004 to examine the stability and repeatability of these patterns. Prevalence and mean number of myxozoan species per fish typically were again higher downstream of the sewage source each year compared to upstream, although there was no significant difference in these measurements pooled across years between localities immediately upstream and downstream of the effluent outflow. Density of the oligochaete Limnodrilus hoffmeistereri, a common alternate host of myxozoans, was much higher at two downstream localities than at an upstream one. At a larger spatial scale, mean myxozoan infracommunity richness across sites in the St. Lawrence River was negatively correlated with mean water levels measured in the 3 months prior to fish sampling. Results suggest that on a local scale, variations in prevalence and diversity among localities are influenced by municipal effluents, but that at a landscape scale annual variations across sites are affected by the hydrological regime and climate. In effect, water level fluctuation had a landscape-wide impact that was superimposed over pollution induced local variations. PMID- 19445949 TI - Dynamic regulatory interactions of rad51, rad52, and replication protein-a in recombination intermediates. AB - Rad51, Rad52, and replication protein-A (RPA) play crucial roles in the repair of DNA double-strand breaks in Saccharomyces cerevisiae. Rad51 mediates DNA strand exchange, a key reaction in DNA recombination. Rad52 recruits Rad51 into single stranded DNAs (ssDNAs) that are saturated with RPA. Rad52 also promotes annealing of ssDNA strands that are complexed with RPA. Specific protein-protein interactions are involved in these reactions. Here we report new biochemical characteristics of these protein interactions. First, Rad52-RPA interaction requires multiple molecules of RPA to be associated with ssDNA, suggesting that multiple contacts between the Rad52 ring and RPA-ssDNA filament are needed for stable binding. Second, RPA-t11, which is a recombination-deficient mutant of RPA, displays a defect in interacting with Rad52 in the presence of salt above 50 mM, explaining the defect in Rad52-mediated ssDNA annealing in the presence of this mutation. Third, ssDNA annealing promoted by Rad52 is preceded by aggregation of multiple RPA-ssDNA complexes with Rad52, and Rad51 inhibits this aggregation. These results suggest a regulatory role for Rad51 that suppresses ssDNA annealing and facilitates DNA strand invasion. Finally, the Rad51-double stranded DNA complex disrupts Rad52-RPA interaction in ssDNA and titrates Rad52 from RPA. This suggests an additional regulatory role for Rad51 following DNA strand invasion, where Rad51-double-stranded DNA may inhibit illegitimate second end capture to ensure the error-free repair of a DNA double-strand break. PMID- 19445950 TI - Kinetic buffering of cross talk between bacterial two-component sensors. AB - Two-component systems are a class of sensors that enable bacteria to respond to environmental and cell-state signals. The canonical system consists of a membrane bound sensor histidine kinase that autophosphorylates in response to a signal and transfers the phosphate to an intracellular response regulator. Bacteria typically have dozens of two-component systems. The key questions are whether these systems are linear and, if they are, how cross talk between systems is buffered. In this work, we studied the EnvZ/OmpR and CpxA/CpxR systems from Escherichia coli, which have been shown previously to exhibit slow cross talk in vitro. Using in vitro radiolabeling and a rapid quenched-flow apparatus, we experimentally measured 10 biochemical parameters capturing the cognate and non cognate phosphotransfer reactions between the systems. These data were used to parameterize a mathematical model that was used to predict how cross talk is affected as different genes are knocked out. It was predicted that significant cross talk between EnvZ and CpxR only occurs for the triple mutant DeltaompR DeltacpxA DeltaactA-pta. All seven combinations of these knockouts were made to test this prediction and only the triple mutant demonstrated significant cross talk, where the cpxP promoter was induced 280-fold upon the activation of EnvZ. Furthermore, the behavior of the other knockouts agrees with the model predictions. These results support a kinetic model of buffering where both the cognate bifunctional phosphatase activity and the competition between regulator proteins for phosphate prevent cross talk in vivo. PMID- 19445951 TI - Different members of a simple three-helix bundle protein family have very different folding rate constants and fold by different mechanisms. AB - The 15th, 16th, and 17th repeats of chicken brain alpha-spectrin (R15, R16, and R17, respectively) are very similar in terms of structure and stability. However, R15 folds and unfolds 3 orders of magnitude faster than R16 and R17. This is unexpected. The rate-limiting transition state for R15 folding is investigated using protein engineering methods (Phi-value analysis) and compared with previously completed analyses of R16 and R17. Characterisation of many mutants suggests that all three proteins have similar complexity in the folding landscape. The early rate-limiting transition states of the three domains are similar in terms of overall structure, but there are significant differences in the patterns of Phi-values. R15 apparently folds via a nucleation-condensation mechanism, which involves concomitant folding and packing of the A- and C helices, establishing the correct topology. R16 and R17 fold via a more framework like mechanism, which may impede the search to find the correct packing of the helices, providing a possible explanation for the fast folding of R15. PMID- 19445952 TI - Analysis of four-way junctions in RNA structures. AB - RNA secondary structures can be divided into helical regions composed of canonical Watson-Crick and related base pairs, as well as single-stranded regions such as hairpin loops, internal loops, and junctions. These elements function as building blocks in the design of diverse RNA molecules with various fundamental functions in the cell. To better understand the intricate architecture of three dimensional (3D) RNAs, we analyze existing RNA four-way junctions in terms of base-pair interactions and 3D configurations. Specifically, we identify nine broad junction families according to coaxial stacking patterns and helical configurations. We find that helices within junctions tend to arrange in roughly parallel and perpendicular patterns and stabilize their conformations using common tertiary motifs such as coaxial stacking, loop-helix interaction, and helix packing interaction. Our analysis also reveals a number of highly conserved base-pair interaction patterns and novel tertiary motifs such as A-minor-coaxial stacking combinations and sarcin/ricin motif variants. Such analyses of RNA building blocks can ultimately help in the difficult task of RNA 3D structure prediction. PMID- 19445953 TI - The vapBC operon from Mycobacterium smegmatis is an autoregulated toxin-antitoxin module that controls growth via inhibition of translation. AB - The largest family of bacterial toxin-antitoxin (TA) modules is formed by the vapBC operons, and these are grouped together by virtue of their toxin components belonging to the PilT N-terminal domain family of proteins that are thought to function as ribonucleases. We have identified a single vapBC operon in the genome of Mycobacterium smegmatis and herein report the molecular and biochemical characterisation of this TA module. In M. smegmatis, the vapBC genes are transcribed as a leaderless mRNA that is constitutively synthesised throughout the growth cycle. The vapBC operon is autoregulated by the VapBC protein complex as demonstrated by a threefold increase in vapBC expression (promoter-vapB-lacZ) in a DeltavapBC mutant. Electrophoretic mobility shift assays using purified VapBC protein complex show that the complex binds to inverted repeat DNA sequences in the vapBC promoter region that overlap the -35 and -10 promoter elements, thus explaining the autoregulation and the low-level constitutive expression of this operon in M. smegmatis. Neither a DeltavapBC nor a DeltavapB mutant strain exhibited any phenotypic deviation to that of the isogenic wild type parent strain under normal laboratory growth conditions, but conditional overexpression of VapC in M. smegmatis inhibited growth by a bacteriostatic mechanism and this phenotype is exacerbated in a DeltavapBC mutant. This effect is mediated through VapC-dependent inhibition of translation, not inhibition of DNA replication or transcription. The growth inhibitory effect of VapC was neutralised when co-expressed with its cognate antitoxin VapB. Western blot analysis revealed the overproduction of VapC under inducing conditions and that the VapC protein is not produced in the DeltavapB mutant despite the presence of mRNA transcript. Taken together, these data demonstrate that VapBC from M. smegmatis has all the hallmarks of a TA module with the capacity to cause growth inhibition by regulating translation. PMID- 19445954 TI - The folding mechanism of BBL: Plasticity of transition-state structure observed within an ultrafast folding protein family. AB - Studies on members of protein families with similar structures but divergent sequences provide insights into the effects of sequence composition on the mechanism of folding. Members of the peripheral subunit-binding domain (PSBD) family fold ultrafast and approach the smallest size for cooperatively folding proteins. Phi-Value analysis of the PSBDs E3BD and POB reveals folding via nucleation-condensation through structurally very similar, polarized transition states. Here, we present a Phi-value analysis of the family member BBL and found that it also folds by a nucleation-condensation mechanism. The mean Phi values of BBL, E3BD, and POB were near identical, indicating similar fractions of non covalent interactions being formed in the transition state. Despite the overall conservation of folding mechanism in this protein family, however, the pattern of Phi values determined for BBL revealed a larger dispersion of the folding nucleus across the entire structure, and the transition state was less polarized. The observed plasticity of transition-state structure can be rationalized by the different helix-forming propensities of PSBD sequences. The very strong helix propensity in the first helix of BBL, relative to E3BD and POB, appears to recruit more structure formation in that helix in the transition state at the expense of weaker interactions in the second helix. Differences in sequence composition can modulate transition-state structure of even the smallest natural protein domains. PMID- 19445955 TI - Xenopus laevis oocytes endogenously express all subunits of the ionotropic glutamate receptor family. AB - Xenopus laevis oocytes are commonly used as a heterologous expression system for the electrophysiological characterization of ionotropic glutamate receptors (iGluRs). Recently, however, several glutamate receptor subunits of the N-methyl d-aspartate receptor subfamily have been found to be expressed endogenously in Xenopus oocytes, thus limiting the use of this expression system for such receptors. We therefore screened oocytes for the Xenopus homologs of all iGluR subunits known to be expressed in mammals to investigate which additional subunits may be present endogenously in oocytes and what, if any, influence such proteins might have on the functional analysis of heterologously expressed receptors. We found Xenopus homologs of every mammalian iGluR subunit to be expressed at the mRNA level. We then cloned, from oocytes, full-length copies of the four Xenopus alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunits XenGluR1 through XenGluR4 and, additionally, XenGluR6 as a representative subunit for the kainate receptor subfamily and electrophysiologically characterized them. Upon analysis, we found only minor functional differences between homologous subunits from Xenopus and rat. Next, we investigated whether endogenous iGluR subunits can be detected electrophysiologically in oocytes. We found no indication for any functional glutamate receptors in native oocytes; however, after heterologous expression of the auxiliary subunit stargazin, endogenous alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionate receptors were detected. These data demonstrate that Xenopus oocytes express glutamate receptor subunits endogenously, albeit at very low levels. Such endogenous receptor proteins can, under certain circumstances, become electrophysiologically detectable and then might influence electrophysiological recordings performed on recombinant receptors in oocytes. PMID- 19445956 TI - RNA dimerization promotes PKR dimerization and activation. AB - The double-stranded RNA (dsRNA)-activated protein kinase [protein kinase R (PKR)] plays a major role in the innate immune response in humans. PKR binds dsRNA non sequence specifically and requires a minimum of 15-bp dsRNA for one protein to bind and 30-bp dsRNA to induce protein dimerization and activation by autophosphorylation. PKR phosphorylates eukaryotic initiation factor 2alpha, a translation initiation factor, resulting in the inhibition of protein synthesis. We investigated the mechanism of PKR activation by an RNA hairpin with a number of base pairs intermediate between these 15- to 30-bp limits: human immunodeficiency virus type 1 transactivation-responsive region (TAR) RNA, a 23 bp hairpin with three bulges that is known to dimerize. TAR monomers and dimers were isolated from native gels and assayed for RNA and protein dimerization to test whether RNA dimerization affects PKR dimerization and activation. To modulate the extent of dimerization, we included TAR mutants with different secondary features. Native gel mixing experiments and analytical ultracentrifugation indicate that TAR monomers bind one PKR monomer and that TAR dimers bind two or three PKRs, demonstrating that RNA dimerization drives the binding of multiple PKR molecules. Consistent with functional dimerization of PKR, TAR dimers activated PKR while TAR monomers did not, and RNA dimers with fewer asymmetrical secondary-structure defects, as determined by enzymatic structure mapping, were more potent activators. Thus, the secondary-structure defects in the TAR RNA stem function as antideterminants to PKR binding and activation. Our studies support that dimerization of a 15- to 30-bp hairpin RNA, which effectively doubles its length, is a key step in driving activation of PKR and provide a model for how RNA folding can be related to human disease. PMID- 19445957 TI - Wind gusts and plant aeroelasticity effects on the aerodynamics of pollen shedding: a hypothetical turbulence-initiated wind-pollination mechanism. AB - Plant reproduction depends on pollen dispersal. For anemophilous (wind pollinated) species, such as grasses and many trees, shedding pollen from the anther must be accomplished by physical mechanisms. The unknown nature of this process has led to its description as the 'paradox of pollen liberation'. A simple scaling analysis, supported by experimental measurements on typical wind pollinated plant species, is used to estimate the suitability of previous resolutions of this paradox based on wind-gust aerodynamic models of fungal-spore liberation. According to this scaling analysis, the steady Stokes drag force is found to be large enough to liberate anemophilous pollen grains, and unsteady boundary-layer forces produced by wind gusts are found to be mostly ineffective since the ratio of the characteristic viscous time scale to the inertial time scale of acceleration of the wind stream is a small parameter for typical anemophilous species. A hypothetical model of a stochastic aeroelastic mechanism, initiated by the atmospheric turbulence typical of the micrometeorological conditions in the vicinity of the plant, is proposed to contribute to wind pollination. PMID- 19445958 TI - Re: Therapy against organophosphate poisoning: the importance of anticholinergic drugs with antiglutamatergic properties (Toxicol. Appl. Pharmacol. 232, 351-358, 2008). PMID- 19445959 TI - A Kazal-type serine proteinase inhibitor from chicken liver (clTI-1): purification, primary structure, and inhibitory properties. AB - Low-molecular-mass trypsin inhibitor (clTI-1; chicken liver Trypsin Inhibitor-1) was purified from chicken liver by extraction with perchloric acid, ammonium sulfate precipitation, a combination of ethanol-acetone fractionation followed by gel filtration, ion-exchange chromatography and RP-HPLC on a C18 column. The inhibitor occurs in two isoforms with molecular masses of 5938.56 and 6026.29 Da (determined by MALDI TOFF mass spectrometry). The complete amino acid sequences of both isoforms were determined (UniProtKB/Swiss-Prot P85000; ISK1L_CHICK). The inhibitor shows a high homology to Kazal-type family inhibitors, especially to trypsin/acrosin inhibitors and pancreatic secretory trypsin inhibitors. clTI-1 inhibits both bovine and porcine trypsin (K(a)=1.1 x 10(9) M(-1) and 2.5 x 10(9) M(-1), respectively). Significant differences were shown in the inhibition of the anionic and cationic forms of chicken trypsin (K(a)=4.5 x 10(8) M(-1) and 1.2 x 10(10) M(-1)). Weak interaction with human plasmin (K(a)=1.2 x 10(7) M(-1)) was also revealed. PMID- 19445960 TI - Selective separation of human serum albumin with copper(II) chelated poly(hydroxyethyl methacrylate) based nanoparticles. AB - Poly(hydroxyethyl methacrylate) (PHEMA) nanoparticles with an average size of 300 nm in diameter and with a polydispersity index of 1.156 were produced by surfactant free emulsion polymerization. Specific surface area of the PHEMA nanoparticles was found to be 996 m(2)/g. Metal-chelating ligand 3-(2-imidazoline 1-yl)propyl(triethoxysilane) (IMEO) was covalently attached to the PHEMA nanoparticles. IMEO content was 0.97 mmol IEMO/g. The morphology and properties of these nanoparticles were characterized with scanning electron microscopy, Fourier transform infrared spectroscopy and atomic force microscopy. The Cu2+ chelated PHEMA-IMEO nanoparticles were used in the adsorption-elution studies of human serum albumin (HSA) in a batch system. Maximum HSA adsorption amount of the Cu2+ chelated nanoparticles was 680 mg HSA/g. The PHEMA-IMEO-Cu2+ nanoparticles exhibited a quite high adsorption capacity and fast adsorption rate due to their high specific surface area and the absence of internal diffusion resistance. PMID- 19445961 TI - Proteome response to ochratoxin A-induced apoptotic cell death in mouse hippocampal HT22 cells. AB - Mycotoxins are commonly encountered natural products, and are capable of poisoning animals or humans that inhale mold particles from mycotoxin contaminated foods. Ochratoxin A (OTA) is produced by Aspergillu ochracus and Penicillium verrucosum, and is often found in cereals and agricultural products. Although previous studies have focused on the potent nephrotoxicity and renal carcinogenicity of OTA, more recent studies suggest that it accumulates in the brain and causes oxidative stress and DNA damage in various brain regions and neuronal populations. In the present study, we undertook to investigate the potential harm caused by environmental exposure to OTA in terms of its effects on neuronal cell viability and proteome profiles. OTA was found to significantly reduce the viabilities of human neuroblastoma SH-SY5Y and mouse hippocampal HT22 cells, as assessed by lactic dehydrogenase release into culture media. Generation of reactive oxygen species was detected in OTA-treated SH-SY5Y and HT22 cells, however, caspase activation and increase in p53 phosphorylation were only detected in HT22 cells, and the expressions of several proteins were found to be significantly altered after treating HT22 cells with OTA. Valosin containing protein, prolyl 4-hydroxylase, Atp5b protein, nucleophosmin 1, eukaryotic translation elongation factor 1 delta isoform, ornithine aminotransferase, prohibitin, and peroxiredoxin 6, which have been suggested to be implicated in the pathogenesis of neurodegenerative disorders, were up-regulated. Our findings suggest that coordinated regulations of molecular networks are involved in the OTA-induced cytotoxicity and that proteome response can be an indicative for neurodegeneration. PMID- 19445963 TI - Distinguishing childhood absence epilepsy patients from controls by the analysis of their background brain electrical activity (II): a combinatorial optimization approach for electrode selection. AB - In this sequel to our previous work [Rosso OA, Mendes A, Rostas JA, Hunter M, Moscato P. Distinguishing childhood absence epilepsy patients from controls by the analysis of their background brain electrical activity. J. Neurosci. Methods 2009;177:461-68], we extend the analysis of background electroencephalography (EEG), recorded with scalp electrodes in a clinical setting, in children with childhood absence epilepsy (CAE) and control individuals. The same set of individuals was considered-five CAE patients, all right-handed females and aged 6 8 years. The EEG was obtained using bipolar connections from a standard 10-20 electrode placement. The functional activity between electrodes was evaluated using a wavelet decomposition in conjunction with the Wootters distance. In the previous study, a Kruskal-Wallis statistical test was used to select the pairs of electrodes with differentiated behavior between CAE and control samples (classes). In this contribution, we present the results for a combinatorial optimization approach to select the pairs of electrodes. The new method produces a better separation between the classes, and at the same time uses a smaller number of features (pairs of electrodes). It managed to almost halve the number of features and also improves the separation between the CAE and control samples. The new results strengthen the hypothesis that mostly fronto-central electrodes carry useful information and patterns that can help to discriminate CAE cases from controls. Finally, we provide a comprehensive set of tests and in-depth explanation of the method and results. PMID- 19445962 TI - Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease. AB - It has been hypothesized that polymorphisms of Tumor Necrosis Factor (TNF)-alpha gene affect the risk of developing Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta analysis the association of the common polymorphisms comprehensively defining the genetic variability of the TNF-alpha gene with AD risk. Hence, the results being stated are of a meta-analysis across studies, and that this meta-analysis does not invalidate the results of the individual studies previously performed. Seventeen studies that investigated the association between 5 TNF-alpha polymorphisms (-850, -308, -863, -238, and -1031) and AD were retrieved and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested a significant association between -850 polymorphism and AD risk (TT vs. TC+CC: pooled odds ratio [OR], 1.61; 95% confidence interval [CI], 1.08-2.29; p=0.02) with no evidence of between-study heterogeneity (chi(2), p>0.1). Subgroup analysis suggested that the possession of T allele significantly increased the risk of AD associated with carriage of the apolipoprotein E epsilon 4 allele in Caucasian Australians and Northern Europeans (TT+TC vs. CC: OR, 1.95; 95% CI, 1.45-2.62; p=0.00001; p>0.1; chi(2) for heterogeneity, p>0.1). No significant difference in genotype distribution of -308 polymorphism in AD was found, with a high degree of between study heterogeneity. For the -863 and -1031 polymorphisms we did not find an association with AD, but significant between-study heterogeneity discouraged genotype data pooling. Only four studies investigated the -238 variant and the results were not significant. Current findings support an association between 850 C>T polymorphism and the risk of developing AD; hence, they strengthen the suggestion of a potential role for anti-TNF therapy to maintain physiologic levels of TNF-alpha. PMID- 19445964 TI - Quantitative RT real time PCR and indirect immunofluorescence for the detection of human parainfluenza virus 1, 2, 3. AB - Human parainfluenza viruses (HPIVs) are distributed worldwide and are involved mainly in the pathogenesis of respiratory tract infections. The development and optimization of three quantitative reverse transcription real time polymerase chain reactions (RT Real Time Qt-PCRs) and an indirect immunofluorescence (IFA) for the detection and quantitation of HPIV-1, -2 and -3 in clinical samples are described. Efficiency, sensitivity, specificity, inter- and intra-assay variability and turnaround time of the two methods were compared. These assays have been validated on 131 bronchoalveolar lavage specimens. Based on the results obtained, the molecular methods represent a valid and rapid tool for clinical management and should be included in diagnostic panels aimed to evaluate suspected respiratory tract infections. PMID- 19445965 TI - Antiviral activity of indole derivatives. AB - Unsymmetrical methylene derivatives 5 were prepared following a known method, by reaction of the Mannich bases of 2-naphthols 4 with indoles. All synthesized compounds were tested against a wide panel of viruses, since previous work showed that Mannich bases on 7-hydroxycoumarin 1 and unsymmetrical methylene derivatives 2 were endowed with some antiviral activities. The symmetrical Mannich bases 4 were completely inactive, whereas the unsymmetrical methylene derivatives 5, although possessing a certain degree of toxicity, showed a significant activity against RSV. Some of compounds 5 showed a moderate antiviral activity against HIV 1, BVDV, YFV and CVB-2. The lack of activity of Mannich bases 4 demonstrates the crucial importance for antiviral activity of coumarin moiety present in Mannich bases 1. PMID- 19445966 TI - Rule learning, visuospatial function and motor performance in the Hdh(Q92) knock in mouse model of Huntington's disease. AB - Among a range of genetic mouse models of Huntington's disease, knock-in models that express full-length mutant huntingtin tend to have a slower developing and less severe behavioural phenotype than transgenic models carrying truncated variations of the human gene; as a result, these more subtle full-length knock-in models have been relatively neglected for behavioural and therapeutic studies. In the current study, we show that full-length knock-in Hdh(Q92) mice exhibit marked impairments at a relatively young age in delayed alternation, a cognitive test conducted in 9-hole operant chambers classically associated with prefrontal and corticostriatal function. Additional tests of motivation, visuomotor and rotarod performance were undertaken to determine the frontal-like specificity of the impairment; aspects of sensorimotor and motivational as well as cognitive performance were deficient in Hdh(Q92/Q92) mice in comparison with their wildtype littermates by 27 months of age. The present results demonstrate that Hdh(Q92/Q92) mice do exhibit clear impairments on a range of sensory, motor, motivational and cognitive tests, provided appropriate sensitive tasks are used. PMID- 19445967 TI - Acoustic features to arousal and identity in disturbance calls of tree shrews (Tupaia belangeri). AB - Across mammalian species, comparable morphological and physiological constraints in the production of airborne vocalisations are suggested to lead to commonalities in the vocal conveyance of acoustic features to specific attributes of callers, such as arousal and individual identity. To explore this hypothesis we examined intra- and interindividual acoustic variation in chatter calls of tree shrews (Tupaia belangeri). The calls were induced experimentally by a disturbance paradigm and related to two defined arousal states of a subject. The arousal state of an animal was primarily operationalised by the habituation of the subject to a new environment and additionally determined by behavioural indicators of stress in tree shrews (tail-position and piloerection). We investigated whether the arousal state and indexical features of the caller, namely individual identity and sex, are conveyed acoustically. Frame-by-frame videographic and multiparametric sound analyses revealed that arousal and identity, but not sex of a caller reliably predicted spectral-temporal variation in sound structure. Furthermore, there was no effect of age or body weight on individual-specific acoustic features. Similar results in another call type of tree shrews and comparable findings in other mammalian lineages provide evidence that comparable physiological and morphological constraints in the production of airborne vocalisations across mammals lead to commonalities in acoustic features conveying arousal and identity, respectively. PMID- 19445968 TI - The bilobe structure of Trypanosoma brucei contains a MORN-repeat protein. AB - The Golgi of the kinetoplastid parasite Trypanosoma brucei is closely apposed to a bilobe structure containing TbCentrin2 and TbCentrin4 in procyclic cells. However, both are additionally localized to the basal bodies. Here we report the characterization of a membrane occupation and recognition nexus (MORN)-repeat protein, TbMORN1, present at the bilobe but not at the basal body. The anterior part of the TbMORN1 structure partially overlapped with the flagellar attachment zone while the posterior part overlapped with the flagellar pocket. Depletion studies using RNAi showed that there was a modest growth inhibition in procyclic cells but lethality in bloodstream cells, showing that it is an essential protein in the bloodstream form of the organism. TbMORN1 appears to be a useful marker for the bilobe in T. brucei. PMID- 19445969 TI - Regional distribution and the dynamics of n-decanoyl ghrelin, another acyl-form of ghrelin, upon fasting in rodents. AB - n-Decanoyl ghrelin (D-ghrelin), a member of ghrelin-derived peptides, is found in plasma and the stomach; however, there have so far been no studies describing its dynamics. A D-ghrelin-specific radioimmunoassay was established to examine the tissue distribution and the kinetics of D-ghrelin in mice. The effect of D ghrelin on food intake was also examined and compared to n-octanoyl ghrelin (O ghrelin). D-ghrelin was detected throughout the gastrointestinal tissue and plasma with highest level in the stomach. An immunofluorescent study revealed the co-localization of D- and O-ghrelin in the same stomach cells. Upon fasting, the levels of D-ghrelin in the stomach and plasma significantly increased, while that of O-ghrelin in the stomach declined. D-ghrelin increased the 2 h food consumption in mice as O-ghrelin does. These findings indicate that D-ghrelin is mainly produced in the stomach to work in concert with O-ghrelin. The different kinetics of D- and O-ghrelin in the stomach upon fasting implies the possibility of D-ghrelin-specific bioregulation. PMID- 19445971 TI - The role of store-operated Ca2+ channels in adrenocorticotropin release by rat pituitary cells. AB - In this study, we investigated the role of store-operated Ca2+ channels (SOCC) on ACTH release using microperifusion system. The SOCC blockers, SKF96365 and MRS1845, did not affect the ACTH response to single AVP stimulation. After the depletion of intracellular Ca2+ stores by treating with ionomycin, SOCC blockers reduced the initial spike phase of ACTH response to AVP, which is mediated by inositol 1,4,5-trisphosphate-induced intracellular Ca2+ release from the endoplasmic reticulum (ER). The sustained plateau phase of ACTH response, which is mediated by protein kinase C leading Ca2+ influx via L-type voltage-dependent Ca2+ channels, was not affected. Addition of L-type voltage-dependent Ca2+ channel blocker nimodipine with the SOCC blockers reduced both the initial spike and sustained phases of ACTH response to AVP. Even after ER Ca2+ depletion, the SOCC blockers did not affect the ACTH response to CRH, which is mediated by cAMP dependent protein kinase A. Transient receptor potential (TRP) C channel is the strongest candidate for SOCC, and RT-PCR revealed that all types of TRPC homologue mRNA were expressed in rat anterior pituitary cells. In conclusion, the SOCC mediates the initial spike phase of ACTH response to AVP, possibly via ER Ca2+ store refilling to induce maximum response. PMID- 19445970 TI - Inhibitory effects of somatostatin on cholecystokinin octapeptide induced bile regurgitation under stress: ionic and molecular mechanisms. AB - OBJECTIVE: To investigate the possible effects and related ionic and molecular mechanisms of changes of plasma cholecystokinin octapeptide and somatostatin on stress-induced bile regurgitation in rats. METHODS: In forty healthy adult rats, changes of plasma cholecystokinin octapeptide, somatostatin and intragastric bile concentration under stressful condition were respectively measured by specific radioimmunoassay methods. Contractile responses of gastric antral smooth strips isolated from healthy adult rats were recorded by polyphysiograph. Immunoprecipitation was used to determine the regulatory effect of protein kinase C on regulating the phosphorylation of type 3 inositol 1,4,5-triphosphate receptor (InsP3R3) in gastric smooth muscle cells. Changes of intracellular calcium fluorescence intensity of smooth muscle cells presented as intracellular calcium ([Ca2+]i) were analyzed under laser scanning confocal microscopy and L type voltage-dependent calcium currents of smooth muscle cells were recorded by patch-clamp techniques. RESULTS: Compared with the normal control group, plasma cholecystokinin octapeptide and gastric bile concentration of each stress group significantly increased during the stress, while adverse effect was obtained in plasma somatostatin, which decreased from the beginning of the stress and attained the minimum nearly at the same time when the plasma cholecystokinin octapeptide concentration reached the maximum. Respective addition of cholecystokinin octapeptide and somatostatin with increasing concentrations caused rapid, sustained, concentration-dependent increase and decrease in muscle contraction of gastric antral strips, and cholecystokinin octapeptide that increased the contractile response could be blocked by respective administration of nifedipine and somatostatin significantly. Similar results were obtained in the changes of calcium fluorescence intensity and calcium currents of smooth muscle cells. Pretreatment with somatostatin significantly increased cholecystokinin octapeptide-increased phosphorylation of InsP3R3 in smooth muscle cells. CONCLUSIONS: Gastric mucosal damage induced by bile regurgitation is closely connected with gastric antral dysmotility evoked by the changes of cholecystokinin octapeptide and somatostatin under stressful condition. Cholecystokinin octapeptide-intensified contraction depends on the release of intracellular calcium stores and the influx of extracellular calcium via L-type voltage-dependent calcium channels, while this excitatory effect of cholecystokinin octapeptide could be blocked by somatostatin, suggesting that both of the two peptides play important roles in the regulation of gastric motility. PMID- 19445972 TI - Losartan exerts renoprotection through NAD(P)H oxidase downregulation in a renovascular model of hypertension. AB - This study was performed to provide insight into the regulatory role of angiotensin II and arterial pressure on the activity of antioxidant enzymes and oxidative stress generation in the hypertensive kidney from an experimental animal model of renovascular hypertension. Aortic coarcted and sham-operated rats received vehicle, losartan or minoxidil in their drinking water. After 7 d of treatment rats were sacrificed; hypertensive kidneys were excised, and the NAD(P)H oxidase subunits expression, TBARS production, glutathione level and the activity of heme oxygenase-1 and classical antioxidant enzymes, were evaluated. Losartan administration significantly reduced oxidative stress generation decreasing NAD(P)H oxidase expression, independently of the drop in arterial pressure. On the other hand, antioxidant enzymes were regulated by arterial pressure and they were not implicated in kidney protection against oxidative damage. Findings here reported strongly suggest that clinical therapeutics with the Ang II type 1 receptor blocker prevents oxidative stress generation and may attenuate the kidney oxidative damage in the renovascular hypertension. We hypothesize that the pathway followed by the Ang II blocker to achieve this renoprotection, though independent of the primary antioxidant enzymatic system, depends on NAD(P)H oxidase downregulation. PMID- 19445973 TI - The expression of human resistin in different leucocyte lineages is modulated by LPS and TNFalpha. AB - OBJECTIVE: Human resistin has been linked to several inflammatory diseases such as atherosclerosis. This study aimed to clarify the expression of resistin in different inflammatory cells and its effect on endothelial cells. RESULTS: In this study, RNA and protein expression of resistin were detected in human primary neutrophils, monocytes, and T cells as well as in human Jurkat T cells, RPMI-8226 B cells, monocytic U937, and myeloblastic HL-60 cell lines. The highest resistin protein and mRNA level were detected in neutrophils, primary monocytes, and monocytic U937 cells. The RNA expression of resistin was upregulated both in neutrophils and in U937 cells after exposure to LPS. Also TNFalpha induced resistin RNA expression in neutrophils, U937, T-lymphocytic Jurkat cells, and B lymphocytic RPMI-8226 cells. The RNA and protein expression of resistin decreased as the monocytic U937 cells differentiated into macrophage-like cells. In endothelial EA.hy 926 cells, resistin increased the expression of MCP-1 and PECAM 1 and adhesion of monocytes to endothelial cells. CONCLUSIONS: The wide-ranging expression of resistin in white blood cells and the upregulation of its expression by inflammatory reagents LPS and TNFalpha support the fact that increased resistin could be involved in several inflammatory diseases. PMID- 19445974 TI - Cannabinoid CB1 receptor elevation of intracellular calcium in neuroblastoma SH SY5Y cells: interactions with muscarinic and delta-opioid receptors. AB - Although coupled to G(i/o) proteins, cannabinoid CB(1) receptors can also activate intracellular Ca(2+) ([Ca(2+)](i)) accumulation through not fully understood mechanisms. We report that in, human neuroblastoma SH-SY5Y cells, CB(1) activation with the specific agonist arachidonoylchloroethanolamide (ACEA), weakly elevates [Ca(2+)](i) and that this effect, when using low (1-100 nM) concentrations of ACEA, is enhanced by the previous activation of G(q/11)-coupled M(3) muscarinic receptors with carbachol, dose-dependently and up to approximately 8-fold. A similar behaviour was also observed with carbachol and the G(i/o)-coupled delta-opioid receptor. Furthermore, stimulation of CB(1) receptors produced a concentration-dependent leftward shift of the elevation of [Ca(2+)](i) by delta-opioid receptors. These stimulatory effects were variedly attenuated by selective antagonists of each receptor, pertussis toxin, inhibitors of phospholipase C (U73122 and D609), and, when assessed in the presence of extracellular Ca(2+), by the block of voltage-activated calcium channels. Cholera toxin only slightly inhibited the G(q/11)-G(i/o)-mediated cross-talk, but induced a stronger inhibition of the G(i/o)-G(i/o)-mediated interaction. These findings suggest that activation of M(3) muscarinic receptors might produce a qualitative alteration of the signaling associated with G(i/o)-coupled receptors, and that sequential activation of CB(1) and delta-opioid receptors, both coupled to G(i/o), produces instead synergistic effects on [Ca(2+)](i) elevation. PMID- 19445975 TI - MALDI-TOF mass spectrometry for quantitative gene expression analysis of acid responses in Staphylococcus aureus. AB - Microorganisms are constantly exposed to new and altered growth conditions, and respond by changing gene expression patterns. Several methods for studying gene expression exist. During the last decade, the analysis of microarrays has been one of the most common approaches applied for large scale gene expression studies. A relatively new method for gene expression analysis is MassARRAY, which combines real competitive-PCR and MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry. In contrast to microarray methods, MassARRAY technology is suitable for analysing a larger number of samples, though for a smaller set of genes. In this study we compare the results from MassARRAY with microarrays on gene expression responses of Staphylococcus aureus exposed to acid stress at pH 4.5. RNA isolated from the same stress experiments was analysed using both the MassARRAY and the microarray methods. The MassARRAY and microarray methods showed good correlation. Both MassARRAY and microarray estimated somewhat lower fold changes compared with quantitative real-time PCR (qRT-PCR). The results confirmed the up-regulation of the urease genes in acidic environments, and also indicated the importance of metal ion regulation. This study shows that the MassARRAY technology is suitable for gene expression analysis in prokaryotes, and has advantages when a set of genes is being analysed for an organism exposed to many different environmental conditions. PMID- 19445976 TI - A modular system for Clostridium shuttle plasmids. AB - Despite their medical and industrial importance, our basic understanding of the biology of the genus Clostridium is rudimentary in comparison to their aerobic counterparts in the genus Bacillus. A major contributing factor has been the comparative lack of sophistication in the gene tools available to the clostridial molecular biologist, which are immature, and in clear need of development. The transfer and maintenance of recombinant, replicative plasmids into various species of Clostridium has been reported, and several elements suitable as shuttle plasmid components are known. However, these components have to-date only been available in disparate plasmid contexts, and their use has not been broadly explored. Here we describe the specification, design and construction of a standardized modular system for Clostridium-Escherichia coli shuttle plasmids. Existing replicons and selectable markers were incorporated, along with a novel clostridial replicon. The properties of these components were compared, and the data allow researchers to identify combinations of components potentially suitable for particular hosts and applications. The system has been extensively tested in our laboratory, where it is utilized in all ongoing recombinant work. We propose that adoption of this modular system as a standard would be of substantial benefit to the Clostridium research community, whom we invite to use and contribute to the system. PMID- 19445977 TI - Efficient pyramidal arrangement of an ordered cosmid library: Rapid screening of genes of the tacrolimus-producer Streptomyces sp. ATCC 55098. AB - A gene library is a useful tool for molecular biology studies, but the classical screening of multiple plates is laborious and time-consuming. Cosmid gene libraries are particularly well suited for isolation of large gene clusters encoding the biosynthetic pathways of secondary metabolites in Streptomyces. A gene library of the immunosuppressant tacrolimus-producer strain Streptomyces sp. ATCC 55098 was constructed in the SuperCos1 vector and 1656 clones were organized in an easy pyramidal arrangement system. This clustering method allows a dual efficient screening (PCR and in situ colony hybridization) of the gene library in a two-step method by using only one 96-well plate. The dual screening combines the advantages of both techniques, the swiftness of PCR and the robustness of colony hybridization. PMID- 19445978 TI - Two types of tyrosine hydroxylase positive GABAergic juxtaglomerular neurons in the mouse main olfactory bulb are different in their time of origin. AB - Tyrosine hydroxylase (TH) positive juxtaglomerular neurons in the olfactory bulb consist of at least two groups with different soma sizes. On the other hand TH positive neurons are known to be generated continuously in the postnatal and even adult periods. We investigated the birth dates of small- and large-sized TH positive juxtaglomerular neurons. 5-Bromo-2'-deoxyuridine (BrdU) was injected at various developmental and juvenile stages and BrdU-labeled neurons were examined in adult mice. We revealed that both small- and large-sized TH positive neurons were generated at embryonic and perinatal periods and that TH positive neurons generated at the juvenile period were small-sized but not large-sized juxtaglomerular cells. PMID- 19445979 TI - Effect of fermentation temperature on validamycin A production by Streptomyces hygroscopicus 5008. AB - Validamycin A (VAL-A), produced by Streptomyces hygroscopicus, is an important anti-fungal agro-antibiotic. In this work, the effect of fermentation temperature on VAL-A biosynthesis by S. hygroscopicus 5008 was investigated between 28 degrees C and 42 degrees C, and an interesting threshold of temperature for VAL-A biosynthesis was found between 35 degrees C and 37 degrees C. At a relatively higher temperature, a much higher VAL-A productivity was obtained together with faster protein synthesis and sugar consumption. Transcriptional analysis of samples from early, middle and late stages of fermentation at various temperatures demonstrated that three operons, valABC, valKLMN and valG, for all eight necessary structure genes, were dramatically promoted when temperature reached the threshold. Activities of both glucose-6-phosphate dehydrogenase (G6PDH) of pentose-phosphate pathway and ValG of VAL-A biosynthesis were also enhanced at a higher cultivation temperature. The interesting temperature effect with a 2 degrees C threshold shift from 35 degrees C to 37 degrees C on the antibiotic biosynthesis was understood to be related to the gene transcriptional levels and key enzyme activities. PMID- 19445980 TI - Mechanistic study of the adjuvant effect of biodegradable nanoparticles in mucosal vaccination. AB - For oral vaccination, incorporation of antigens into nanoparticles has been shown to protect the antigen from degradation, but may also increase its uptake through the intestinal epithelium via M-cells. The aim of this study was to understand the mechanisms by which oral administration of antigen-loaded nanoparticles induces an immune response and to analyze the effect of the nanoparticle composition on these mechanisms. Nanoparticles made from chitosan (CS) and its N trimethylated derivative, TMC, loaded with a model antigen ovalbumin (OVA) were prepared by ionic gelation with tripolyphosphate. Intraduodenal vaccination with OVA-loaded nanoparticles led to significantly higher antibody responses than immunization with OVA alone. TMC nanoparticles induced anti-OVA antibodies after only a priming dose. To explain these results, the interaction of nanoparticles with the intestinal epithelium was explored, in vitro, using a follicle associated epithelium model and visualized, ex vivo, using confocal laser scanning microscopy. The transport of FITC-OVA-loaded TMC nanoparticles by Caco-2 cells or follicle associated epithelium model was higher than FITC-OVA-loaded CS or PLGA nanoparticles. The association of nanoparticles with human monocyte derived dendritic cells and their effect on their maturation were determined with flow cytometry. TMC nanoparticles but not CS or PLGA nanoparticles had intrinsic adjuvant effect on DCs. In conclusion, depending on their composition, nanoparticles can increase the M-cell dependent uptake and enhance the association of the antigen with DC. In this respect, TMC nanoparticles are a promising strategy for oral vaccination. PMID- 19445981 TI - Drug delivery systems in HIV pharmacotherapy: what has been done and the challenges standing ahead. AB - Worldwide, over 40 million people are infected with the Human Immunodeficiency Virus (HIV). The High Activity Antiretroviral Therapy (HAART) combines at least three antiretroviral (ARV) drugs and, for over a decade, has been used to extend the lifespan of the HIV-infected patients. Chronic intake of HAART is mandatory to control HIV infection. The frequent administration of several drugs in relatively high doses is a main cause of patient incompliance and a hurdle toward the fulfillment of the pharmacotherapy. High adherence to HAART does not lead to complete HIV virus elimination from the host. Intracellular and anatomical viral reservoirs are responsible for the perpetuation of the infection. Active transport mechanisms involving proteins of the ATP-binding cassette superfamily prevent the penetration of ARV drugs into the brain and may account for the limited bioavailability after oral administration. A new research that addresses from simple organoleptic or technological problems to more complex issues involving the targeting of specific tissues and organs has emerged. With the aim to reduce dosing frequency, to improve the compliance of the existing pharmacotherapy and to target viral reservoirs, the design of drug delivery systems (DDS) is becoming complementary to new drug discovery. Based on the common molecular features that characterize the different families of ARV drugs, the present review describes state-of-the-art ARV DDS and thoroughly discusses the challenges in the development of medicines with enhanced biopharmaceutical properties. In addition, a number of specific issues such as pediatric HAART, preventive pharmacotherapy and specific HIV-associated ethical issues are addressed in an integrative manner. Finally, the impact of such novel drug development on the Pharmaceutical Technology field is discussed. PMID- 19445982 TI - Diagnostic nanocarriers for sentinel lymph node imaging. AB - In the last decade, methods for the precise localization of sentinel lymph node (SLN) have drawn tremendous attention by cancer surgeons and researchers in the field of medical diagnosis. The accurate identification and characterization of lymph nodes by imaging has important therapeutic and prognostic significance in patients with newly diagnosed cancers. The SLN is the first lymph node that receives lymphatic drainage from the site of a primary tumor. The sentinel node is much more likely to contain metastatic tumor cells than other lymph nodes in the same region. Amongst the various exploited methods for SLN diagnosis, nanocarriers have received increasing attention as lymph node delivery agents. The present review focuses on various such particulate carriers namely radiolabeled sulfur colloids, liposomes, quantum dots, dendrimers and magnetic nanoparticles, which are most extensively studied and have been attributed with the most desirable characteristics for SLN imaging. PMID- 19445983 TI - Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis. AB - Protease-sensitive macromolecular prodrugs have attracted interest for bio responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation. PMID- 19445984 TI - Mirena (Levonorgestrel intrauterine system): a successful novel drug delivery option in contraception. AB - This manuscript serves as a review of Mirena, the levonorgestrel intrauterine system (LNG IUS) as a very successful drug delivery system. The LNG IUS has a very high contraceptive efficacy rate, and low rates of patient discontinuation. In addition to its contraceptive benefits, most users experience a decrease in menstrual bleeding over the 5 years of use. LNG IUS has also been used for management of menorrhagia, dysmenorrhea, adenomyosis, and endometrial hyperplasia in some cases. The LNG IUS provides long term efficacy, high rates of compliance, rapid return to fertility, and minimal adverse effects during use. PMID- 19445985 TI - An association between eating disorder behaviors and autonomic dysfunction in a nonclinical population. A pilot study. AB - This pilot study examines the relationship between eating disorder behaviors and autonomic dysfunction in a nonclinical sample (n = 27). Baseline indices of eating disorder behaviors were evaluated via the Eating Disorder Examination Questionnaire. Supine resting heart rate variability was assessed via electrocardiogram for a 5-min recording period. A spectral analysis was performed. High frequency power density (s2/Hz) increased as a function of heightened disordered eating behaviors. Autonomic dysfunction, as indicated by increased high frequency power density due to hypervagal activity, is associated with eating disorder behaviors. Results suggest autonomic dysfunction may exist in nonclinical eating disorder populations. Future research needs to further examine this possibility. PMID- 19445986 TI - Effects of social modeling on young women's nutrient-dense food intake. AB - We examined whether a same-sex peer's vegetable consumption would predict the number of vegetable pieces eaten by the participant. A total of 116 Dutch women (M age = 20.28; M BMI = 21.68) participated. Their nutrient-dense food intake was measured during a 15-min break between two tasks, consisting of rating television advertisements. Participants consumed more vegetables when exposed to a peer eating a large number of vegetables than when exposed to a peer eating a small number or nothing. These findings suggest that social modeling processes may be relevant to interventions aimed at encouraging young women's nutrient-dense food intake. PMID- 19445987 TI - The effect of the consumption of water on the memory and attention of children. AB - The impact of asking children to drink water during their school days, and its possible influence on school performance, has been little considered using intervention studies. Therefore in the afternoon the cognitive functioning of 40 children (mean of 8 years and 7 months) was assessed twice, once after drinking 300 ml of water and on another day when no water was provided. Memory was assessed by the recall of 15 previously presented objects. Recall was significantly better on the occasions when water had been consumed. The ability to sustain attention was measured by asking the child to respond to a light that followed an auditory warning after a delay of either 3 or 12 s. The ability to sustain attention was not significantly influenced by whether water had been drunk. PMID- 19445988 TI - Functional expression of the calcitonin receptor by human T and B cells. AB - The calcitonin receptor (CTR) is a seven-transmembrane-domain G-protein-coupled receptor that regulates calcium metabolism and bone resorption by osteoclasts. Here we demonstrate that high levels are expressed by normal human T and B lymphocytes from tonsils and peripheral blood in relation to their activation status, as CTR(+) T cells are prone to produce IFN-gamma after TCR stimulation. The receptor is also highly expressed on B cells from chronic lymphocytic leukemia patients, thus suggesting a correlation between its expression, their proliferative extent as well as their memory, antigen-experienced phenotype. Moreover, we found that binding of the receptor with salmon calcitonin induces an increase of intracellular calcium(2+) in peripheral lymphocytes. This effect is involved in several lymphocyte immune functions, as cytosolic calcium(2+) levels regulate both cell proliferation and cytokine production. In our hands, the increase of calcium(2+) levels by CTR binding with sCT induced a dose-dependent cell proliferation. We therefore suppose that expression of this functional receptor may contribute to the modulation of cytoplasmic calcium(2+) levels needed to regulate T and B cell activation and perhaps other immune functions. PMID- 19445989 TI - Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells. AB - Mycophenolic acid (MPA) is considered an immunosuppressive compound mainly because of its inhibitory effects on lymphocyte proliferation. Here we studied specifically the effects of MPA on the ability of dendritic cells (DCs) to activate T cells via the indirect pathway and on the maturation and function of B lineage cells. We demonstrated that DC cell-surface receptors, associated with antigen uptake and antigen processing and presentation (CD83 and CD205), were differentially downregulated in the presence of MPA, translating into a decreased uptake of alloantigens and reduced stimulation of T cells with decreased cytokine secretion (interleukin (IL)-1Ra and transforming growth factor (TGF)-alpha). Similarly, MPA significantly inhibited B-cell differentiation into memory and plasma cells in vitro and decreased secretion of TNF-alpha, IL-1Ra, and IL-10. We further demonstrated for the first time that not only the amount of antibody secretion was significantly lowered in the presence of MPA but also the total number of antibody-producing cells was reduced. Importantly, we provide direct evidence that HLA-specific antibody secretion was also affected using a newly developed HLA antibody-specific B-cell enzyme-linked immunospot assay. Our data indicate additional pathways by which MPA downregulates the immune system. This in turn may lead to improved conditions for allograft tolerance and control of allograft rejection. PMID- 19445990 TI - TLR2 and TLR4 polymorphisms in familial Mediterranean fever. AB - It has been suggested that MEVF mutations offer advantage against infections, including tuberculosis. Bearing in mind the central role of TLR-2 and TLR-4 in the recognition of pathogens, we conducted this study to examine whether the TLR2 R753Q, TLR4-D299G, TLR4-T399I common polymorphisms are associated with susceptibility to familial Mediterranean fever (FMF) or affect the course of the disease. A cohort of 169 FMF patients and 245 healthy bone marrow donors were enrolled in the study. FMF patients appeared with a significantly lower frequency of the TLR4-D299G mutated allele (3.2% vs 6.9%, p = 0.032). No association was observed with the other analyzed polymorphisms. Moreover, we found no association between polymorphisms and the frequency of attacks or the development of amyloidosis. Our results may reinforce the hypothesis that FMF patients display a better defense against pathogens, providing an additional mechanism and suggesting a positive selection advantage in the area of the Mediterranean basin. PMID- 19445991 TI - Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population. AB - Excessive immune response is believed to play a role in the development of severe acute respiratory syndrome (SARS). Inhomogeneous spread of SARS led one to think of an Asian genetic predisposition and contribution of human leukocyte antigen (HLA) to the disease susceptibility. However, past case-control studies showed inconsistent results. In Viet Nam, of 62 patients with SARS, 44 participated in the present study together with 103 individuals who had contact with SARS patients and 50 without contact history. HLA-DRB1*12 was more frequently shown in SARS patients than in controls (corrected p = 0.042). HLA-DRB1*1202, the predominant allele in the Vietnamese population showed the strongest association with SARS in a dominant model (corrected p = 0.0065 and 0.0052, depending on the controls to be compared). Our results and accumulated data on HLA in the Asian populations would help in the understanding of associations with emerging infectious diseases. PMID- 19445992 TI - Back to the future: application of contemporary technology to long-standing questions about the clinical relevance of human leukocyte antigen-specific alloantibodies in renal transplantation. AB - Luminex technology allows the accurate identification of human leukocyte antigen (HLA) class I and class II-specific antibodies at levels below the threshold detectable by either conventional complement-dependent lymphocytotoxicity or flow cytometry. The technology enables the analysis of complex antibody profiles in sensitized patients and gives improved definition of acceptable and unacceptable HLA specificities to guide donor kidney allocation. This helps to facilitate virtual cross-matching and avoid inappropriate shipping of kidneys for incompatible patients in distant centers. Luminex allows the cause of a positive cross-match test to be determined in a clinically relevant time scale and, when used in conjunction with lymphocytotoxic and flow cytometric cross-matching, it provides an assessment of the level of immunological risk in patients being considered as potential recipients for a particular donor kidney. Information is now emerging to enable the full clinical potential of Luminex to be realized. PMID- 19445993 TI - Binary weight-of-evidence evaluations of chemical interactions--15 years of experience. AB - The paper reflects on the last 15years of experience in the field of mixtures risk assessment. It summarizes results found in various documents developed by the Agency for Toxic Substances and Disease Registry (ATSDR) of the weight-of evidence (WOE) approach applied to 380 binary combinations of chemicals. Of these evaluations, 156 assessments indicated possible additivity of effects [=], 76 indicated synergism (greater-than-additive effects [>]), and 57 indicated antagonism (less-than-additive effects [<]). However, 91 combinations lacked the minimum information needed for making any assessments and, hence, were undetermined. The paper provides examples of the rationale behind some of the WOE decisions and discusses the importance of expert judgments in risk assessment evaluations. Examples are given regarding the importance of human variability in mixtures' ability to affect human health and regarding the dose versus effect relationships. PMID- 19445994 TI - Mutagenicity studies with N-acetyl-L-aspartic acid. AB - Analytical studies have reported that N-acetyl-L-aspartic acid (NAA) is present at low concentrations in many foods. The current studies were conducted to assess the mutagenicity of NAA using standard OECD guideline in vitro bacterial and in vivo mammalian mutagenicity studies. For comparison and control data, mutagenicity studies were also conducted with its constituent amino acid L aspartate (ASP) because NAA is metabolized to ASP. The combination of an in vitro method for assessing point mutations in bacteria and an in vivo method to assess clastogenicity in an animal model provided adequate evidence for mutagenicity hazard assessment of NAA. No evidence of mutagenicity was observed in either test system with either NAA or ASP. The results from the current studies demonstrate that the presence of NAA in foods is not likely to represent a risk for mutagenicity. PMID- 19445995 TI - Dose-response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles. AB - Grapefruit juice (GFJ) has been shown to affect the pharmacokinetics of a large number of drugs, essentially by inhibition of efflux transporters and CYP3A4 monooxygenase in the small intestine. The GFJ dose usually used in human studies was one glass single-strength (1x). Information on a respective dose-response relationship is not available. We investigated the effect of GFJ of different concentration (0.25 x, 0.5x, 1x, 2x) dosed in biweekly intervals in 19 volunteers. Components considered responsible for drug interactions, naringin, naringenin, bergamottin, and 6',7'-dihydroxybergamottin were determined by LC tandem mass spectrometry. Immediately after ingestion of GFJ, participants took an aqueous solution of dextromethorphan (DEX) as probe drug. Urine was collected in two sampling periods, 0-2 and 2-4h, and excreted amounts of DEX and five metabolites associated with CYP3A4 and/or CYP2D6 enzyme activity were determined. Effects of GFJ were analyzed by the Wilcoxon matched-pairs signed-rank test against an average of four water control experiments. Two effects were highly significant: (i) a delay of total metabolite excretion in the first 2h and (ii) an inhibition of the CYP3A4-dependent metabolic pathways. Effect magnitude and significance levels were dose-dependent and indicated 200 ml 1x GFJ as "lowest observed effect level" LOEL. PMID- 19445996 TI - A different kinetic profile of ochratoxin A in mature male rats. AB - Ochratoxin A (OTA) is a mycotoxin that causes renal tumors in rodents, particularly in male rats. The present work explored the impact of gender and age on OTA toxicokinetics in F344 rats after a single oral dose (0.5mg/kg b.w.). OTA plasma concentrations were analysed with a validated HPLC-FLD method and a population approach (NONMEM VI) was used to perform the kinetic analysis and the one year exposure simulation (0.21 mg/kg daily). Maximum observed OTA concentration (CMAX(obs)) was at 2h in all groups except in mature females (6h). Mature females reached higher CMAX(obs) than males of the same age. Apparent volume of distribution, but not apparent total plasma clearance, increased significantly with body weight (P<0.01) resulting in the following values for the terminal plasma half life (h) in males: 219 (young), 264 (matures) and females: 191 (young), 205 (matures). In addition mature males showed a significant lower relative bioavailability. The simulation showed similar plasma concentrations in males and females after two-months. Thus, toxicokinetic does not seem to explain sex-differences in toxicity in long-term studies. However, the age and weight should be taken into account in short-term toxicological studies if sex differences are studied. PMID- 19445997 TI - The comparative characteristics of snake and kiwi fruits. AB - In the time of globalization many of the tropical fruits can be find at the markets of Europe and North America. Most customers are not familiar with the nutritional and proliferative values of these fruits. Therefore, a less known snake fruit was compared with better known kiwi fruit, using fluorometry, FT-IR spectroscopy, several radical scavenging and proliferative assays and statistical evaluation. It was found similarity between snake fruit (cultivar Sumalee) and kiwi fruit (cultivar Hayward) in the contents of polyphenols (8.15-7.91, mg GAE g(-1) DW), antioxidant values by DPPH (11.28-10.24, microMTE g(-1) DW), and antiproliferative activities on both human cancer cell lines (Calu-6 for human pulmonary carcinoma, and SMU-601 for human gastric carcinoma, 90.5-87.6 and 89.3 87.1%, cell survival, respectively). In conclusion, snake fruit cultivar Sumalee is comparable with kiwi fruit cultivar Hayward. Two fruits can be used as supplements to the normal diet. Consumption of a combination of both fruits could be recommended in order to receive the best results. PMID- 19445998 TI - Protective effect of isorhamnetin 3-O-beta-D-glucopyranoside from Salicornia herbacea against oxidation-induced cell damage. AB - Isorhamnetin 3-O-beta-D-glucopyranoside (1) was isolated from Salicornia herbacea. The inhibitory effects of compound 1 on oxidative stress were evaluated in free-cellular and cellular systems. An increased concentration of compound 1 not only exhibited dose-dependent scavenging activities on the generation of 1,1 diphenyl-2-picrylhydrazyl (DPPH), hydroxyl and carbon-centered radicals, but also significantly decreased levels of intracellular reactive oxygen species (ROS) in a dose-dependent manner. Further, antioxidative mechanisms by compound 1 were examined by measuring the intracellular glutathione (GSH) level and expression levels of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione reductase and heme oxygenase-1 (HO-1). Compound 1 significantly elevated GSH level as well as expression levels of antioxidant enzymes which were closely related with amount of cellular ROS. In addition, it significantly inhibited oxidative damage of purified genomic DNA and suppressed activity of myeloperoxidase (MPO), a generator of potent oxidant (hypochlorous acid), in tumor necrosis factor-alpha (TNF-alpha) stimulated human myeloid cells. Therefore, these results suggested that compound 1 has a therapeutic effectiveness in prevention of ROS-induced cellular damage and is a candidate worthy of being developed as a potential natural antioxidant related to oxidative stress. PMID- 19445999 TI - Characterization of the mannose 6-phosphate receptor (Mr 300 kDa) protein dependent pathway of lysosomal enzyme targeting in Biomphalaria glabrata mollusc cells. AB - Mammalian mannose 6-phosphate receptors (MPR 300 and 46) are involved in the targeting of newly synthesized lysosomal enzymes and only MPR 300 also participates in the endocytosis of various exogenous ligands. The present study describes for the first time the MPR 300 dependent pathway of lysosomal enzyme sorting in the Biomphalaria glabrata embryonic (Bge) cells. Lysosomal enzymes (arylsulfatase A, beta-hexosaminidase and alpha-fucosidase) were identified by their enzymatic activities and by immunoprecipitation with specific antisera. Exposure of Bge cells to unio MPR 300 antiserum resulted in a dramatic loss of MPR 300 protein with a shortened half life of approximately 20 min as compared to control cells exposed to preimmune serum in which the half life of MPR 300 was of approximately 13 h. Loss of receptor proteins resulted in a significant misrouting of newly synthesized lysosomal enzymes and their secretion in cell culture medium as demonstrated by immunoprecipitation. The ability of Bge cells to uptake and internalize labeled arylsulfatase A, beta-hexosaminidase and alpha fucosidase enzymes contained in cell secretion products also indicated the role of B. glabrata MPR 300 (CIMPR) protein in internalization and targeting of lysosomal enzymes. M6P dependent binding of lysosomal enzymes to MPR 300 was shown by confocal microscopy and coimmunoprecipitation experiments. PMID- 19446001 TI - A cellular mechanism for multi-robot construction via evolutionary multi objective optimization of a gene regulatory network. AB - A major research challenge of multi-robot systems is to predict the emerging behaviors from the local interactions of the individual agents. Biological systems can generate robust and complex behaviors through relatively simple local interactions in a world characterized by rapid changes, high uncertainty, infinite richness, and limited availability of information. Gene Regulatory Networks (GRNs) play a central role in understanding natural evolution and development of biological organisms from cells. In this paper, inspired by biological organisms, we propose a distributed GRN-based algorithm for a multi robot construction task. Through this algorithm, multiple robots can self organize autonomously into different predefined shapes, and self-reorganize adaptively under dynamic environments. This developmental process is evolved using a multi-objective optimization algorithm to achieve a shorter travel distance and less convergence time. Furthermore, a theoretical proof of the system's convergence is also provided. Various case studies have been conducted in the simulation, and the results show the efficiency and convergence of the proposed method. PMID- 19446000 TI - Tolerance in DLA-haploidentical canine littermates following CD6-depleted marrow transplantation and donor lymphocyte transfusion. AB - OBJECTIVE: Donor lymphocyte transfusions (DLT) are effective in the treatment of leukemia after allogeneic stem cell transplantation. Graft-vs-host-disease (GVHD) is the major risk factor of DLT. In dog leukocyte antigen (DLA)-identical littermate dogs, DLT given within 3 weeks after transplantation of marrow depleted of T cells using absorbed antithymocyte globulin produced fatal GVHD, whereas at 2 months or later after transplantation, DLT were tolerated without GVHD. Here, we studied tolerance to DLT in DLA-haploidentical recipients of CD6 depleted bone marrow. MATERIALS AND METHODS: Bone marrow recipients were DLA heterozygous and DLA-haploidentical to their DLA-homozygous donors. Marrow transplantation was performed on day 0, one day after total body irradiation with 10Gy. CD6 depletion was achieved by treatment of the marrow with CD6 antibody and rabbit complement. Natural killer cell activity of CD6-depleted cells was studied against canine thyroid adenocarcinoma cells. DLT were given at various time points after transplantation. RESULTS: Seven DLA-heterozygous dogs given undepleted marrow died of GVHD within 28 days. In contrast, three dogs given CD6 depleted marrow had sustained engraftment without occurrence of GVHD. DLT given on either day 3, 7, or 14 produced fatal GVHD. DLT on day 20, however, produced fatal GVHD in only two of four dogs. Mixed chimerism was converted into complete chimerism in all cases. Contrary to T-cell depletion with antithymocyte globulin, CD6 depletion spares canine natural killer cells. CONCLUSIONS: We conclude that T cell depletion with CD6 antibody and complement induces graft-vs-host tolerance without jeopardizing engraftment. DLT on days 3, 7, and 14 after transplantation produced GVHD, but it failed to abrogate tolerance in two of four dogs transfused on day 20. PMID- 19446002 TI - Temporal constraints of a gene regulatory network: Refining a qualitative simulation. AB - The modelling of gene regulatory networks (GRNs) has classically been addressed through very different approaches. Among others, extensions of Thomas's asynchronous Boolean approach have been proposed, to better fit the dynamics of biological systems: genes may reach different discrete expression levels, depending on the states of other genes, called the regulators: thus, activations and inhibitions are triggered conditionally on the proper expression levels of these regulators. In contrast, some fine-grained propositions have focused on the molecular level as modelling the evolution of biological compound concentrations through differential equation systems. Both approaches are limited. The first one leads to an oversimplification of the system, whereas the second is incapable to tackle large GRNs. In this context, hybrid paradigms, that mix discrete and continuous features underlying distinct biological properties, achieve significant advances for investigating biological properties. One of these hybrid formalisms proposes to focus, within a GRN abstraction, on the time delay to pass from a gene expression level to the next. Until now, no research work has been carried out, which attempts to benefit from the modelling of a GRN by differential equations, converting it into a multi-valued logical formalism of Thomas, with the aim of performing biological applications. This paper fills this gap by describing a whole pipelined process which orchestrates the following stages: (i) model conversion from a piece-wise affine differential equation (PADE) modelization scheme into a discrete model with focal points, (ii) characterization of subgraphs through a graph simplification phase which is based on probabilistic criteria, (iii) conversion of the subgraphs into parametric linear hybrid automata, (iv) analysis of dynamical properties (e.g. cyclic behaviours) using hybrid model-checking techniques. The present work is the outcome of a methodological investigation launched to cope with the GRN responsible for the reaction of Escherichia coli bacterium to carbon starvation. As expected, we retrieve a remarkable cycle already exhibited by a previous analysis of the PADE model. Above all, hybrid model-checking enables us to infer temporal properties, whose biological signification is then discussed. PMID- 19446003 TI - Astrogliosis is temporally correlated with enhanced neurogenesis in adult rat hippocampus following a glucoprivic insult. AB - 2-Deoxy-d-glucose (2-DG) administration causes transient depletion of glucose derivates and ATP. Hence, it can be used in a model system to study the effects of a mild glycoprivic brain insult mimicking transient hypoglycemia, which often occurs when insulin or oral hypoglycemic agents are administered for diabetes control. In the present study, the effect of a single 2-DG application (500mg/kg, a clinically applicable dose) on glial reactivity and neurogenesis in adult rat hippocampus was examined, as well as a possible temporal correlation between these two phenomena. Post-insult (PI) glial reactivity time course was assessed by immunoreaction against glial-fibrillary acidic protein (GFAP) during the following 5 consecutive days. A clear increase of GFAP immunoreactivity in hilus was observed from 48 to 96h PI. Moreover, enhanced labeling of long radial processes in the granule cell layer adjacent to hilus was evidenced. On the other hand, a transient increase of progenitor cell proliferation was detected in the subgranular zone, prominently at 48h PI, coinciding with the temporal peak of glial activation. This increase resulted in an augment of neuroblasts double labeled with 5-bromo-deoxyuridine (BrdU) and with double cortin (DCX) at day 7 PI. Around half of these cells survived 28 days showing matured neuronal phenotype double labeled by BrdU and a neuronal specific nuclear protein marker (NeuN). These findings suggest that a transient neuroglycoprivic state exerts a short-term effect on glial activation that possibly triggers a long-term effect on neurogenesis in hippocampus. PMID- 19446004 TI - Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. AB - BACKGROUND AND PURPOSE: We sought to determine the effect of vagus nerve stimulation (VNS) on infarct size after transient focal cerebral ischemia in rats. METHODS: Ischemia was produced by transient filament occlusion of the right middle cerebral artery. Stimulating electrodes were implanted on the cervical part of the right vagus nerve. Electrical stimulation was initiated 30 min after the induction of ischemia, and delivered for 30s at every 30 min for 3h in experimental group 1 and at every 5 min for 1h in experimental group 2. All the procedures were duplicated but no stimulus was delivered in the control group. Functional deficit was evaluated and animals were killed to determine the infarct size 24h after ischemia. RESULTS: Ischemic lesion volume was smaller in VNS treated animals as compared with control animals; the relative percentage of contralateral hemispheric volume that underwent infarction was 16.2+/-3.2% in the VNS and 33.0+/-5.0% in the control arms in experimental group 1 (p<0.05). The respective values for experimental group 2 were 19.8+/-0.5% and 37.9+/-2.6% (p<0.05). VNS-treated animals were significantly more likely to have better functional scores at 24h as compared with control animals. The functional score improved by 50% in experimental group 1 and 44% in experimental group 2 (p<0.05 for both groups). CONCLUSION: VNS appears to offer protection against acute ischemic brain injury. PMID- 19446006 TI - Light scattering change precedes loss of cerebral adenosine triphosphate in a rat global ischemic brain model. AB - Measurement of intrinsic optical signals (IOSs) is an attractive technique for monitoring tissue viability in brains since it enables noninvasive, real-time monitoring of morphological characteristics as well as physiological and biochemical characteristics of tissue. We previously showed that light scattering signals reflecting cellular morphological characteristics were closely related to the IOSs associated with the redox states of cytochrome c oxidase in the mitochondrial respiratory chain. In the present study, we examined the relationship between light scattering and energy metabolism. Light scattering signals were transcranially measured in rat brains after oxygen and glucose deprivation, and the results were compared with concentrations of cerebral adenosine triphosphate (ATP) measured by luciferin-luciferase bioluminescence assay. Electrophysiological signal was also recorded simultaneously. After starting saline infusion, EEG activity ceased at 108+/-17s, even after which both the light scattering signal and ATP concentration remained at initial levels. However, light scattering started to change in three phases at 236+/-15s and then cerebral ATP concentration started to decrease at about 260s. ATP concentration significantly decreased during the triphasic scattering change, indicating that the start of scattering change preceded the loss of cerebral ATP. The mean time difference between the start of triphasic scattering change and the onset of ATP loss was about 24s in the present model. DC potential measurement showed that the triphasic scattering change was associated with anoxic depolarization. These findings suggest that light scattering signal can be used as an indicator of loss of tissue viability in brains. PMID- 19446005 TI - Hypoxia up-regulates vascular endothelial growth factor in U-87 MG cells: involvement of TRPC1. AB - Canonical Transient Receptor Potential (TRPC) channels play important roles in diverse physiological processes. The contribution of TRPC channels to up-regulate VEGF expression under hypoxic conditions was studied in a malignant glioma cell line, U-87 MG cells. Up-regulation of VEGF gene expression by hypoxia was markedly suppressed by a TRPC channel blocker. RT-PCR showed that U-87 MG cells expressed four TRPC isoforms in normoxia: TRPC1, 3, 4, and 5. In addition, the expression of TRPC3, 4, and 5 decreased greatly under hypoxia exposure in U-87 MG cells. In contrast, TRPC1 expression was unchanged. These results suggest TRPC channels were involved in hypoxia-induced VEGF expression, and compared with other TRPC isoforms, TRPC1 might play a different role in this process. Furthermore, we determined the function of TRPC1 by RNAi. Two different siRNAs against TRPC1 largely inhibited hypoxia-induced up-regulation of VEGF mRNA and protein levels. However, overexpression of TRPC3 or 5 neither enhanced hypoxia induced VEGF expression, nor prevented it. Taken together, our present data suggest that TRPC1, but not TRPC3 or 5, is involved in hypoxia-induced VEGF expression in U-87 MG cells. PMID- 19446007 TI - Changes in calbindin expression within the flocculus after unilateral labyrinthectomy in rats. AB - The role of flocculus in vestibular compensation is still a controversial issue. Calbindin regulates intracellular signaling and has been reported to be a reliable marker of Purkinje cell. Expression of calbindin in flocculus was examined using immunohistochemistry following unilateral labyrinthectomy (UL) in rats. Both the staining intensity and number of calbindin-positive Purkinje cells in the ipsilateral flocculus to the lesion side decreased 6h after UL compared to the control and contralateral side. Forty-eight hours after UL, the expression of calbindin returned to control levels and asymmetric expression in bilateral flocculus subsided. These transient reduction of calbindin expression in the ipsilateral flocculus may reflect a decrease in the GABAergic inhibition of the floccular Purkinje cell to the ipsilateral vestibular nuclei during vestibular compensation. PMID- 19446008 TI - Plagiochin E, an antifungal bis(bibenzyl), exerts its antifungal activity through mitochondrial dysfunction-induced reactive oxygen species accumulation in Candida albicans. AB - BACKGROUND: Plagiochin E (PLE) is an antifungal macrocyclic bis(bibenzyl) isolated from liverwort Marchantia polymorpha L. Its antifungal mechanism is unknown. To elucidate the mechanism of action, its effect on mitochondria function in Candida albicans was studied. METHODS: We assayed the mitochondrial membrane potential (mtDeltapsi) using rhodamine 123, measured ATP level in mitochondria by HPLC, and detected the activities of mitochondrial F(0)F(1) ATPase and dehydrogenases. Besides, the mitochondrial dysfunction-induced reactive oxygen species (ROS) production was determined by a fluorometric assay, and the effects of antioxidant L-cysteine on PLE-induced ROS production and the antifungal effect of PLE on C. albicans were also investigated. RESULTS: Exposure to PLE resulted in an elevation of mtDeltapsi, and a decrease of ATP level in mitochondria. The ATP depletion owed to PLE-induced enhancement of mitochondrial F(0)F(1)-ATPase and inhibition of the mitochondrial dehydrogenases. These dysfunctions of mitochondria caused ROS accumulation in C. albicans, and this increase in the level of ROS production and PLE-induced decrease in cell viability were prevented by addition of L-cysteine, indicating that ROS was an important mediator of the antifungal action of PLE. CONCLUSIONS: PLE exerts its antifungal activity through mitochondrial dysfunction-induced ROS accumulation in C. albicans. GENERAL SIGNIFICANCE: The effect of PLE on the mitochondria function in C. albicans was assayed for the first time. These results would conduce to elucidate its underlying antifungal mechanism. PMID- 19446009 TI - The genetic basis of individual differences in reward processing and the link to addictive behavior and social cognition. AB - Dopaminergic neurotransmission is widely recognized to be critical to the neurobiology of reward, motivation and addiction. Interestingly, social interactions and related behavior also activate the same neuronal system. Consequently, genetic variations of dopamine neurotransmission are thought influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. This review focuses on advances made to date in an effort to link genetic individual variations and reward processing as a possible basis for addictive behaviors. PMID- 19446010 TI - The effects of aging on N-methyl-D-aspartate receptor subunits in the synaptic membrane and relationships to long-term spatial memory. AB - There are declines in the protein expression of the NR2B (mouse epsilon2) and NR1 (mouse zeta1) subunits of the N-methyl-D-aspartate (NMDA) receptor in the cerebral cortex and hippocampus during aging in C57BL/6 mice. This study was designed to determine if there is a greater effect of aging on subunit expression and a stronger relationship between long-term spatial memory and subunit expression within the synaptic membrane than in the cell as a whole. Male, C57BL/6JNIA mice (4, 11 and 26 months old) were tested for long-term spatial memory in the Morris water maze. Frontal cortex, including prefrontal regions, and hippocampus were homogenized and fractionated into light and synaptosomal membrane fractions. Western blots were used to analyze protein expression of NR2B and NR1 subunits of the NMDA receptor. Old mice performed significantly worse than other ages in the spatial task. In the frontal cortex, the protein levels of the NR2B subunit showed a greater decline with aging in the synaptic membrane fraction than in the whole homogenate, while in the hippocampus a similar age related decline was observed in both fractions. There were no significant effects of aging on the expression of the NR1 subunit. Within the middle-aged mouse group, higher expression of both NR2B and NR1 subunits in the synaptic membrane of the hippocampus was associated with better memory. In the aged mice, however, higher expression of both subunits was associated with poorer memory. These results indicate that aging could be altering the localization of the NR2B subunit to the synaptic membrane within the frontal cortex. The correlational results suggest that NMDA receptor functions, receptor subunit composition, and/or the environment in which the receptor interacted in the hippocampus were not the same in the old animals as in younger mice and this may have contributed to memory declines during aging. PMID- 19446011 TI - gamma-Hydroxybutyrate (GHB) induces GABA(B) receptor independent intracellular Ca2+ transients in astrocytes, but has no effect on GHB or GABA(B) receptors of medium spiny neurons in the nucleus accumbens. AB - We report on cellular actions of the illicit recreational drug gamma hydroxybutyrate (GHB) in the brain reward area nucleus accumbens. First, we compared the effects of GHB and the GABA(B) receptor agonist baclofen. Neither of them affected the membrane currents of medium spiny neurons in rat nucleus accumbens slices. GABAergic and glutamatergic synaptic potentials of medium spiny neurons, however, were reduced by baclofen but not GHB. These results indicate the lack of GHB as well as postsynaptic GABA(B) receptors, and the presence of GHB insensitive presynaptic GABA(B) receptors in medium spiny neurons. In astrocytes GHB induced intracellular Ca(2+) transients, preserved in slices from GABA(B) receptor type 1 subunit knockout mice. The effects of tetrodotoxin, zero added Ca(2+) with/without intracellular Ca(2+) store depletor cyclopiazonic acid or vacuolar H-ATPase inhibitor bafilomycin A1 indicate that GHB-evoked Ca(2+) transients depend on external Ca(2+) and intracellular Ca(2+) stores, but not on vesicular transmitter release. GHB-induced astrocytic Ca(2+) transients were not affected by the GHB receptor-specific antagonist NCS-382, suggesting the presence of a novel NCS-382-insensitive target for GHB in astrocytes. The activation of astrocytes by GHB implies their involvement in physiological actions of GHB. Our findings disclose a novel profile of GHB action in the nucleus accumbens. Here, unlike in other brain areas, GHB does not act on GABA(B) receptors, but activates an NCS-382 insensitive GHB-specific target in a subpopulation of astrocytes. The lack of either post- or presynaptic effects on medium spiny neurons in the nucleus accumbens distinguishes GHB from many drugs and natural rewards with addictive properties and might explain why GHB has only a weak reinforcing capacity. PMID- 19446013 TI - Down-regulation of 67LR reduces the migratory activity of human glioma cells in vitro. AB - OBJECTIVES: Glioma is the most common brain tumor in central nervous system. Traditional therapies are not effective to cure this disease. Experimental evidence indicates that the 67 kDa elastin-laminin receptor (67LR) subunit is a high-affinity non-integrin laminin-binding protein that is over-expressed on the tumor cell surface in a variety of human carcinomas, and directly correlates with a higher proliferation rate of malignant cells and tendency to metastasize. However, little is known of the expression and function of 67LR in glioma cells. METHODS: In this study, we estimated whether 67LR was constitutively over expressed in high-grade astrocytomas by immunohistochemical staining and Western blotting, and investigated the role of a low level of 67LR expression in glioma cell line-U251 by constructing an interfering RNA expression plasmid. RESULTS: The results showed that the 67LR had an enhanced over-expression in high-grade astrocytomas against normal brain tissues samples, and that the migratory activity of glioma cells was reduced after the down-regulation of the 67LR gene by RNAi. DISCUSSION: It was hypothesized that a low level of 67LR expression could reduce migratory activity of glioma cells, which further proved that 67LR played an important role in glioma invasion by mediating tumor cell functions leading to sarcomata. This study provided a new alternative to gene therapy for glioma treatment. PMID- 19446014 TI - Use of the native flp gene to generate in-frame unmarked mutations in Streptomyces spp. AB - The generation of unmarked deletion mutants free from polar effects on downstream genes is typically a lengthy and arduous process in Streptomyces spp. The use of FLP recombinase can greatly facilitate this process when combined with established polymerase chain reaction (PCR)-targeting techniques. In vivo production of FLP within Streptomyces cells would streamline the process further, but expression of flp in Streptomyces spp. has proven difficult to achieve. Two Escherichia coli-Streptomyces shuttle plasmids that constitutively express native flp within Streptomyces cells were constructed and tested within Streptomyces clavuligerus and Streptomyces coelicolor to produce in-frame mutations in genes associated with antibiotic production. Only one of the flp-expressing plasmids was functional in S. clavuligerus, but both functioned in S. coelicolor and both were easily lost from cells. Although a separate study has recently shown successful expression of a synthetic flp gene in Streptomyces, this is the first report of expression of the native flp gene within Streptomyces spp. Through the use of these plasmids to generate unmarked deletion mutants, C7p was shown to be essential for production of 5S clavams in S. clavuligerus, and RedJ was demonstrated to be important for optimal undecylprodigiosin biosynthesis in S. coelicolor but traces of the antibiotic were still produced in a DeltaredJ mutant. PMID- 19446012 TI - Genes, cognition and brain through a COMT lens. AB - Various genes are known to modulate the delicate balance of dopamine in prefrontal cortex and influence cortical information processing. Catechol-O methyltransferase (COMT) on chromosome 22q11 is the most widely studied of these genes. Val158Met, a common, functional variant in the coding sequence that increases or decreases the enzymatic activity of the gene has been shown to impact the efficiency of prefrontally-mediated cognition, specifically executive functioning, working memory, fluid intelligence and attentional control. We review the rapidly evolving literature exploring the association between COMT genotype and cognitive performance, and illustrate how this polymorphism has served a pivotal role in characterizing various interacting dimensions of complexity in the relationship between genes and cognition. We review how Val158Met has been used to help develop and validate behavioral and neurophysiological phenotypes, as a critical tool in dissecting overlapping neural functional systems and exploring interactions within and between genes, and in exploring how gene effects on cognition are modulated by environmental, demographic and developmental factors. Despite the impressive range of findings, the COMT story is also a bracing reminder of how much work remains to translate this knowledge into practical clinical applications. PMID- 19446015 TI - Biomonitoring for occupational health risk assessment (BOHRA). AB - Biological monitoring (BM or biomonitoring) deals with the assessment of individual human exposure, effect and susceptibility to occupational risk factors. It is a fundamental tool in occupational health risk assessment (OHRA) and occupational health practice (OHP) and it has become one of the most, if not the most active area in occupational health (OH) research today. From the few hundred BM papers published in the 80s, there are now several tens of thousand papers published in the peer review literature each year, and the trend is still rising exponentially. As a result, BM has become a priority for the Scientific Committee on Occupational Toxicology (SCOT) of the International Commission on Occupational Health (ICOH). Moreover, there has been a long-term interest in biological monitoring by other SCs of ICOH such as the Scientific Committees on Toxicology of Metals (SCTM) and on Rural Health (SCRH). Despite its current popularity, though, BM is not always correctly used or interpreted by those involved in OHRA or OHP. The present review has been prepared to fill this gap and to help preventing misuse and misinterpretation of data. Although the document is meant to be a reference primarily for those involved in OH research and/or practice, it might become of interest for a wider audience within and outside ICOH, including scientists, occupational physicians, industrial hygienists and occupational or public health professionals in general, involved in chemical risk assessment for occupational health. The mission of SCOT and also of other SCs of ICOH, such as SCTM and SCRH, is indeed to promote the advancement and diffusion of knowledge on biological monitoring and other relevant occupational toxicology aspects and to make them available and useful to the entire OH scientific community. All articles retrieved as of 3 January, 2007 as "Review" with the combined key words "biological monitoring" in PubMed from 2000 to 2007 have been scanned individually. This yielded a total of 1400 articles from a grand total of 2486 (excluding limitation on year of publication). When the title was related to human occupational biological monitoring, the abstract was read and its content was included. Articles outside the 2000-2007 time frame or that are not classified as "Review" in PubMed have also been included, when relevant. The review is in four parts: (a) the introduction, containing the basic principles and definitions of BM and the different types of biomarkers (BMK), their toxicological significance, practical use and limitations, (b) the methodological and analytical aspects of BM in exposed workers, (c) the interpretation and management of BM data, including a number of recommendations to be considered when planning, performing and interpreting BM results and, finally, (d) the ethical aspects of BM. A list of key references to relevant papers or documents has been included. The BM of specific chemicals or groups of chemicals is outside the purpose of the review. The document is aimed to represent the state of the art on biological monitoring in occupational risk assessment. We expect that reference to its content will be made, whenever appropriate, by those involved in occupational health practice and research when dealing with BM issues. The document is not meant, though, to represent a rigid nor a permanent set of rules and it will be periodically updated according to new developments and any significant advance in BM science. Any part of the document, therefore, is open to suggestions by scientifically qualified persons or institutions officially involved in BM and comments should be sent directly to the authors. A preliminary draft of the document has been presented at the 7th International Symposium on Biological Monitoring, Beijing, 10-12 September, 2007. PMID- 19446016 TI - Anatomical connections suitable for the direct processing of neuronal information of different modalities via the rodent primary auditory cortex. AB - During the last years it has become increasingly apparent that primary sensory cortices, like the primary auditory field AI, are not purely unisensory but also process complex information from other sensory modalities as well as non-sensory information. Here, we review our anatomical work on the connections of the auditory cortex in a small rodent, the Mongolian gerbil (Meriones unguiculatus), a common animal model in auditory research, and the related literature from other mammalian species. In particular we will show that AI has multiple connections with auditory, non-auditory sensory (visual, somatosensory, olfactory), multisensory, motor, "higher order" associative and neuromodulatory brain structures. These connections are suitable to mediate multimodal integration processes observed at the level of AI and, in turn, enable AI to influence other sensory and non-sensory systems at several cortical and subcortical levels. PMID- 19446017 TI - The potential role of phrenic nucleus glutamate receptor subunits in mediating spontaneous crossed phrenic activity in neonatal rat. AB - Cervical spinal cord hemisection rostral to the phrenic nucleus leads to paralysis of the ipsilateral hemidiaphragm in adult rats. Respiratory function can be restored to the paralyzed hemidiaphragm by activating a latent respiratory motor pathway. The latent pathway is called the crossed phrenic pathway. In adult rats, the pathway can be activated by drug-induced upregulation of NMDA receptor NR2A subunit and AMPA receptor GluR1 subunit in the phrenic nucleus following hemisection. In neonatal rats, this pathway is not latent as shown by the spontaneous expression of activity in the ipsilateral hemidiaphragm following hemisection. We hypothesized that the NR2A and GluR1 subunits may be highly expressed naturally on phrenic motoneurons of neonatal rats and may play a potential role in mediating the spontaneous expression of activity in the ipsilateral hemidiaphragm after hemisection. To test this hypothesis, the protein levels of NR2A and GluR1 in different age rats were assessed via Western blot analysis immediately following C2 hemisection and EMG recording of crossed phrenic activity. The protein levels of NR2A and GluR1 were transiently high in postnatal day 2 (P2) rats and then was significantly reduced in P7 and P35 animals. An immunofluorescence study qualitatively supported these findings. The present results indicate that the developmental downregulation of the phrenic nucleus glutamate receptor subunits correlates with the conversion of the crossed phrenic pathway in older postnatal animals from an active state to a latent state. PMID- 19446019 TI - Apoptosis-like cell death induced by Salmonella in Acanthamoeba rhysodes. AB - Free-living amoebae act as environmental hosts of several intracellular pathogens. We examined the interaction between Acanthamoeba rhysodes and Salmonella, a human intracellular pathogen. There was no difference among three different serovars of Salmonella in terms of their growth within A. rhysodes over time. The number of intracellular bacteria increased at 6 h post-infection, and the viability of A. rhysodes was significantly reduced at 24 h post-infection. Amoebic cell death was characterized by TUNEL and Annexin V assay, without DNA ladder identified, indicating an apoptosis-like cell death in Salmonella-infected A. rhysodes. Global gene expression screening between intracellular and extracellular Salmonella by microarray and quantitative PCR showed that genes from Salmonella pathogenicity islands and virulence plasmid were up-regulated within A. rhysodes. The phase-dependent expression pattern suggests their distinct roles in the pathogenesis. A. rhysodes and Salmonella provide a model to study transient symbiosis between bacterial pathogens and protozoa in an aquatic ecosystem. PMID- 19446018 TI - Differences in gene expression profiles from asbestos-treated SPARC-null and wild type mouse lungs. AB - The role of SPARC in the in vivo lung response to crocidolite asbestos was addressed by instillation of crocidolite asbestos in a series of wild-type or SPARC-null mice. Animals were sacrificed at one week, one month, and three months post-instillation to assess the impact of SPARC on multiple stages in the development of fibrosis. RNA was harvested from 10 animals/time point, pooled, and used to probe a mouse array containing approximately 10,000 probes. Gene expression data were analyzed for fold change, and for broader functional group alterations. As expected, the one-week time point displayed alterations in genes involved in immune recognition, energy utilization, and growth factor production. Later time points showed expression alterations for genes involved in protein degradation, Wnt receptor signaling, membrane protein activity, and transport. Molecules in the Wnt pathway have been implicated in bone growth, mediation of fibroblast activity, and have been directly linked to SPARC regulation. PMID- 19446020 TI - A novel approach to detect differentially expressed genes from count-based digital databases by normalizing with housekeeping genes. AB - Sequence tag count-based gene expression analysis is potent for the identification of candidate genes relevant to the cancerous phenotype. With the public availability of count-based data, the computational approaches for differentially expressed genes, which are mainly based on Binomial or beta Binomial distribution, become practical and important in cancer biology. It remains a permanent need to select a proper statistical model for these methods. In this study, we developed a novel Bayesian algorithm-based method, Electronic Differential Gene Expression Screener (EDGES), in which a statistical model was determined by geometric averaging of 12 common housekeeping genes. EDGES identified a set of differentially expressed genes in lung, breast and colorectal cancers by using publically available Serial Analysis of Gene Expression (SAGE) and Expressed Sequence Tag (EST data). Gene expression microarray analysis and quantitative reverse transcription real-time PCR demonstrated the effectiveness of this procedure. We conclude that current normalization of calibrators provides a new insight into count-based digital subtraction in cancer research. PMID- 19446021 TI - Eukaryotic snoRNAs: a paradigm for gene expression flexibility. AB - Small nucleolar RNAs (snoRNAs) are one of the most ancient and numerous families of non-protein-coding RNAs (ncRNAs). The main function of snoRNAs - to guide site specific rRNA modification - is the same in Archaea and all eukaryotic lineages. In contrast, as revealed by recent genomic and RNomic studies, their genomic organization and expression strategies are the most varied. Seemingly snoRNA coding units have adopted, in the course of evolution, all the possible ways of being transcribed, thus providing a unique paradigm of gene expression flexibility. By focusing on representative fungal, plant and animal genomes, we review here all the documented types of snoRNA gene organization and expression, and we provide a comprehensive account of snoRNA expressional freedom by precisely estimating the frequency, in each genome, of each type of genomic organization. We finally discuss the relevance of snoRNA genomic studies for our general understanding of ncRNA family evolution and expression in eukaryotes. PMID- 19446022 TI - Brain-specific Galphaz interacts with Src tyrosine kinase to regulate Mu-opioid receptor-NMDAR signaling pathway. AB - There is a certain cross-talk in the nervous system between N-methyl-D-aspartate receptors (NMDARs) and Mu-opioid receptors (MORs). While NMDARs participate in the desensitization of MORs, these in turn modulate NMDAR-mediated glutamate responses. The G protein coupled receptors (GPCRs) activate NMDARs via Src although the role of Galpha subunits in this process is not well defined. We have found that in the absence of MOR activation, the brain specific Galphaz subunit binds to and stabilizes Src in its inactive form. The administration of morphine provokes the phosphorylation of specific cytosolic tyrosine residues in NMDAR2A subunits. This was achieved by PKCgamma disrupting this Galphaz-Src complex, enabling Src to be activated (pTyr416) by binding to GalphaiGTP proteins. These changes increased the activation of the calcium/calmodulin-dependent protein kinase II (CaMKII), thereby promoting MOR desensitization. This regulatory pathway is disrupted by inhibiting PKC, preventing MOR-activated Galphai2 subunits from gaining control over Src. Thus, in neural cells the Galphaz subunits exert a negative control on Src function reducing the activating influence of MORs on this tyrosine kinase. This MOR-triggered signaling pathway recruits PKCgamma and Galphai subunits to activate Src tyrosine kinase, resulting in the potentiation of NMDAR function. Most relevant, this mechanism which operates in neural cells is essential for the development of tolerance to the analgesic effects of morphine. PMID- 19446023 TI - Molecular adaptation of sourdough Lactobacillus plantarum DC400 under co cultivation with other lactobacilli. AB - This work was aimed at investigating the molecular mechanisms of Quorum Sensing (QS) in Lactobacillus plantarum DC400 when co-cultured with other sourdough lactobacilli. The growth and survival of L. plantarum DC400 was not affected when co-cultivated with Lactobacillus sanfranciscensis DPPMA174 or Lactobacillus rossiae A7. Nevertheless, 2-DE analysis showed that the level of protein expression of L. plantarum DC400 increased under co-culture conditions. Although several proteins were commonly induced in both co-cultures, the highest induction was found in co-culture with L. rossiae A7. Overexpressed proteins, related to QS and stress response mechanisms, were identified: DnaK, GroEL, 30S ribosomal protein S1 and S6, ATP synthase subunit beta, adenosylmethionine synthetase (MetK), phosphopyruvate hydratase, phosphoglycerate kinase, elongation factor Tu, putative manganese-dependent inorganic pyrophosphatase, d-lactate dehydrogenase, triosephosphate isomerase, fructose-bisphosphate aldolase and nucleoside diphosphate kinase. As shown by real-time PCR, expression of the luxS gene of L. plantarum DC400 was also affected during co-cultivation. According to overexpression of MetK and luxS during co-cultivation, synthesis of AI-2-like substances was also influenced by the type of microbial co-cultures. This study showed that expression of some genes/proteins, also QS-related, in L. plantarum was influenced by co-cultivation of other sourdough lactobacilli. PMID- 19446024 TI - Optimisation of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes. AB - This study aims to develop and characterise a beclomethasone diproprionate:gamma cyclodextrin (BDP:gamma-CYD) complex and to optimise the variables on the spray drying process, in order to obtain a powder with the most suitable characteristics for lung delivery. The spray-dried powder--in a mass ratio of 2:5 (BDP:gamma-CYD)--was physically mixed with three carriers of different particle sizes and in different ratios. Particle-size distribution, shape and morphology, moisture content, and uniformity in BDP content of formulations were studied. In vitro aerolisation behaviour of the formulations was evaluated using the Rotahaler, and the performance was characterised based on the uniformity of emitted dose and aerodynamic particle-size distribution (respirable fraction (RF), as a percentage of nominal dose (RFN) and emitted dose (RFE)). The most suitable conditions for the preparation of BDP:gamma-CYD complexes were obtained with the solution flow of 5 ml/min, T(in) of 70 degrees C and T(out) of 50 degrees C. Statistically significant differences in the aerodynamic performances were obtained for formulations containing BDP:gamma-CYD complexes prepared using different solution flows and different T(in) (p<0.05). RFN and RFE vary in direct proportion with T(in), while an inverse relationship was observed for the solution flow. A direct correlation between the RFE and the T(out) was identified. Performance of the formulations was compared with an established commercial product (Beclotaide Rotacaps 100 microg) with improved performance of RF: formulations with respitose carrier attained RFN and RFE twofold greater, and formulations based on 63-90 microm fraction lactose and trehalose achieved a threefold improvement; also, all formulations showed that the percentage of dose of BDP deposited in the "oropharynx" compartment was reduced to half. PMID- 19446025 TI - Importance of glassy-to-rubbery state transitions in moisture-protective polymer coatings. AB - The aim of this study was to better understand the mechanisms governing water transport in polymeric film coatings used for moisture protection. Tablets containing garlic powder were coated with Methocel E5 (hydroxypropyl methylcellulose), Opadry AMB [poly(vinylalcohol)-based formulation] and Eudragit E PO [poly(methacrylate-methylmethacrylate)]. Their water content at different temperatures and relative humidities were determined. The polymers were characterized by X-ray powder diffraction and differential scanning calorimetry (DSC). The latter revealed significant physical changes in Opadry AMB during storage, while Eudragit E PO remained unchanged. For Opadry AMB, a strong dependence of the vapor permeability on the water content of the system was observed. The water uptake drastically increased with increasing relative humidity and storage temperature due to structural polymer changes (glassy-to rubbery state transition). Linear relationships between the initial uptake rate and the relative humidity or temperature were established. Storage below critical threshold values of 66% RH (at room temperature) and 16 degrees C (at 75% RH) significantly reduced water imbibition. Opadry AMB-based film coatings undergo a glassy-to-rubbery state transition upon storage at room temperature and elevated relative humidity, resulting in significantly increased mobility of the polymer chains and, thus, increased water uptake rates. PMID- 19446026 TI - Exocrine pancreas trans-differentiation to hepatocytes--a physiological response to elevated glucocorticoid in vivo. AB - Damage or ectopic expression of some growth factors can lead to the appearance of hepatocyte-like cells within the pancreas. Since glucocorticoids promote liver hepatocyte phenotype in vitro, the effect of glucocorticoid on pancreatic differentiation in vivo was examined. Treatment of rats with glucocorticoid for 25 days at levels that significantly inhibited weight gain resulted in the appearance of acinar cells expressing cytokeratin 7 and hepatocyte markers glutamine synthetase, carbamoyl phosphate synthetase and cytochrome P450 2E (the nomenclature employed is that given at http://drnelson.utmem.edu/CytochromeP450.html). Using a plastic pancreatic acinar cell line, this response was shown to be associated with changes in the regulation of WNT signalling-related gene expression and a repression of WNT signalling activity. These data suggest that a pathological response of the pancreas in vivo to elevated glucocorticoid is a differentiation of exocrine pancreatic cells or pancreatic progenitor cells to an hepatocyte-like phenotype. PMID- 19446027 TI - Atrial natriuretic peptide decreases aorta stiffness in cholesterol-fed anesthetized rabbits. AB - Aortas from Watanabe heritable hyperlipidemic rabbits show in vitro impaired vasodilatory response to atrial natriuretic peptide (ANP) during atherosclerosis progression. To test a similar reaction in vivo, the effect of ANP administration on pulse wave velocity (PWV, index of aorta stiffness) was investigated in 10 normal and 10 cholesterol-fed (2% cholesterol-loaded feeding for 4 weeks) anesthetized male New Zealand White (NZW) rabbits. Invasively taken carotid and femoral blood pressures (BP) were recorded, simultaneously with ECG, and blood samples for ANP measurement (by RIA) were taken at 0 min and 20, 40, 60 min following an intravenous 20-min administration of either 0.2 microg kg(-1)min(-1) hANP in 5 ml normal saline or only 5 ml saline. Mild to moderate atherosclerosis was found in ascending aorta. BP decreased by ANP only at 20 min in both groups, whereas only in cholesterol-fed rabbits the borderline (p=0.09) increased at 0 min PWV was lowered (p=0.008) in all recording times. With any degree of increase of systolic BP (SBP) PWV increased less in ANP receivers. Atherosclerosis and SBP were the most important determinants of PWV and the effect of ANP was independent of confounding factors. It is concluded that short-term ANP administration in doses to achieve levels approximately threefold the pretreatment ones in normal and mildly to moderately atherosclerotic anesthetized NZW rabbits, causes an improvement of aorta stiffness only in atherosclerotic rabbits. PMID- 19446028 TI - DNA hypomethylation as Achilles' heel of tumorigenesis: a working hypothesis. AB - There are at least two findings that show DNA hypomethylation plays a key role in carcinogenesis. The first major evidence is that DNA hypomethylation induces target chromosomal and genomic instability with cancer manifestations. The second reason that cancer progression is associated with deepening DNA hypomethylation. Nevertheless, the evolution of this crucial epigenomic alteration in the somatic cellular malignant transformation remains unclear. From some of the experimental data to be present, a key role of DNA hypomethylation in early development of epigenetic somatic cancer biology is proposed. We have observed the significant increasing of genome ploidy at the level of peripheral blood lymphocytes taken from the patients with different solid carcinomas. Similarly, 5-azacytidine demethylating DNA treatment of cultured healthy lymphocytes induces increased nuclear DNA content. We argue that somatic lymphocyte ploidy induced by genomic DNA hypomethylation during carcinogenesis is related to global demethylation and decondensation of mitotic constitutive pericentromeric heterochromatin. This results in disturbances of pericentromeric heterochromatin that are expressed in nuclear heterochromatinization on the basis of extrachromosomal chromomerization. On the basis of literature searches and experimental findings, it is proposed that DNA hypomethylation plays the role of an initiator in epigenetic somatic cancer biology. PMID- 19446029 TI - An rRNA-based analysis for evaluating the effect of heat stress on the rumen microbial composition of Holstein heifers. AB - We performed a set of heifer feeding trials to investigate the effect of heat and humidity stresses on the rumen bacterial molecular diversity of Holstein heifers (Tajima K, Nonaka I, Higuchi K, Takusari N, Kurihara M, Takenaka A, et al. Anaerobe 2007;13:57-64). To further characterize the response of the microbial community to the physiological changes caused by the stresses, we evaluated changes in the ruminal bacterial community composition in the same trials by applying an RNA-based method (sequence-specific small-subunit (SSU) rRNA cleavage method), which was optimized for a comprehensive description of the predominant bacterial groups inhabiting the rumen. Four Holstein heifers were kept at three temperatures (20 degrees C, 28 degrees C, 33 degrees C) in a climatic chamber for two weeks each, and rumen fluid samples were obtained on the last day of each temperature experiment. For quantitative detection, we applied a set of 15 oligonucleotide probes, including those targeting taxa comprised of uncultured rumen bacteria (URB) belonging to phylum Firmicutes, to the RNAs extracted from the fluid samples. The relative populations of the Clostridium coccoides Eubacterium rectale group, and the genus Streptococcus increased, and that of the genus Fibrobacter decreased in response to increasing temperature both in the first (nine months old, 80% relative humidity) and second (15 months old, 60% relative humidity) experiments. In addition, the population of a defined URB group was higher at 33 degrees C than at 20 degrees C in the second trial, whereas one of the other URB groups showed a decreasing trend with the temperature rise. These results indicate that the exposure to heat affects the population levels of specific bacterial groups in the ruminal microbial community. PMID- 19446030 TI - Biofilm growth kinetics of a monomethylamine producing Alphaproteobacteria strain isolated from an anaerobic reactor. AB - Industrial fishing effluents are characterized by high loads of protein and sulfate that stimulate the activity of proteolytic and sulfate reducing bacteria during anaerobic digestion. Their metabolic products (NH3 and H2S respectively) have a well-known detrimental effect on the activity of methanogens. Since methylamine is a carbon source used by methylaminotrophic methane producing archaea (mMPA) but not by sulfate reducing bacteria (SRB), enriched mMPA anaerobic biofilms have been developed on ceramics. We propose that methylated amines could be produced in the biofilm by using betaine, a known precursor of methylamine, as a carbon and energy source. We isolated an anaerobic betainotrophic methylaminogenic bacterial strain (bMB) from an anaerobic bioreactor, using betaine as the only carbon and energy source. This strain was identified by a standard biochemical test (API 20NE), cloning, and 16S rDNA sequencing. bMB biofilm structure and biofilm growth kinetic parameters were determined by means of scanning electron microscopy (SEM), and the Gompertz growth model, respectively. Monomethylamine production was determined by infrared spectroscopy and by high pressure liquid chromatography. The isolated bMB strain was determined as Stappia stellulata (Proteobacteria phylum). It was able to form biofilm on ceramics and its kinetic growth parameters resulted in: maximum biofilm bacterial count (A) of 6.25 x 10(8) UFC/cm(2) and maximum specific growth rate (mu(m)) of 0.0221/h. Production of monomethylamine was about 4.027 atogram/cell/day (at/cell/day) after 15 days of incubation in biofilms. This study confirms the adhesion capacity of this bMB strain on ceramic supports, assuring that monomethylamine production in biofilms could be enriched with mMPA that use monomethylamine. PMID- 19446031 TI - Editorial: the vertebrate forebrain. PMID- 19446032 TI - Transcriptome analysis guided metabolic engineering of Bacillus subtilis for riboflavin production. AB - A comparative transcriptome profiling between a riboflavin-producing Bacillus subtilis strain RH33 and the wild-type strain B. subtilis 168 was performed, complemented with metabolite pool and nucleotide sequence analysis, to rationally identify new targets for improving riboflavin production. The pur operon (purEKBCSQLFMNHD) together with other PurR-regulated genes (glyA, guaC, pbuG, xpt pbuX, yqhZ-folD, and pbuO) was all down-regulated in RH33, which consequently limited the supply of the riboflavin precursors. As 5-phospho-ribosyl-1(a) pyrophosphate (PRPP) strongly inhibits the binding of PurR to its targets, it was inferred that the reduced expression of PurR-regulated genes might be caused by a low PRPP pool, which was subsequently confirmed by metabolite analysis. Thus, we selected and co-overexpressed prs and ywlF genes in RH33, which are involved in the biosynthetic pathway of PRPP from ribulose-5-phosphate. This co-amplification led to an elevated PRPP pool and thus the increased transcript abundances of PurR regulated genes participated in riboflavin precursor biosynthesis. The riboflavin titer was increased by 25% (up to 15 g l(-1)) in fed-batch fermentation. PMID- 19446033 TI - Metabolic impact of redox cofactor perturbations in Saccharomyces cerevisiae. AB - Redox cofactors play a pivotal role in coupling catabolism with anabolism and energy generation during metabolism. There exists a delicate balance in the intracellular level of these cofactors to ascertain an optimal metabolic output. Therefore, cofactors are emerging to be attractive targets to induce widespread changes in metabolism. We present a detailed analysis of the impact of perturbations in redox cofactors in the cytosol or mitochondria on glucose and energy metabolism in Saccharomyces cerevisiae to aid metabolic engineering decisions that involve cofactor engineering. We enhanced NADH oxidation by introducing NADH oxidase or alternative oxidase, its ATP-mediated conversion to NADPH using NADH kinase as well as the interconversion of NADH and NADPH independent of ATP by the soluble, non-proton-translocating bacterial transhydrogenase. Decreasing cytosolic NADH level lowered glycerol production, while decreasing mitochondrial NADH lowered ethanol production. However, when these reactions were coupled with NADPH production, the metabolic changes were more moderated. The direct consequence of these perturbations could be seen in the shift of the intracellular concentrations of the cofactors. The changes in product profile and intracellular metabolite levels were closely linked to the ATP requirement for biomass synthesis and the efficiency of oxidative phosphorylation, as estimated from a simple stoichiometric model. The results presented here will provide valuable insights for a quantitative understanding and prediction of cellular response to redox-based perturbations for metabolic engineering applications. PMID- 19446035 TI - Multiple sequence elements determine the intron retention in histamine H3 receptors in rats and mice. AB - Intron retention in histamine H(3) receptors has been found in many mammals, including rats and mice. The short transcript isoforms that exclude alternatively spliced introns are readily detected in very low abundance in rats and are undetectable in mice using the regular PCR approach. The detailed mechanism for the special alternative splicing remains poorly understood. The aim of this work was to investigate the effects of essential splice signals on intron retention and to identify sequence elements that determine the differences in splicing between rats and mice. We have constructed a minigene-splicing system to mimic natural alternative receptor splicing and analyzed the regulatory elements in HEK293 cells. Mutating suboptimal 5' and 3' splice sites toward the consensus sequences can enhance the splicing of corresponding alternative introns. The effect is much more significant for the 3' splice site of the longer intron than for the other two splice sites; it is also more significant in rats than in mice. The splicing differences between rats and mice are primarily determined by the six discrepant nucleotides within the alternative introns, which promote or suppress the intron splicing in different ways and cooperate to make splicing of the two introns more efficient in rats. From these results we conclude that (1) the weakness of the splice sites is an important determinant for very low efficiency during intron splicing and, (2) multiple sequence elements determine the splicing differences between rats and mice. The results provide insight into special alternative splicing regulation in H(3) receptors. PMID- 19446036 TI - Macrophage responses to interferon-gamma are dependent on cystatin C levels. AB - The aim of the present investigation was to elucidate possible effects of cystatin C on inflammatory responses mediated by macrophages. Previously it has been shown that in vitro treatment of murine peritoneal macrophages with interferon-gamma (IFN-gamma) causes a down-regulation of cystatin C secretion. To investigate whether such changes in cystatin C expression in turn can affect inflammatory responses mediated by macrophages, we have compared effects of IFN gamma on macrophages isolated from wild-type (cysC(+/+)) and cystatin C knockout (cysC(-/-)) mice. It was shown that IFN-gamma-primed cysC(-/-) macrophages exhibit significantly higher interleukin-10 (IL-10) but lower tumor necrosis factor-alpha (TNF-alpha) expression, and reduced nuclear factor (NF)-kappaB p65 activation, compared to similarly primed cysC(+/+) cells. Exogenously added cystatin C enhanced IFN-gamma-induced activation of NF-kappaB p65 and increased mRNA levels for inducible NO synthase (iNOS) in cysC(-/-) macrophages as well as levels of nitric oxide and TNF-alpha in the cell culture medium, in agreement with an enhanced pro-inflammatory response. Accordingly, IFN-gamma-induced IL-10 mRNA expression in cysC(-/-) macrophages was down-regulated by exogenously added cystatin C. Taken together, our data provide evidence that changes in cystatin C levels alter macrophage responses to IFN-gamma. The latter down-regulates the production of cystatin C, which leads to a suppressed inflammatory condition with enhanced IL-10 levels and down-regulated TNF-alpha and NF-kappaB. It is concluded that cystatin C through this effect can act as an immunomodulatory molecule. PMID- 19446037 TI - Regulation of chemokine gene expression by hypoxia via cooperative activation of NF-kappaB and histone deacetylase. AB - Hypoxia is a microenvironmental factor frequently associated with tumors and inflammation. This study addresses the question of how hypoxia modulates the basal and IL-1 beta-induced production of cytokines and aims to identify the underlying mechanism of hypoxic transcriptional repression. We found that despite the similarities of the promoter structures of IL-8 and MCP-1, these chemokines were differently regulated by hypoxia (an increase in IL-8, but a decrease in MCP 1 mRNA and protein expression). Such differences were not observed in a reporter gene assay, in which both of the promoters were activated by hypoxia. The difference in the response to hypoxia between MCP-1 expression and the promoter assay was not due to mRNA instability. Using proteosome inhibitor MG132 and I kappaB overexpression we demonstrated that an NF-kappaB-dependent mechanism was involved in both the activation of IL-8 and the repression of MCP-1 mRNA expression in response to hypoxia. The histone deacetylase inhibitor Trihostatin A abolished the inhibitory actions of hypoxia on IL-1 beta-induced MCP-1 gene expression. Furthermore, hypoxia induced histone deacetylase activity in the nuclear extracts. Although stimulation with IL-1 beta and/or hypoxia increased the acetylation of histones H3 and H4 in the presence of Trihostatin A, histone acetylation remained unchanged when the cells were treated without histone deacetylase inhibitor. Collectively, our findings suggest that transiently transfected promoters are not subject to the same NF-kappaB regulatory mechanisms as their chromatinized counterparts. NF-kappaB, activated by hypoxia, can act as a transcriptional repressor via a mechanism that involves deacetylation of histones. PMID- 19446034 TI - Ideal observer analysis of signal quality in retinal circuits. AB - The function of the retina is crucial, for it must encode visual signals so the brain can detect objects in the visual world. However, the biological mechanisms of the retina add noise to the visual signal and therefore reduce its quality and capacity to inform about the world. Because an organism's survival depends on its ability to unambiguously detect visual stimuli in the presence of noise, its retinal circuits must have evolved to maximize signal quality, suggesting that each retinal circuit has a specific functional role. Here we explain how an ideal observer can measure signal quality to determine the functional roles of retinal circuits. In a visual discrimination task the ideal observer can measure from a neural response the increment threshold, the number of distinguishable response levels, and the neural code, which are fundamental measures of signal quality relevant to behavior. It can compare the signal quality in stimulus and response to determine the optimal stimulus, and can measure the specific loss of signal quality by a neuron's receptive field for non-optimal stimuli. Taking into account noise correlations, the ideal observer can track the signal-to-noise ratio available from one stage to the next, allowing one to determine each stage's role in preserving signal quality. A comparison between the ideal performance of the photon flux absorbed from the stimulus and actual performance of a retinal ganglion cell shows that in daylight a ganglion cell and its presynaptic circuit loses a factor of approximately 10-fold in contrast sensitivity, suggesting specific signal-processing roles for synaptic connections and other neural circuit elements. The ideal observer is a powerful tool for characterizing signal processing in single neurons and arrays along a neural pathway. PMID- 19446039 TI - The role of aquatic birds in the environmental dissemination of human pathogenic Giardia duodenalis cysts and Cryptosporidium oocysts in Hungary. AB - Fecal samples were taken from 132 (103 wild and 29 domestic) aquatic birds on selected areas in Hungary from February 2008 to March 2008. Cryptosporidium oocysts and Giardia cysts were purified from the samples and were viewed via fluorescent antibody staining. Molecular detection tools, such as PCR-sequencing and Loop mediated isothermal amplification (LAMP) were used in order to determine the Cryptosporidium species and Giardia duodenalis assemblages present. All together 6 (5.8%) and 6 (5.8%) samples out of the 103 wild bird samples and 4 (13%) and 7 (24%) samples out of the 29 domestic bird samples have been found to be Cryptosporidium and G. duodenalis positive respectively. The results of this study indicate that aquatic ducks, geese, coot and cormorant can play role in the environmental dissemination of human pathogenic Giardia cysts and Cryptosporidium oocysts in Hungary. To our knowledge, this is the first description of Cryptosporidium sp. in Anser fabalis and Anser anser, furthermore Giardia sp. in Fulica atra, A. fabalis and P. carbo and the first PCR-sequence confirmed detection of C. parvum in A. platyrhynchos and F. atra, G. duodenalis Assemblage A in A. strepera and G. duodenalis Assemblage B in A. anser. PMID- 19446040 TI - Hemoglobinase activity of a cysteine protease from the ixodid tick Haemaphysalis longicornis. AB - We report here the molecular characterization and possible function of a cysteine protease (termed HlCPL-A) identified in the midgut of the hard tick Haemaphysalis longicornis. HlCPL-A is a 333 amino acid protein belonging to the papain family of the cysteine protease. A construct encoding proHlCPL-A was expressed in Escherichia coli and purified as both procathepsin L and active processed cathepsin L forms. The HlCPL-A gene expression was up-regulated by blood-feeding process. HlCPL-A exhibited substrate specificity against synthetic peptidyl substrates (Z-Phe-Arg-MCA and Z-Arg-Arg-MCA; k(cat)/K(m)=0.19 and 0.0023 M(-1) S( 1), respectively). The proteolytic activity of HlCPL-A was inhibited by leupeptin, antipain and E-64 but was unaffected by pepstatin. HlCPL-A was capable of degrading bovine hemoglobin at pH 3.2 to 5.6. These results suggest that HlCPL A may play important roles in the digestion of host hemoglobin in ticks. PMID- 19446041 TI - Stigma and quality of life in individuals with epilepsy: a preliminary report. AB - OBJECTIVE: Epilepsy is considered to be a debilitating illness associated with a high level of stigma and impaired quality of life. This study was aimed at evaluating whether exposure to treatment is associated with a decrease in the level of stigma in individuals with epilepsy and its relationship to quality of life. METHODS: Participants were divided into three groups. The first group comprised 15 newly registered patients at the Epilepsy Clinic of the Central Institute of Psychiatry. The second group included 15 patients of the clinic who had been receiving regular treatment, including comprehensive psychosocial intervention per clinic protocol, for at least 1 year. The control group comprised 15 community-dwelling normal healthy participants. The Stigma Scale for Epilepsy, Quality of Life in Epilepsy Inventory-89, and World Health Organization Quality of Life-Brief Version were administered to measure stigma and quality of life. RESULTS: The perception of stigma was strongly associated with epilepsy, but there was no difference between the treated and untreated groups with epilepsy. Also, stigma and quality of life were negatively correlated. CONCLUSION: There is a need for a community-level awareness program to deal with the stigma associated with epilepsy. PMID- 19446042 TI - Central action of Araucaria angustifolia seed lectin in mice. AB - Possible central nervous system effects of the gymnosperm lectin from Araucaria angustifolia seeds were studied in seizure and open field tests. Male Swiss mice were administered saline (control), lectin (0.1, 1, and 10 mg/kg), flumazenil (1 mg/kg), or diazepam (1 mg/kg) intraperitoneally. Lectin at the highest dose increased time to death in the pentylenetetrazole- and strychnine-induced seizure models as compared with control, but not in the pilocarpine model. In the open field test, lectin reduced locomotor activity at all doses tested, as did diazepam, when compared with control. These locomotor effects were reversed by flumazenil pretreatment. In conclusion, A. angustifolia lectin had a protective effect in the pentylenetetrazole- and strychnine-induced seizure models, suggestive of activity in the GABAergic and glycinergic systems, respectively, and also caused a reduction in animal movements, which was reversed by flumazenil, pointing to a depressant action mediated by a GABAergic mechanism. PMID- 19446043 TI - Electroconvulsive treatment for nonepileptic seizure disorders. AB - Because of its striking prevalence among females, the paroxysmal disorder presenting with nonepileptic seizures was termed hysteria in premodern times. In our time, the disorder has remained widely misunderstood and mistreated. The diagnostic early history of painful traumatic events as the source of the nonepileptic seizures is hidden by the shame of the victim and remains ignored. Early effective psychotherapeutic intervention is rarely carried out. Antiepileptic treatment is commonly initiated, and tends to worsen the seizure condition, which commonly becomes chronic. Key evidence from our treatment of patients with both epileptic and nonepileptic seizures had shown that low doses of antiepileptic drugs were required, because the patients markedly improved as some epileptic seizures were allowed to occur. This prompted our use of electroconvulsive treatment for a select series of 18 patients with the most severe chronic nonepileptic seizure condition. This treatment proved remarkably effective for 11 of the 15 patients who tolerated the treatment. Together with their seizures, the patients had had bodily pains, depressive moods, and often anxiety. Their disorder can be clearly distinguished from ordinary depression, and the remarkable effect of electroconvulsive treatment in its treatment seems to be in accordance with premodern views of a polarity between the two paroxysmal disorders epilepsy and hysteria. Further studies of our topic are called for. PMID- 19446044 TI - Two learning approaches for protein name extraction. AB - Protein name extraction, one of the basic tasks in automatic extraction of information from biological texts, remains challenging. In this paper, we explore the use of two different machine learning techniques and present the results of the conducted experiments. In the first method, Bigram language model is used to extract protein names. In the latter, we use an automatic rule learning method that can identify protein names located in the biological texts. In both cases, we generalize protein names by using hierarchically categorized syntactic token types. We conducted our experiments on two different datasets. Our first method based on Bigram language model achieved an F-score of 67.7% on the YAPEX dataset and 66.8% on the GENIA corpus. The developed rule learning method obtained 61.8% F-score value on the YAPEX dataset and 61.0% on the GENIA corpus. The results of the comparative experiments demonstrate that both techniques are applicable to the task of automatic protein name extraction, a prerequisite for the large-scale processing of biomedical literature. PMID- 19446046 TI - Baroreflex and metaboreflex control of cardiovascular system during exercise in space. AB - This brief review summarizes current knowledge on the neural mechanisms of cardiovascular regulation during exercise in space, with specific emphasis on the role of the arterial baroreflex and the muscle metaboreflex, with the attendant modifications in autonomic nervous system activity, in determining the cardiovascular responses to exercise in microgravity conditions. Available data suggest that the muscle metaboreflex is enhanced during dynamic exercise in space and that the potentiation of the muscle metaboreflex affects the vagally mediated arterial baroreflex contribution to HR control. PMID- 19446045 TI - Polyoma BK virus-associated nephropathy in kidney-transplant patients: Effects of leflunomide on T-cell functions and disease outcome. AB - BACKGROUND: In kidney-transplant recipients, leflunomide has been shown to be efficient for treating polyomavirus BK virus-associated-nephropathy (PVAN). However, it is unknown whether the beneficial effect of leflunomide is related to it having a lower immunosuppressive effect than mycophenolate mofetil (MMF), or to its anti-viral activity. The aim of this study was to assess i) T-cell functions before and after conversion from MMF to leflunomide in kidney transplant patients with PVAN, and ii) effects of leflunomide on PVAN outcome. PATIENTS AND METHODS: Twelve patients were enrolled in this study. At PVAN diagnosis, MMF was replaced by leflunomide. Other immunosuppressive drug doses and levels were maintained unchanged. T-cell functions, i.e., intralymphocyte cytokine expression (IL-2 and TNF-alpha), T-cell activation [i.e., transferrin receptor (CD71) and interleukin (IL)-2 alpha-chain (CD25) expression], and T-cell proliferation were measured using a flow-cytometry whole-blood assay before and at one month after conversion. RESULTS: Despite a slight decrease in tacrolimus trough levels, no significant change in T-cell-function biomarkers was observed after conversion. After a follow-up of 6 (4-30) months, five patients were cleared of the virus, and decreased viral load was observed in four patients. Only one patient suffered a graft loss. No difference in immunological parameters was observed between patients who were cleared or not of BKV. CONCLUSION: Results of this pilot study suggest that the potential benefits of leflunomide to treat PVAN in kidney-transplant patients is not related to reduced immunosuppression induced by replacing MMF by leflunomide. Virological studies are required to determine the anti-BKV effect of leflunomide. PMID- 19446047 TI - Mechanical and in vitro biological performances of hydroxyapatite-carbon nanotube composite coatings deposited on Ti by aerosol deposition. AB - Hydroxyapatite (HA)-carbon nanotube (CNT) composite coatings on Ti plate, produced by aerosol deposition using HA-CNT powders, were developed for biomedical applications. For the deposition process HA-CNT powder mixtures with CNT contents of 1 and 3 wt.% were used. Dense coatings with a thickness of 5 microm were fabricated, irrespective of the content of CNTs. No pores or microcracks were observed in the coatings. The coatings had good adhesion to the substrate, exhibiting a high adhesion strength, ranging from 27.3 to 29.0 MPa. Microstructural observation using field-emission gun scanning electron microscopy and transmission electron microscopy showed that CNTs with a typical tubular structure were found in the HA-CNT composite coatings. Nanoindentation tests revealed that the mechanical properties, such as the hardness and elastic modulus, were significantly improved by the addition of the CNTs to the HA coating. In addition, the proliferation and alkaline phosphatase (ALP) activity of MC3T3-E1 pre-osteoblast cells grown on the HA-CNT composite coatings were higher than those on the bare Ti and pure HA coating. The ALP activity of the composite coatings considerably improved as the CNT content increased. These results suggest that CNTs would be an effective reinforcing agent to enhance both the mechanical and biological performances of HA coatings. PMID- 19446048 TI - Corrosion behaviour of AZ31 magnesium alloy with different grain sizes in simulated biological fluids. AB - The corrosion behaviour of AZ31 magnesium alloy with different grain sizes immersed in simulated body fluids was compared in chloride solution (8 gl(-1)) and in phosphate-buffer solution (PBS). The influence of immersion time was also analyzed. Electrochemical techniques such as open circuit potential, polarization curves, transient currents and electrochemical impedance spectroscopy, complemented with scanning electron microscopy and energy dispersive spectroscopy, were used. Immediately after the immersion in the corrosive media the corrosion resistance was similar for both grain sizes of the AZ31 alloy and higher in NaCl solutions than in PBS. However, this corrosion behaviour was reversed after longer periods of immersion due to the stabilizing of the corrosion products of MgO by P-containing compounds. These P-compounds contribute to a higher level of protection by hindering the aggressive action of chloride ions. The best corrosion behaviour of the AZ31 alloy was obtained for the finest grain alloy associated with the highest transfer resistance value, after long periods of immersion in PBS. PMID- 19446049 TI - Titanium implants alter endothelial function and vasoconstriction via a protein kinase C-regulated pathway. AB - The application of titanium (Ti) alloy in joint prostheses is a good choice in orthopedic reconstruction. An elevated serum concentration of Ti has been shown in the patients with loosened knee prostheses. The precise actions of elevated Ti on the circulation remain unclear. In this study the maximal contractile responses elicited by phenylephrine in the aortas of rats 4 weeks after Ti alloy implantation and in cultured rat aortas treated with a soluble form of Ti for a period of 18h were significantly decreased as compared with controls. Aortas isolated from rats with Ti alloy implants or aortas treated with a soluble form of Ti had enhanced protein expression of endothelial nitric oxide synthase (eNOS) and protein kinase C (PKC)-alpha and enhanced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Treatment of human umbilical vein endothelial cells (HUVECs) with a soluble form of Ti for 24h dose-dependently increased eNOS protein expression. Short-term treatment of HUVECs with Ti for 1h effectively enhanced the phosphorylation of eNOS, PKC (pan) and ERK1/2. PKC inhibitors RO320432 and chelerythrine effectively inhibited Ti-enhanced phosphorylation of eNOS and PKC (pan). These results indicate that Ti in the circulation may alter endothelial function and reduce vasoconstriction. PMID- 19446050 TI - Photopatterned collagen-hyaluronic acid interpenetrating polymer network hydrogels. AB - To engineer complex tissues, it is necessary to create hybrid scaffolds with micropatterned structural and biomechanical properties, which can closely mimic the intricate body tissues. The current report describes the synthesis of a novel photocrosslinkable interpenetrating polymeric network (IPN) of collagen and hyaluronic acid (HA) with precisely controlled structural and biomechanical properties. Both collagen and HA are present in crosslinked form in IPNs, and the two networks are entangled with each other. IPNs were also compared with semi IPNs (SIPN), in which only collagen was in network form and HA chains were entangled in the collagen network without being photocrosslinked. Scanning electron microscopy images revealed that IPNs are denser than SIPNs, which results in their molecular reinforcement. This was further confirmed by rheological experiments. Because of the presence of the HA crosslinked network, the storage modulus of IPNs was almost two orders of magnitude higher than SIPNs. The degradation of the collagen-HA IPNs was slower than the SIPNs because of the presence of the crosslinked HA network. Increasing concentration of HA further altered the properties among IPNs. Cytocompatibility of IPNs was confirmed by Schwann cell and dermal fibroblasts adhesion and proliferation studies. We also fabricated patterned scaffolds with regions of IPNs and SIPNs within a bulk hydrogel, resulting in zonal distribution of crosslinking densities, viscoelasticities, water content and pore sizes at the micro- and macro-scales. With the ability to fine-tune the scaffold properties by performing structural modifications and to create patterned scaffolds, these hydrogels can be employed as potential candidates for regenerative medicine applications. PMID- 19446051 TI - Comparative proteome analysis to explore p53 pathway disruption in head and neck carcinogenesis. AB - The 5-year-survival rate of head and neck squamous cell carcinoma (HNSCC) has been only moderately improved over the last few decades. HNSCC develops in precursor fields of genetically altered mucosal cells, typically characterized by p53 pathway disruption, that mostly do not give any clinical symptoms. Patients present therefore often with invasive carcinomas in an advanced stage. After tumor resection, part of these fields frequently stays behind unnoticed, causing secondary tumors. Identification of these precursor fields would allow screening and early detection of both primary and secondary tumors. Our aim was to identify differential proteins related to p53 dysfunction. These proteins may serve as valuable biomarkers that can predict the presence of a precursor field. We used a squamous cell model for p53 inactivation, which was analyzed by 2D-DIGE and LC MS/MS. This approach enabled us to identify a set of 74 proteins that were differentially expressed in cells with normal versus disrupted p53 function. For six proteins the major changes in expression were verified with immunohistochemical staining. The most promising result was the identification of peroxiredoxin-1 which allowed immunohistochemical discrimination between normal epithelium and precursor field tissue with a TP53 mutation. PMID- 19446052 TI - Systemic effects of zoledronic acid in children with traumatic femoral head avascular necrosis and Legg-Calve-Perthes disease. AB - BACKGROUND: Intravenous bisphosphonate therapy is associated with preservation of femoral head sphericity and congruence in 77% of children with traumatic avascular necrosis. The aim was to describe the systemic effects of intravenous zoledronic acid (ZA) on bone and mineral metabolism in otherwise normal children and adolescents with femoral head AVN. MATERIAL AND METHODS: 37 children (age 10.8+/-2.76 years) diagnosed with avascular necrosis AVN (Slipped Capital Femoral Epiphysis (SCFE), N=20 or Legg-Calve-Perthes disease (LCPD), N=17) were treated with at least 12 months of ZA. Bone mineral density (BMD) by DXA, bone morphometry and mineral homeostasis were evaluated at baseline, 6, 12 and 18 months. Data was retrieved retrospectively. RESULTS: All children maintained height SD during treatment. BMI SD increased in the SCFE subgroup during the first 12 month period. Bone age increased appropriately. Age adjusted total body BMD, lumbar spine BMD and lean tissue mass adjusted bone mineral content (BMC) Z scores increased significantly over the 18 months of treatment. The LS.BMD increase was greater in LCPD than in SCFE leading to more individuals with LCPD having a LS.BMD((age))Z-score over 2 SD at 12 months follow-up. Biochemical markers of bone turnover were decreased and PTH increased during the first 12 months of treatment and bone modeling was reduced. All markers stabilised over the next 6 months. There were no incidences of fracture, spondylolisthesis or osteonecrosis of the jaw. CONCLUSION: We here report that ZA in otherwise healthy children with femoral head AVN increases BMD - most pronounced in the LCPD group and reduces bone modeling and turnover. Further efficacy and safety data are required before this therapy can be widely recommended. PMID- 19446053 TI - Associations between components of the metabolic syndrome versus bone mineral density and vertebral fractures in patients with type 2 diabetes. AB - The association of bone with the metabolic syndrome and its features, visceral fat accumulation or insulin resistance, remains unclear. We determined visceral and subcutaneous fat areas (V and S) by computed tomography on 187 men (28-83 years) and 125 postmenopausal women (46-82 years) with type 2 diabetes. Men whose V was 100 cm(2) or more had significantly lower urinary N-terminal cross-linked telopeptide of type-I collagen (p=0.005), higher femoral neck bone mineral density (FN-BMD) (p=0.004), and lower prevalence of vertebral fractures (VFs) (p=0.04) than controls. Fat mass, V, S, and lean body mass positively correlated with FN-BMD in men and with lumbar (L) and FN-BMD in women. When adjusted for weight, these correlations became negative. Urinary C-peptide positively correlated with FN-BMD in both genders. Multivariate logistic regression analysis adjusted for age, height, weight, L-BMD, duration of diabetes, and diabetes therapies identified V in men and urinary C-peptide in women as factors inversely associated with the presence of VFs [odds ratio (OR)=0.61 per SD increase, p=0.04, and OR=0.32, p=0.01, respectively]. These findings suggest that, of the components of the metabolic syndrome, body fat in gravity and hyperinsulinemia could increase FN-BMD in diabetic subjects. Visceral fat in men and hyperinsulinemia in women may protect against VFs independent of weight, L-BMD, diabetes duration, or therapies. PMID- 19446054 TI - Interference by adrenaline with chondrogenic differentiation through suppression of gene transactivation mediated by Sox9 family members. AB - In contrast to osteoblasts, little attention has been paid to the functional expression of adrenergic signaling machineries in chondrocytes. Expression of mRNA was for the first time demonstrated for different adrenergic receptor (AdR) subtypes in chondrogenic ATDC5 cells and mouse metatarsals isolated before vascularization in culture, but not for other molecules related to adrenergic signaling. In neonatal mouse tibial sections, beta(2)AdR and alpha(2a)AdR mRNA expression was found in chondrocytes at different developmental stages by in situ hybridization. Exposure to adrenaline significantly suppressed expression of several maturation markers through the cAMP/protein kinase A pathway activated by beta(2)AdR without affecting cellular proliferation in both cultured ATDC5 cells and metatarsals. Adrenaline also significantly inhibited gene transactivation by sry-type HMG box 9 (Sox9) family members essential for chondrogenic differentiation in a manner prevented by the general betaAdR antagonist propranolol, with a concomitant significant decrease in the levels of Sox6 mRNA and corresponding protein, in ATDC5 cells and primary cultured mouse costal chondrocytes. Systemic administration of propranolol significantly promoted the increased expression of mRNA for collagen I and collagen X, but not for collagen II, in callus of fractured femur in mice. These results suggest that adrenaline may interfere with chondrogenic differentiation through downregulation of Sox6 expression for subsequent suppression of gene transactivation mediated by Sox9 family members after activation of beta(2)AdR expressed by chondrocytes. PMID- 19446055 TI - Characterization and structural analysis of zinc-substituted hydroxyapatites. AB - The substitution of Zn in hydroxyapatite (HA) crystals was examined via comprehensive characterization techniques. Nanosized HA crystals were synthesized by the wet chemical method in aqueous solutions including various amounts of Zn ions. X-ray fluorescent spectroscopy was used to examine the amount of Zn in the HA precipitates. Scanning electron microscopy and high-resolution transmission electron microscopy were employed to examine the effects of Zn on the morphology and crystal size of the precipitates. Conventional powder X-ray diffraction and the Rietveld refinement method revealed the apatite lattice parameters and phase changes with the inclusion of Zn. The results indicated that Zn ions partially substituted for Ca ions in the apatite structure. They were not simply adsorbed on the apatite surface or in the amorphous phase. The precipitates maintained the apatite phase up to a Zn:(Zn+Ca) ratio of 15-20 mol.% in the solution. Pure HA was well crystallized and the crystals had regular shapes, whereas the Zn substituted apatite crystals became irregular and formed agglomerates. The lattice parameters, a and c, decreased at a Zn:(Zn+Ca) ratio of 10 mol.%. PMID- 19446056 TI - Injectable poly(lactic-co-glycolic) acid scaffolds with in situ pore formation for tissue engineering. AB - Appropriate porosity is an important biomaterial design criterion for scaffolds used in tissue engineering applications as it can permit increased cell adhesion, migration, proliferation and extracellular matrix production within the scaffold at a tissue defect site. Tissue engineering scaffolds can either be injected in a minimally invasive manner or implanted through surgical procedures. Many injectable scaffolds are hydrogel-based; these materials often possess nanoscale porosity, which is suboptimal for cell migration and proliferation. Solid scaffolds with engineered micron-scale porosity are widely used, but these scaffolds are usually pre-formed and then must be implanted. Here we report on the development of a solid, injectable, biomaterial scaffold that solidifies in situ via phase inversion with microporous, interconnected architecture on the surface and within the bulk. This injectable system utilizes the biodegradable polymer poly(lactic-co-glycolic acid), a nontoxic FDA-approved solvent, and biocompatible porogens. Various scaffold formulations are examined in terms of morphology, porosity, degradation, elastic modulus, and ability to support cellular adhesion and growth. Furthermore, the ability to form a microporous architecture upon injection in vivo is verified. This technology is a promising noninvasive approach for in vivo formation of porous biodegradable scaffolds. PMID- 19446057 TI - Potential of high temperature liquid chromatography for the improvement of separation efficiency--a review. AB - This review has been written in the context of critically evaluating the potential of high temperature liquid chromatography for the improvement of separation efficiency. The focus of this review is also laid on a critical evaluation of the applicability of this technique in a regulated environment. The review tries to give an overview over all aspects which can lead to a deterioration of the separation efficiency. This means that the discussion is not limited to a theoretical treatment of the van Deemter equation, but that all aspects which can contribute to a loss of efficiency are covered. This includes the design of the heating equipment as well as the possible degradation of the stationary phase or analytes. Therefore, the review is also a general review which tries to include the latest findings on high temperature HPLC. Also, temperature programming is critically evaluated. It is outlined that this technique is a prerequisite for certain hyphenation techniques like isotope ratio mass spectrometry or flame ionisation detection. However, it is critically discussed if temperature programming also will improve the separation efficiency. PMID- 19446058 TI - A novel biosensor based on photoelectro-synergistic catalysis for flow-injection analysis system/amperometric detection of organophosphorous pesticides. AB - In this study, a highly sensitive amperometric biosensor based on photoelectro synergistic catalysis for detecting organophosphorus pesticides (OPs) in flow injection analysis (FIA) system has been developed. The acetylcholinesterase enzyme (AChE) was immobilized by adsorption into the nanostructured PbO2/TiO2/Ti, which also acted as the working electrode. This strategy was found to catalyze the oxidative reaction of thiocholine effectively, make the AChE/PbO2/TiO2/Ti biosensor detect the substrate at 0.30 V (vs. SCE), hundreds milli-volts lower than others reported. PbO2/TiO2/Ti and TiO2/Ti electrodes were prepared and investigated with atomic force microscope (AFM). Factors influencing the performance were optimized. The resulting flow system offered a fast, sensitive, and stable response. A value of 1.34 mM for the apparent Michaelis-Menten constant (K(M)(app)) was obtained. A wide linear inhibition response for trichlorfon was observed in the range of 0.01-20 microM with the detection limit of 0.1 nM. The results using this biosensor agreed very well with chromatographic method and we also examined the real samples successfully in this work. PMID- 19446059 TI - Trace vanadium analysis by catalytic adsorptive stripping voltammetry using mercury-coated micro-wire and polystyrene-coated bismuth film electrodes. AB - An electrochemical technique has been developed for ultra-trace (ng L(-1)) vanadium (V) measurement. Catalytic adsorptive stripping voltammetry for V analysis was developed at mercury-coated gold micro-wire electrodes (MWEs, 100 microm) in the presence of gallic acid (GA) and bromate ion. A potential of 0.275 V (vs Ag/AgCl) was used to accumulate the complex in acetate buffer (pH 5.0) at the electrode surface followed by a differential pulse voltammetric scan. Parameters affecting the electrochemical response, including pH, concentration of GA and bromate, deposition potential and time have been optimized. Linear response was obtained in the 0-1000 ng L(-1) range (2 min deposition), with a detection limit of 0.88 ng L(-1). The method was validated by comparison of results for an unknown solution of V by atomic absorption measurement. The protocol was evaluated in a real sample by measuring the amount of V in river water samples. Thick bismuth film electrodes with protective polystyrene films have also been made and evaluated as a mercury free alternative. However, ng L( 1) level detection was only attainable with extended (10 min) deposition times. The proposed use of MWEs for the detection of V is sensitive enough for future use to test V concentration in biological fluids treated by the advanced oxidation process (AOP). PMID- 19446060 TI - Immobilization, hybridization, and oxidation of synthetic DNA on gold surface: electron transfer investigated by electrochemistry and scanning tunneling microscopy. AB - Fundamental understanding of interfacial electron transfer (ET) among electrolyte/DNA/solid-surface will facilitate the design for electrical detection of DNA molecules. In this report, the electron transfer characteristics of synthetic DNA (sequence from pathogenic Cryptosporidium parvum) self-assembled on a gold surface was electrochemically studied. The effects of immobilization order on the interface ET related parameters such as diffusion coefficient (D0), surface coverage (thetaR), and monolayer thickness (d(i)) were determined by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). DNA surface density (Gamma(DNA)) was determined by the integration of the charge of the electro-oxidation current peaks during the initial cyclic voltammetry scans. It was found that the DNA surface densities at different modifications followed the order: Gamma(DNA) (dsS-DNA/Au) > Gamma(DNA) (MCH/dsS-DNA/Au) > Gamma(DNA) (dsS-DNA/MCH/Au). It was also revealed that the electro-oxidation of the DNA modified gold surface would involve the oxidation of nucleotides (guanine and adenine) with a 5.51 electron transfer mechanism and the oxidative desorption of DNA and MCH molecules by a 3 electron transfer mechanism. STM topography and current image analysis indicated that the surface conductivity after each surface modification followed the order: dsS-DNA/Au < MCH/dsS-DNA/Au < oxidized MCH/dsS DNA/Au < Hoechst/oxidized MCH/dsS-DNA/Au. The results from this study suggested a combination of variations in immobilization order may provide an alternative approach for the optimization of DNA hybridization and the further development for electrical detection of DNA. PMID- 19446061 TI - Fabrication of a molecularly imprinted polymer sensor by self-assembling monolayer/mediator system. AB - Detection of dopamine (DA) by using a molecularly imprinted polymer (MIP) which fabricated by the self-assembling monolayer (SAM)/mediator system was studied. The SAM was made by attaching thioglycolic acid (TGA) on a gold electrode and quercetin (Q) was selected as an electron transfer mediator in this system. Methyl methacrylate (MMA) was polymerized by photopolymerization with the addition of dopamine to form a MIP electrode. The MIP and non-MIP (NMIP) modified electrodes were identified by FTIR and scanning electrochemical microscopy (SECM) approach curves. DA was detected by an amperometric method at a constant potential of 0.45 V and obtained a sensitivity of 0.445 mA cm(-2) M(-1). The imprinting efficiency approaches infinity due to a non-reactive surface of NMIP. In the interference test, ascorbic acid contributed less than 12% of current response in the coexistence solution with DA and the performance is highly related to the concentration of template added during the fabrication process. PMID- 19446062 TI - Electrochemical investigations of the interaction of C-reactive protein (CRP) with a CRP antibody chemically immobilized on a gold surface. AB - A possibility of using a range of dc and ac electrochemical techniques to probe associative interactions of C-reactive protein (CRP) with CRP antibody (aCRP) immobilized on a gold electrode surface was investigated. It was demonstrated that the investigated electrochemical techniques can be used efficiently to probe these interactions over a wide CRP concentration range, from 1.15 x 10(-5) to 1.15 mg L(-1). The measured sensitivity of the techniques is in the following decreasing order: differential pulse voltammetry, charge-transfer resistance obtained from electrochemical impedance spectroscopy (EIS), cyclic voltammetry, chronoamperometry, and double-layer capacitance deduced from EIS measurements which gave the poorest sensitivity. Measurements of kinetic parameters demonstrated that the associative interactions of CRP with the immobilized aCRP reached quasi-equilibrium after 20-30 min. The kinetics of these interactions was modeled successfully using a two-step kinetic model. In this model, the first step represents reversible CRP-aCRP associative-dissociative interactions, while the second step represents the irreversible transformation of the bound CRP into a thermodynamically stable configuration. It was demonstrated that the thermodynamically stable configuration of CRP starts prevailing after 7 min of interaction of CRP with the immobilized aCRP. PMID- 19446063 TI - ASE extraction method for simultaneous carbon and nitrogen stable isotope analysis in soft tissues of aquatic organisms. AB - Since lipids are depleted in 13C relative to proteins and carbohydrates, variations in lipid composition among species and within individuals significantly influence delta13C and may result in misleading ecological interpretations. Whereas lipid extraction before IRMS analysis constitutes a way of stable isotope result lipid-normalisation, such a procedure was given up because of the un-controlled effects of the methods used (i.e., "Bligh & Dyer", Soxhlet, etc.) on delta15N. The aim of this work was to develop a simple, rapid and efficient lipid extraction method allowing for simultaneous C and N stable isotope analysis in the biological soft tissues of aquatic organisms. The goal was to be free from the lipid influence on delta13C values without interfering with delta15N values. For that purpose, the modern automated pressurized liquid extraction technique ASE (accelerated solvent extraction) was selected. Eel muscles representative of a broad range of fat contents were extracted via ASE by using different semi-polar solvents (100% dichloromethane and 80% n-hexane/20% acetone) and by operating at different temperature (ambient temperature and 100 degrees C) and pressure (750 and 1900 psi) conditions. The results were discussed in terms of lipid extraction efficiency as well as delta13C and delta15N variability. PMID- 19446064 TI - Production of immunoaffinity membranes for direct analysis of antigen after antibody separation and blotting under non-denaturing conditions. AB - Membrane-immobilized anti-transferrin antibody, which was produced after antibody was separated using non-denaturing two-dimensional electrophoresis (2DE), was transferred to a polyvinylidene difluoride (PVDF) membrane and was stained by direct blue 71. The antigen, transferrin, specifically bound to the membrane immobilized antibody and was eluted only after rinsing the membrane with glutamic acid or aspartic acid solution. The antigen was analyzed directly by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) when the membrane was incubated with human plasma after the removal of human serum albumin using polyethylene glycol. The transferrin extracted by glutamic acid or aspartic acid solution retained the binding of Fe3+ in the presence of the carbonate anion. We found that immunoaffinity membranes can be useful for simple and rapid removal and extraction of intact proteins after antibody separation and blotting under non-denaturing conditions. PMID- 19446065 TI - Classification of red wines by chemometric analysis of voltammetric signals from PEDOT-modified electrodes. AB - Nine different types of Italian red wines of four different varieties were analysed, without any sample pre-treatments, by voltammetric techniques using a poly(3,4-ethylenedioxythiophene)-modified electrode. The data matrices consisting of the currents measured at different potentials, by repeated Cyclic Voltammetry or Differential Pulse Voltammetry, are submitted to chemometric analysis. After explorative tests based on Principal Component Analysis, Partial Least Squares Discriminant Analysis classification models are built both for the training and for the test sets. To this aim, different classification strategies are adopted, considering the responses from the two techniques either separately or joined together to form a data matrix including the whole voltammetric information. PMID- 19446066 TI - Nano-level monitoring of Yb(III) by fabrication of coated graphite electrode based on newly synthesized hexaaza macrocyclic ligand. AB - The two macrocyclic ligands 2,12-(2-methoxyaniline)2-4,14-Me2-[20]-1,4,11,14 tetraene-1,5,8,11,15,18-N6 (L1) and 2,12-(2-methoxyaniline)(2)-4,14-Me2-8,18 dimethylacrylate-[20]-1,4,11,14-tetraene-1,5,8,11,15,18-N6 (L2) have been synthesized and explored as neutral ionophores for preparing poly(vinylchloride) (PVC) based membrane sensors selective to Yb(III) ions. Effects of various plasticizers and anion excluders were studied in detail and improved performance was observed. The best performance was obtained for the membrane sensor having a composition of L2:PVC:BA:NaTPB in the ratio of 5: 40: 52: 3 (w/w; mg). The performance of the membrane based on L2 was compared with polymeric membrane electrode (PME) as well as with coated graphite electrode (CGE). The electrodes exhibit Nernstian slope for Yb3+ ions with limits of detection of 4.3 x 10(-8) M for PME and 5.8 x 10(-9) M for CGE. The response time for PME and CGE was found to be 10 s and 8 s, respectively. The potentiometric responses are independent of the pH of the test solution in the pH range 3.0-8.0 for PME and 2.5-8.5 for CGE. The CGE has found to work satisfactorily in partially non-aqueous media upto 30% (v/v) content of methanol, ethanol and 20% (v/v) content of acetonitrile and could be used for a period of 5 months. The CGE was used as indicator electrode in the potentiometric titration of Yb3+ ions with EDTA and in determination of fluoride ions in mouthwash samples. It can be used for determination of sulfite in red and white wine samples and also in determination of Yb3+ in various binary mixtures with quantitative results. PMID- 19446067 TI - Characterization of redox polymer based electrode and electrochemical behavior for DNA detection. AB - Characterization of redox polymer, poly(vinylferrocenium) perchlorate (PVF+ClO4-) coated as a film on Pt electrodes, and the detection of DNA based on the electrochemical behavior of the polymer were described in this study. PVF+ClO4- modified electrodes were prepared by the electrooxidation of poly(vinylferrocene) (PVF), and DNA immobilized polymer modified electrode was then prepared. The characterization of the polymer modified electrodes were performed by scanning tunneling microscopy (STM), Raman spectroscopy and alternating current (AC) impedance. The effects of DNA concentration, pH, and polymer films in various thicknesses based on the electrode response were also investigated. The electrochemical behavior of DNA modified polymer electrode by using double stranded DNA (dsDNA) or single-stranded DNA (ssDNA) was compared. DNA hybridization was also investigated. PMID- 19446068 TI - Immunoassay channels for alpha-fetoprotein based on encapsulation of biorecognition molecules into SBA-15 mesopores. AB - A novel immunoassay channeling sensor for alpha-fetoprotein (AFP) was proposed by incorporating biorecognition molecules into the mesopores of well-ordered hexagonal SBA-15. As the biosensing element, alkaline phosphatase (ALP)-labeled antibody was embedded into the mesopores with the substrate of 1-naphthyl phosphate (1-NP). The encapsulated ALP-labeled antibody retained its bioactivities on catalytic hydrolysis reaction with 1-NP and immunological reaction with antigen. Ionic liquid-chitosan hybrid was chosen to increase film adherence and prevent the leakage of the immobilized molecules. The peak current responses decreased due to the increasing spatial blocking and impedance from the formation of nonconductive immunoconjugates on the surface of the electrode. The experimental parameters were optimized including the concentrations of the immobilized 1-NP and ALP-labeled antibody, and the amounts of SBA-15 and ionic liquid for the electrode modification. Under the optimized conditions, the constructed immunosensor could detect AFP in a linear range from 1.0 to 150 ng mL(-1) with a detection limit of 0.8 ng mL(-1). It provided an alternative strategy for the detection of antigens or other proteins by the mesoporous materials. PMID- 19446069 TI - Effect of substrate and embedded metallic impurities of fullerene in the determination of nandrolone. AB - A comparison of edge plane pyrolytic graphite substrate is made with other substrates like indium tin oxide, glassy carbon, gold and basal plane pyrolytic graphite as a substrate for fullerene modification for the determination of nandrolone by Osteryoung square wave voltammetry (OSWV) in phosphate buffer media. Comparative study of voltammetric response of nandrolone at untreated, purified and super-purified fullerene modified edge plane pyrolytic graphite electrode (EPPGE) is also carried out to determine the role of embedded metallic impurities of fullerene on determination of nandrolone. It is observed that EPPGE serves as best substrate among the studied for casting fullerene. The removal of embedded metals from fullerene shifts the peak potential of nandrolone to more positive potentials and peak current decreases. A linear calibration curve is obtained in the concentration range of 0.01-50 nM with a detection limit and sensitivity of 1.5 x 10(-11) M and 1.838 microA nM(-1), respectively. The developed method was satisfactorily applied to the determination of nandrolone in several commercially available medicinal samples. PMID- 19446070 TI - Determination of foodborne pathogenic bacteria by multiplex PCR-microchip capillary electrophoresis with genetic algorithm-support vector regression optimization. AB - A rapid and sensitive method based on microchip capillary electrophoresis with condition optimization of genetic algorithm-support vector regression (GA-SVR) was developed and applied to simultaneous analysis of multiplex PCR products of four foodborne pathogenic bacteria. Four pairs of oligonucleotide primers were designed to exclusively amplify the targeted gene of Vibrio parahemolyticus, Salmonella, Escherichia coli (E. coli) O157:H7, Shigella and the quadruplex PCR parameters were optimized. At the same time, GA-SVR was employed to optimize the separation conditions of DNA fragments in microchip capillary electrophoresis. The proposed method was applied to simultaneously detect the multiplex PCR products of four foodborne pathogenic bacteria under the optimal conditions within 8 min. The levels of detection were as low as 1.2 x 10(2) CFU mL(-1) of Vibrio parahemolyticus, 2.9 x 10(2) CFU mL(-1) of Salmonella, 8.7 x 10(1) CFU mL( 1) of E. coli O157:H7 and 5.2 x 10(1) CFU mL(-1) of Shigella, respectively. The relative standard deviation of migration time was in the range of 0.74-2.09%. The results demonstrated that the good resolution and less analytical time were achieved due to the application of the multivariate strategy. This study offers an efficient alternative to routine foodborne pathogenic bacteria detection in a fast, reliable, and sensitive way. PMID- 19446071 TI - Characterization of synthetic polymers and speck impurities in cellulose pulp: a comparison between pyrolysis-gas chromatography-mass spectrometry and Fourier transform infrared spectroscopy. AB - Pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) and Fourier transform infrared (FT-IR) spectroscopy were used for characterizing specks in cellulose pulp, polymeric materials and pitch formed during the cellulose extraction and paper production in the Brazilian mill. Three samples were analyzed and the pyrograms and infrared spectra obtained were compared. The results showed that the analytical pyrolysis more effectively differentiated between impurities (dirt specks) when compared to the infrared spectroscopy. PMID- 19446072 TI - The Organizational Hypothesis: Reflections on the 50th anniversary of the publication of Phoenix, Goy, Gerall, and Young (1959). AB - The 1959 publication of "Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig" by Charles H. Phoenix, Robert W. Goy, Arnold A. Gerall, and William C. Young transformed how sex differences in mating behavior were thought to develop. Previous work provided extensive evidence that steroid hormones activated patterns of male and female sexual behavior, but only activated the behavioral patterns typical of a given sex. The 1959 paper explained this phenomenon by arguing that androgens, or their metabolites, acting at specific time(s) during development sexually dimorphically organized the tissues mediating mating behavior, which were activated by appropriate hormonal stimulation in adulthood. Thus, exposure to steroids at specific time(s) permanently altered the structure or function of the organism. The exact hormone, exact timing, exact mechanism, and exact tissues were unspecified in the article. The last two paragraphs of the discussion illustrate the investigators' unresolved views. The first proposes that the 'organization' was likely to be functional and not evident in visible structure, whereas the next paragraph argues that behavioral change implies structural change and thus structural changes are the likely consequence of steroid actions. These unresolved issues have produced extensive work in the intervening 50 years. The papers in this issue mark the 50th anniversary of this landmark paper and reflect the scope and relevance of the issues raised in the original paper and demonstrate the progress that has been made in understanding the Organizational Hypothesis and its impact on sexual differentiation. PMID- 19446073 TI - The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. AB - The 1959 publication of the paper by Phoenix et al. was a major turning point in the study of sexual differentiation of the brain. That study showed that sex differences in behavior, and by extension in the brain, were permanently sexually differentiated by testosterone, a testicular secretion, during an early critical period of development. The study placed the brain together in a class with other major sexually dimorphic tissues (external genitalia and genital tracts), and proposed an integrated hormonal theory of sexual differentiation for all of these non-gonadal tissues. Since 1959, the organizational-activational theory has been amended but survives as a central concept that explains many sex differences in phenotype, in diverse tissues and at all levels of analysis from the molecular to the behavioral. In the last two decades, however, sex differences have been found that are not explained by such gonadal hormonal effects, but rather because of the primary action of genes encoded on the sex chromosomes. To integrate the classic organizational and activational effects with the more recently discovered sex chromosome effects, we propose a unified theory of sexual differentiation that applies to all mammalian tissues. PMID- 19446074 TI - Sexual differentiation of pheromone processing: links to male-typical mating behavior and partner preference. AB - Phoenix et al. (Phoenix, C., Goy, R., Gerall, A., Young, W., 1959. Organizing actions of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369-382.) were the first to propose an essential role of fetal testosterone exposure in the sexual differentiation of the capacity of mammals to display male-typical mating behavior. In one experiment control male and female guinea pigs as well as females given fetal testosterone actually showed equivalent levels of mounting behavior when gonadectomized and given ovarian steroids prior to adult tests with a stimulus female. This finding is discussed in the context of a recent, high profile paper by Kimchi et al. (Kimchi, T., Xu, J., Dulac, C., 2007. A functional circuit underlying male sexual behaviour in the female mouse brain. Nature 448, 1009-1014.) arguing that female rodents possess the circuits that control the expression of male-typical mating behavior and that their function is normally suppressed in this sex by pheromonal inputs that are processed via the vomeronasal organ (VNO)-accessory olfactory nervous system. In another Phoenix et al. experiment, significantly more mounting behavior was observed in male guinea pigs and in females given fetal testosterone than in control females following adult gonadectomy and treatment with testosterone. Literature is reviewed that attempts to link sex differences in the anatomy and function of the accessory versus the main olfactory projections to the amygdala and hypothalamus to parallel sex differences in courtship behaviors, including sex partner preference, as well as the capacity to display mounting behavior. PMID- 19446076 TI - Back to the future: The organizational-activational hypothesis adapted to puberty and adolescence. AB - Phoenix, Goy, Gerall, and Young first proposed in 1959 the organizational activational hypothesis of hormone-driven sex differences in brain and behavior. The original hypothesis posited that exposure to steroid hormones early in development masculinizes and defeminizes neural circuits, programming behavioral responses to hormones in adulthood. This hypothesis has inspired a multitude of experiments demonstrating that the perinatal period is a time of maximal sensitivity to gonadal steroid hormones. However, recent work from our laboratory and others demonstrates that steroid-dependent organization of behavior also occurs during adolescence, prompting a reassessment of the developmental time frame within which organizational effects are possible. In addition, we present evidence that adolescence is part of a single protracted postnatal sensitive period for steroid-dependent organization of male mating behavior that begins perinatally and ends in late adolescence. These findings are consistent with the original formulation of the organizational/activational hypothesis, but extend our notions of what constitutes "early" development considerably. Finally, we present evidence that female behaviors also undergo steroid-dependent organization during adolescence, and that social experience modulates steroid dependent adolescent brain and behavioral development. The implications for human adolescent development are also discussed, especially with respect to how animal models can help to elucidate the factors underlying the association between pubertal timing and adult psychopathology in humans. PMID- 19446075 TI - Sex differences in the brain: the relation between structure and function. AB - In the fifty years since the organizational hypothesis was proposed, many sex differences have been found in behavior as well as structure of the brain that depend on the organizational effects of gonadal hormones early in development. Remarkably, in most cases we do not understand how the two are related. This paper makes the case that overstating the magnitude or constancy of sex differences in behavior and too narrowly interpreting the functional consequences of structural differences are significant roadblocks in resolving this issue. PMID- 19446077 TI - The organizational hypothesis and final common pathways: Sexual differentiation of the spinal cord and peripheral nervous system. AB - In honor of the 50th anniversary of the "organizational hypothesis," this paper reviews work on sexual differentiation of the spinal cord and peripheral nervous system. Topics considered include the spinal nucleus of the bulbocavernosus, the ejaculation center, the cremaster nucleus, sensory and autonomic neurons, and pain. These relatively simple neural systems offer ample confirmation that early exposure to testicular hormones masculinizes the nervous system, including final common pathways. However, I also discuss findings that challenge, or at least stretch, the organizational hypothesis, with important implications for understanding sex differences throughout the nervous system. PMID- 19446078 TI - The neurobiology of sexual partner preferences in rams. AB - The question of what causes a male animal to seek out and choose a female as opposed to another male mating partner is unresolved and remains an issue of considerable debate. The most developed biologic theory is the perinatal organizational hypothesis, which states that perinatal hormone exposure mediates sexual differentiation of the brain. Numerous animal experiments have assessed the contribution of perinatal testosterone and/or estradiol exposure to the development of a male-typical mate preference, but almost all have used hormonally manipulated animals. In contrast, variations in sexual partner preferences occur spontaneously in domestic rams, with as many as 8% of the population exhibiting a preference for same-sex mating partners (male-oriented rams). Thus, the domestic ram is an excellent experimental model to study possible links between fetal neuroendocrine programming of neural mechanisms and adult sexual partner preferences. In this review, we present an overview of sexual differentiation in relation to sexual partner preferences. We then summarize results that test the relevance of the organizational hypothesis to expression of same-sex sexual partner preferences in rams. Finally, we demonstrate that the sexual differentiation of brain and behavior in sheep does not depend critically on aromatization of testosterone to estradiol. PMID- 19446079 TI - Clinical implications of the organizational and activational effects of hormones. AB - Debate on the relative contributions of nature and nurture to an individual's gender patterns, sexual orientation and gender identity are reviewed as they appeared to this observer starting from the middle of the last century. Particular attention is given to the organization-activation theory in comparison to what might be called a theory of psychosexual neutrality at birth or rearing consistency theory. The organization-activation theory posits that the nervous system of a developing fetus responds to prenatal androgens so that, at a postnatal time, it will determine how sexual behavior is manifest. How organization-activation was or was not considered among different groups and under which circumstances it is considered is basically understood from the research and comments of different investigators and clinicians. The preponderance of evidence seems to indicate that the theory of organization activation for the development of sexual behavior is certain for non-human mammals and almost certain for humans. This article also follows up on previous clinical critiques and recommendations and makes some new suggestions. PMID- 19446080 TI - Effects of prenatal androgens on rhesus monkeys: a model system to explore the organizational hypothesis in primates. AB - After proposing the organizational hypothesis from research in prenatally androgenized guinea pigs (Phoenix, C.H., Goy, R.W., Gerall, A.A., Young, W.C., 1959. Organizational action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369-382.), the same authors almost immediately extended the hypothesis to a nonhuman primate model, the rhesus monkey. Studies over the last 50 years have verified that prenatal androgens have permanent effects in rhesus monkeys on the neural circuits that underlie sexually dimorphic behaviors. These behaviors include both sexual and social behaviors, all of which are also influenced by social experience. Many juvenile behaviors such as play, mounting, and vocal behaviors are masculinized and/or defeminized, and aspects of adult sexual behavior are both masculinized (e.g. approaches, sex contacts, and mounts) and defeminized (e.g. sexual solicits). Different behavioral endpoints have different periods of maximal susceptibility to the organizing actions of prenatal androgens. Aromatization is not important, as both testosterone and dihydrotestosterone are equally effective in rhesus monkeys. Although the full story of the effects of prenatal androgens on sexual and social behaviors in the rhesus monkey has not yet completely unfolded, much progress has been made. Amazingly, a large number of the inferences drawn from the original 1959 study have proved applicable to this nonhuman primate model. PMID- 19446082 TI - Delayed diagnosis in common variable immunodeficiency. PMID- 19446083 TI - CMV transmission in human milk. PMID- 19446084 TI - Bagging the bag. PMID- 19446081 TI - Sexual differentiation of motivation: a novel mechanism? AB - Sex differences in motivation are apparent for the motivation to engage in sexual behavior, the motivation to take drugs of abuse, and the motivation to engage in parental behavior. In both males and females there is an increase in NAcc DA associated with motivated behaviors. Here it proposed that sex differences in the regulation of DA activity in the ascending mesolimbic projections may underlie sex differences in motivation. In particular, sex differences in the neuroendocrine regulation of this brain system play a role in the expression of sex differences in motivated behaviors. Here it is proposed that sexual differentiation of motivation is mediated, at least in part, by a novel mechanism in which ovarian hormones secreted at puberty in the female actively feminize the DA system. PMID- 19446085 TI - Amplitude integrated EEG--the future? PMID- 19446086 TI - Imaging after UTI--always a VCUG? PMID- 19446087 TI - Could PDA ligation be a course of bronchopulmonary dysplasia? PMID- 19446088 TI - Disability rates in preterms. PMID- 19446089 TI - Sleep and obesity. PMID- 19446090 TI - Premature adrenarche may start earlier than one thinks. PMID- 19446091 TI - How could sugar-sweetened beverages cause blood pressure elevation? PMID- 19446092 TI - Ethics in everyday pediatrics. PMID- 19446093 TI - Sour notes on sweet drinks. PMID- 19446094 TI - "Guidelines" for guideline implementation. PMID- 19446095 TI - Seventeen years of asthma guidelines: why hasn't the outcome improved for children? PMID- 19446101 TI - New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia. AB - Mesenchymal stem cells (MSCs) can show osteogenic differentiation capability when implanted in vivo, as well as cultured in vitro; therefore we attempted to use allogeneic MSCs for an 8-month-old patient with hypophosphatasia. MSCs were obtained by culture expansion of fresh marrow from the patient's father. Some of the MSCs were further cultured under osteogenic conditions on a culture dish or porous hydroxyapatite ceramics, resulting in cultured osteoblasts and osteogenic constructs, respectively. The MSCs and osteoblasts were injected into the patient, and the constructs were implanted locally. After traditional bone marrow transplantation, the MSCs, osteoblasts, and osteogenic constructs were used for treatment and to improve the patient's respiratory condition and skeletal abnormality. The condition worsened again, and an MSC booster shot was administered. At the same time, the construct was retrieved. The respiratory condition improved, and the retrieved construct showed de novo bone derived from both donor and patient cells. We demonstrated the importance of allogeneic MSC transplantation for hypophosphatasia and the constructs as an alternative to bone fragments that provided further osteogenic capability in the patient. PMID- 19446102 TI - Autonomous thyroid adenoma: only an adulthood disease? AB - We identified somatic activating thyrotropin-receptor gene mutations within autonomous thyroid nodules (ATN) in 2 girls with 1 ATN and in 1 girl with 3 ATN. A fourth patient had a somatic activating gene mutation of the alpha-subunit of the stimulating G-protein in 2 ATN. Activating somatic mutations in ATN can cause non-autoimmune hyperthyroidism in children. PMID- 19446103 TI - Skull fracture in an infant not visible with computed tomography. PMID- 19446104 TI - Breast-feeding does a lot more than reduce pain in vaccinated neonates and infants. PMID- 19446105 TI - Use of aminoglycosides in preterm neonates: a simple task? PMID- 19446107 TI - The importance of treatment regimens and pubertal status for growth in IBD. PMID- 19446109 TI - [On minors' refusal to receive a blood transfusion]. PMID- 19446110 TI - Long-term pioglitazone therapy improves arterial stiffness in patients with type 2 diabetes mellitus. AB - Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, not only improves insulin resistance and glycemic control, but may also have additional beneficial vascular effects in patients with type 2 diabetes mellitus. We investigated whether pioglitazone had an influence on arterial stiffness, which is an independent predictor of cardiovascular events, in 204 patients with type 2 diabetes mellitus. A prospective, nonrandomized, open-label trial was performed that involved 41 patients treated with pioglitazone, 46 patients receiving sulfonylureas, 67 patients on insulin, and 50 patients on diet/exercise only. The follow-up period was 56 +/- 3 months. Arterial stiffness was evaluated by using the arterial stiffness index (ASI), which was based on analysis of the pulse wave amplitude pattern obtained during automated blood pressure measurement in the upper limb. The 4 groups had a similar baseline ASI, which was greater than the reference range in each group. Although antidiabetic therapies improved hemoglobin A(1c) and low-density lipoprotein cholesterol, ASI only decreased significantly in the pioglitazone group. Thus, pioglitazone improved abnormal arterial stiffness in patients with type 2 diabetes mellitus via a mechanism beyond the metabolic improvement. These findings may have important clinical implications in the use of pioglitazone in patients with type 2 diabetes mellitus. PMID- 19446111 TI - Impact of different metabolic syndrome classifications on the metabolic syndrome prevalence in a young Middle Eastern population. AB - The metabolic syndrome (MetS) prevalence in a young Middle Eastern population has never been studied. We studied this prevalence in a randomly selected population of Lebanese students using different MetS classifications. Three hundred eighty one subjects aged 18 to 30 years were included in the study. Anthropometric and biological parameters (waist circumference [WC], systolic and diastolic blood pressures, fasting plasma glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and homeostasis model assessment [HOMA] index to assess insulin resistance) were measured. Receiver operating characteristic (ROC) curves were generated to determine population-specific cutoff values for MetS parameters and HOMA index. The MetS prevalence was calculated using the National Cholesterol Education Program's Adult Treatment Panel III (ATP-III), the actualized ATP-III, and our cutoffs, either with or without HOMA index as an extra risk factor. The MetS prevalence using the ATP-III and the actualized ATP-III was, respectively, 5.25% and 5.28%. It increased to 9.19% when using our cutoff values and to 12.64% when HOMA index was added. This increase was significant only in men. The identified cutoff values are, for WC, 91 cm in women and 99.5 cm in men and, for HOMA index, 2.32. Among the MetS components, WC was the best MetS predictor, whereas fasting plasma glucose was the poorest. Our study shows that the MetS prevalence in Lebanon is comparable with other countries. In addition, we identified in our population new cutoff points for MetS parameters and HOMA index that allow the detection of a higher number of subjects with the MetS, mainly in the male population. PMID- 19446112 TI - The estimation of cardiovascular risk factors by body mass index and body fat percentage in Korean male adults. AB - The aim of the study was to assess cardiovascular risk in men with high body fat percentage (BF%) and normal body mass index (BMI) and men with normal BF% and high BMI. This study was a cross-sectional study using data on 5534 Korean male adults. Body mass index, BF%, and waist circumference were measured as adiposity indices. Bioelectrical impedance analysis was used for measuring BF%. Blood pressure, fasting plasma glucose, total cholesterol, triglyceride, and high density lipoprotein cholesterol were measured routinely. Information regarding alcohol consumption, smoking, exercise, and past/current medical history was obtained by structured questionnaires. Subjects were categorized into 4 groups by means of BMI and BF% (group 1, BMI <25 kg/m(2) and BF% <25%; group 2, BMI <25 kg/m(2) and BF% > or =25%; group 3, BMI > or =25 kg/m(2) and BF% <25%; group 4, BMI > or =25 kg/m(2) and BF% > or =25%). Cardiovascular risk factors (CVRFs) such as high blood pressure, hyperglycemia, and dyslipidemia were estimated in each group. As might be expected, the prevalences of high blood pressure, hyperglycemia, and dyslipidemia were lowest in group 1 and were highest in group 4. Multivariate analyses showed that subjects in group 2 or group 4 had a 1.8 times increased risk of clustering of 2 or more CVRFs compared with subjects in group 1 (P < .001). The adjusted odds ratio (1.15; 95% confidence interval, 0.94 1.40) of subjects in group 3 on clustering of 2 or CVRFs was not significantly increased (P = .180). High BF% was related to increase of cardiovascular risk regardless of the level of BMI in Korean men. However, cardiovascular risk of men with high BMI without high BF% was not significantly increased. PMID- 19446113 TI - Factors associated with glycemic control after an inpatient program. AB - In this study, we investigated the factors predicting poor glycemic control after an inpatient program. Using the hospital database from April 1999 to May 2003, we retrospectively identified patients with type 2 diabetes mellitus and hemoglobin A(1C) (HbA(1C)) of at least 8.0% at the time of admission for an inpatient program. In the primary analysis, factors potentially related to poor glycemic control (HbA(1C) > or =7.0%) at 6 months after admission were investigated. Stepwise multivariate regression analysis identified the duration of diabetes (odds ratio, 2.43; 95% confidence interval [CI], 1.54-3.82; P < .001), period from the first attendance at our hospital until admission (odds ratio, 1.60; 95% CI, 1.01-2.54; P = .047), and number of admissions (odds ratio, 2.28; 95% CI, 1.36-3.82; P = .002) as predictors of poor glycemic control. In the secondary analysis, factors related to poor glycemic response (an absolute decrease of HbA(1C) by <1.5% from the baseline) at 6 months after admission were investigated. Stepwise multivariate regression analysis identified the duration of diabetes (odds ratio, 2.17; 95% CI, 1.19-3.93; P = .011), period from the first attendance at our hospital until admission (odds ratio, 2.17; 95% CI, 1.43 3.29; P < .001), treatment of diabetes at discharge (oral hypoglycemic agents: odds ratio, 2.52; 95% CI, 1.15-5.51; P = .021; insulin: odds ratio, 4.44; 95% CI, 1.96-10.07; P < .001), baseline HbA(1C) (odds ratio, 0.44; 95% CI, 0.37-0.53; P < .001), and addition of new medications (odds ratio, 0.41; 95% CI, 0.27-0.62; P < .001) as predictors of poor glycemic control. PMID- 19446114 TI - Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. AB - This clinical policy from the American College of Emergency Physicians is an update of a 2002 clinical policy on the evaluation and management of adult patients presenting to the emergency department (ED) with acute, nontraumatic headache. A writing subcommittee reviewed the literature to derive evidence-based recommendations to help clinicians answer the following 5 critical questions: (1) Does a response to therapy predict the etiology of an acute headache? (2) Which patients with headache require neuroimaging in the ED? (3) Does lumbar puncture need to be routinely performed on ED patients being worked up for nontraumatic subarachnoid hemorrhage whose noncontrast brain computed tomography (CT) scans are interpreted as normal? (4) In which adult patients with a complaint of headache can a lumbar puncture be safely performed without a neuroimaging study? (5) Is there a need for further emergent diagnostic imaging in the patient with sudden-onset, severe headache who has negative findings in both CT and lumbar puncture? Evidence was graded and recommendations were given based on the strength of the available data in the medical literature. PMID- 19446115 TI - Answering the question, "Why do we need nurses?". PMID- 19446117 TI - Concern about the nursing profession. PMID- 19446116 TI - Here is one example that is working! PMID- 19446118 TI - System factors and patient falls in emergency departments. PMID- 19446119 TI - January febrile neutropenia article. PMID- 19446121 TI - An examination of adherence strategies and challenges in poison control communication. AB - INTRODUCTION: The principal objective of this study was to characterize how nurses and pharmacists at a poison control center (PCC) determine the likelihood of caller adherence to a health care facility referral. METHODS: A focus group was conducted with 6 nurses and 4 pharmacists from a regional PCC. Content analysis was used to determine themes within the discussion. All participants were certified as specialists in poison information (SPIs). RESULTS: Four themes were identified: (1) SPIs' generation of informal "likelihood-of-adherence" assessments as to whether a caller will follow the recommendation to go to a health care facility, (2) SPI communication strategies used to promote adherence, (3) behavior of SPIs during periods of high call volume, and (4) communication training for PCC staff members. DISCUSSION: This pilot study provides insights in SPIs' current assessment and communication, particularly those related to promoting caller adherence to recommendations. PMID- 19446122 TI - Characteristics and predictors of frequent utilization of emergency services. AB - INTRODUCTION: Although frequent ED users account for a small percentage of ED visits, these patients can drain the system, contributing to overcrowding and lowered quality of care. METHODS: This retrospective descriptive correlational study explored characteristics of frequent ED users at a large Midwestern urban hospital and factors predictive of high ED utilization. The sample included adult patients with at least 6 visits in 2005-2006 (N = 201). For each, 6 visits were randomly chosen for chart review (N = 1200 visits) of demographic, health history, and clinical factors such as chief complaints. RESULTS: Frequent users were commonly female, 35 years old, white, single, unemployed, living alone, with private insurance/Medicaid and a primary care physician. Top chief complaints were abdominal pain, headache, chest pain, low back pain, and lower extremity pain. However, a Poisson regression found that the following characteristics were associated with a higher number of ED visits: male, non-Black race, part-time employment, retired/unemployed, having Medicare, and having a chief complaint of upper respiratory infection. Headache approached significance as an independent predictor of more visits. DISCUSSION: Almost 95% had fewer than 10 ED visits per year, with pain the overall top chief complaint. Seventy percent of frequent visits occurred during either the evening or night shift, perhaps indicating access issues to primary physicians or urgent care clinics. The rate of frequent users was comparable with other investigations, yet few similarities in patient characteristics and predictors of high ED utilization were found, partly because of the retrospective design, but certainly reinforcing limited generalizability of ED utilization patterns across centers in different metropolitan and geographic regions. PMID- 19446123 TI - Prevalence of secondary traumatic stress among emergency nurses. AB - INTRODUCTION: Emergency nurses often care for persons exposed to traumatic events. In the presence of empathetic caring, nurses exposed to such stressors over time can suffer from Secondary Traumatic Stress (STS), or Compassion Fatigue (CF). STS symptoms (intrusion, avoidance, and arousal) may lead to job dissatisfaction or burnout. The purpose of this study is to investigate the prevalence of STS in emergency nurses. METHODS: Exploratory comparative design, with 67 emergency nurses from three general community hospitals in California. Survey instruments included a demographic tool and the STS Survey (STSS). RESULTS: Nurses were most likely to have Arousal symptoms (irritability reported by 54% of nurses), followed by Avoidance symptoms (avoidance of patients 52%), and Intrusion symptoms (intrusive thoughts about patients 46%). The majority of nurses (85%) reported at least one symptom in the past week. Utilizing Bride's algorithm to identify STS, 15% of nurses met no criteria, while 33% met all. Nurse participation in stress management activities was associated with less prevalence of STS symptoms. DISCUSSION: High prevalence of STS in our sample indicates that potentially large numbers of emergency nurses may be experiencing the negative effects of STS. Symptoms may contribute to emotional exhaustion and job separation of emergency nurses. Subsequent studies should be done to evaluate the association of CF/STS on actual burnout and attrition among emergency nurses. PMID- 19446124 TI - A survey of needlesticks and sharp instrument injuries in emergency health care in Turkey. PMID- 19446125 TI - A study of the workforce for an ED triage area in a tertiary care hospital. PMID- 19446126 TI - Evidence-based ED Disaster Planning. PMID- 19446127 TI - Community-associated methicillin-resistant Staphylococcus aureus: implications for emergency department nursing. PMID- 19446128 TI - A 46-year-old man with an equestrian-related head injury. PMID- 19446130 TI - Development of a certified emergency nurse certification initiative. PMID- 19446131 TI - ED Information Systems: a guideline for successful implementation. PMID- 19446132 TI - Allergies: essential patient information for safe practice. PMID- 19446133 TI - Creating a safer work environment. PMID- 19446134 TI - Discover the data. PMID- 19446135 TI - "M & M" ... to the rescue. PMID- 19446137 TI - Preparing for precipitous vaginal deliveries in the emergency department. PMID- 19446138 TI - More big help from little tools. PMID- 19446139 TI - What is that smell? PMID- 19446140 TI - Use of a tourniquet after a gunshot wound to the thigh. PMID- 19446141 TI - Charting the course for triage decisions. PMID- 19446142 TI - A safety review of topical bovine thrombin-induced generation of antibodies to bovine proteins. AB - BACKGROUND: Topical bovine thrombin has been used to accelerate attainment of hemostasis in the surgical setting for >60 years, and its immunogenicity has been widely reported. Although the development of antibodies is inherent in the introduction of any non-self-therapeutic protein such as bovine-sourced thrombin, there are questions about the relationship between the presence of antibodies to constituents of the therapeutic protein preparation and the occurrence of clinically relevant adverse events (AEs). OBJECTIVE: This review examines the proposed mechanisms for the immunogenicity of topical bovine thrombin preparations and summarizes available evidence from randomized clinical trials, observational studies, and case reports to explore possible relationships between the reported immunogenicity of topical bovine thrombin and the occurrence of AEs. METHODS: A search of MEDLINE (1966-August 2008) for studies published in English was conducted using the Medical Subject Heading terms surgery, antibodies, and hemorrhage, as well as equivalent key words for bovine, adverse events, and thrombin. For inclusion in the review, studies had to report clinical or laboratory safety data for patients exposed to topical bovine thrombin during surgery. RESULTS: The evidence suggests that patients with repeated perioperative exposure to topical bovine thrombin have a 3- to 10-fold greater risk for development of antibodies to topical bovine thrombin than do patients with no history of surgery-related exposure to this agent. Early case reports associated the development of anti-bovine protein antibodies with bleeding and/or thrombotic complications. However, in one prospective, randomized controlled trial comparing topical bovine thrombin with topical recombinant human thrombin, 99.5% of patients in each treatment arm developed postoperative AEs. In an-other, 54% and 55% of patients in the respective treatment arms developed postoperative AEs. In a prospective, randomized controlled trial that compared topical bovine thrombin and plasma-derived human thrombin, 95.5% of patients in each treatment arm developed postoperative AEs. CONCLUSIONS: Repeated perioperative exposure to topical bovine thrombin may increase both the prevalence and titers of antibodies to >or=1 protein contained in nonhomogeneous topical bovine thrombin preparations. However, the evidence reviewed does not support a definitive association between preoperative or postoperative generation of anti-bovine protein antibodies and an increased risk of AEs in surgical patients treated with topical bovine thrombin. PMID- 19446143 TI - Etravirine: a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) active against NNRTI-resistant strains of HIV. AB - BACKGROUND: Since 1981, the AIDs epidemic has continued to expand and, at the end of 2007, there were ~33 million people worldwide living with HIV, including 1.2 million in North America. OBJECTIVE: This article provides a comprehensive overview of the nonnucleoside reverse transcriptase inhibitor (NNRTI) etravirine when used in treatment-experienced adult patients with multidrug-resistant HIV infections. METHODS: Relevant information was gathered through a search of MEDLINE (1966-December 2008) and International Pharmaceutical Abstracts (1970 December 2008) databases, as well as abstracts of the Conference on Retroviruses and Opportunistic Infections (2006-2008) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (2002-2008). Clinical trial data were limited to human studies that were Phase IIa or higher. The search terms used were etravirine and TMC125. References were also identified through screening of citations in the articles gathered. RESULTS: Etravirine is an NNRTI that is able to adapt its binding orientation and overcome common NNRTI resistance associated mutations (RAMs) such as K103N. It was originally formulated in polyethylene glycol (PEG), but pharmacokinetic studies using an updated tablet formulation identified a more favorable absorption profile that has allowed the study of lower doses (200 mg instead of 900 mg BID). Phase IIa studies using the PEG formulation of etravirine found that viral loads were reduced in both treatment naive and treatment-experienced patients with HIV (-1.99 vs -0.86 log10 copies/mL; P < 0.001). Phase IIb studies expanded on this finding by using various doses of the reformulated tablet to evaluate virologic efficacy in highly treatment-experienced patients with triple-class (protease inhibitor, nucleoside/nucleotide reverse transcriptase inhibitors [NRTI], and NNRTI) resistance. Patients in an open-label, partially blinded, Phase IIb study (N = 199) were randomized to receive an optimized background regimen alone or in combination with either 400 or 800 mg of etravirine BID. Regardless of the dose, patients in the etravirine arms had a greater decrease in viral load from baseline (-1.04 and -1.18 log10 copies/mL, respectively) compared with patients in the placebo arm (-0.19 log10 copies/mL; P = 0.005 and P < 0.001, respectively). The DUET studies (DUET-1, N = 612; DUET-2, N = 593) are 2 ongoing, international, randomized, double-blind, placebo-controlled, Phase III trials in which patients with preexisting RAMs are treated with darunavir/ ritonavir and an optimized NRTI background in combination with etravirine or placebo and the optional use of enfuvirtide. According to pooled, 48-week data from these studies, significantly more patients who received etravirine achieved an HIV RNA <50 copies/ mL (61% vs 40%; P < 0.001) and had greater virologic (-2.25 vs -1.49 log10 copies/mL reduction in HIV RNA from baseline; P < 0.001) and immuno-logic (98 vs 73 cells/mm(3) CD4 cell count change from baseline; P < 0.001) responses compared with placebo. Additionally, the incidence of adverse events, including diarrhea, nausea, and headache, was similar between treatment groups in the DUET studies; rash, however, was significantly more common in the etravirine group (17% vs 9%; P < 0.001). CONCLUSION: Etravirine is an NNRTI that was reported to be effective when used as part of an optimized, highly active antiretroviral therapy regimen in NNRTI treatment-experienced adult patients with HIV. PMID- 19446144 TI - A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. AB - BACKGROUND: Myofascial pain syndrome (MPS), a regional pain condition caused by trigger points in muscle or muscle fascia, produces muscle pain, tenderness, and disability. The gold standard of treatment for MPS-infiltration of trigger points with anesthetic-may provoke discomfort to the patients and require medical intervention. OBJECTIVES: This study was designed to compare the effects of a topical lidocaine patch, a placebo patch, and injection of anesthetic (infiltration) for the symptoms of MPS in terms of pain, disability, and local tissue hypersensitivity, and to determine the acceptability of the lidocaine patch to the patients. METHODS: Patients were randomly allocated to receive 1 of 3 treatments: a lidocaine patch applied to the trigger point for 4 days (replacement every 12 hours; total daily dose, 350 mg), a placebo patch applied to the trigger point for 4 days (replacement every 12 hours), or infiltration of the trigger point with two 1-mL injections of 0.5% bupivacaine hydrochloride given 2 days apart. Treatment with the patches was double-blinded, whereas treatment with infiltration was single-blinded. The number of pain attacks, pain intensity at rest and on movement, and pain-related interference with daily activity, work activity, mood, and quality of life were recorded before, during, and after treatment using a visual analog scale (VAS). Pressure and electrical pain thresholds of the skin, subcutis, and muscle in the trigger point, target area, and a pain-free area were evaluated before starting therapy (day 1) and on days 5 and 9. A VAS was used to measure discomfort from therapy, and a diary was given to each patient to record requests for additional treatment (if needed) and adverse effects. RESULTS: Sixty white patients (46 women and 14 men) 19 to 76 years of age were studied. Mean (SD) age was 46.88 (15.37) years, and mean (SD) weight was 69.58 (13.94) kg. Twenty patients were assigned to each treatment group. Subjective symptoms did not change with placebo, but decreased significantly with the lidocaine patch and infiltration (both, P < 0.001) relative to baseline. Pain thresholds did not vary with the placebo patch, but increased significantly with the lidocaine patch and infiltration (all, P < 0.001); effects at muscle trigger points and target areas were greater with infiltration. Discomfort from therapy was greater with infiltration than with the lidocaine patch. Only patients in the placebo group requested additional treatment (P < 0.001). No adverse events occurred in any group. CONCLUSION: Lidocaine patches were effective in, and highly acceptable to, these patients with MPS and high tissue hypersensitivity. PMID- 19446145 TI - Pretreatment with flurbiprofen axetil, flurbiprofen axetil preceded by venous occlusion, and a mixture of flurbiprofen axetil and propofol in reducing pain on injection of propofol in adult Japanese surgical patients: a prospective, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Pain on injection of propofol is a common clinical problem. Flurbiprofen axetil, an injectable prodrug of flurbiprofen, with or without venous occlusion has been reported to reduce this pain. A search of the existing literature did not identify comparative studies of 3 different techniques, including pretreatment with flurbiprofen axetil, flurbiprofen axetil preceded by venous occlusion, and mixture of propofol and flurbiprofen axetil, for reducing pain on injection of propofol. OBJECTIVE: The aim of this study was to compare the effectiveness of these 3 different techniques of flurbiprofen axetil administration in reducing pain on injection of propofol. METHODS: This prospective, randomized, doubleblind, placebo-controlled study was conducted at the Department of Anesthesiology, Ushiku Aiwa General Hospital, Ibaraki, Japan. Japanese elective surgical patients, aged 20 to 65 years, were enrolled and were randomly divided into 6 groups: the control group received placebo (saline) before administration of IV propofol 0.5 mg/kg; the flurbiprofen group was pretreated with IV flurbiprofen axetil 50 mg before injection of propofol 0.5 mg/kg; the tourniquet control group received placebo (saline) with a tourniquet for 2 minutes followed by administering propofol 0.5 mg/kg; the tourniquet flurbiprofen group was pretreated with flurbiprofen axetil 50 mg with a tourniquet for 2 minutes followed by administering propofol 0.5 mg/kg; the mixed control group was induced with a mixture of placebo (saline) and propofol 0.5 mg/kg; and the mixed flurbiprofen group was induced with a mixture of flurbiprofen axetil 50 mg and propofol 0.5 mg/kg. Immediately after administering propofol into the largest vein of the hand through a 20-gauge intravenous cannula, an investigator blinded to group assignment asked the patient to assess pain intensity at the injection site using a 4-point verbal rating scale: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Adverse effects (AEs) at the injection site (pain, edema, wheal, or inflammation) were assessed by the investigator for 24 hours after surgery using spontaneous reporting and patient interview. RESULTS: One hundred fifty-five patients were assessed for inclusion. A total of 150 patients (71 males, 79 females; mean [SD] age, 41 [10] years; mean [SD] height, 161 [9] cm; mean [SD] body weight, 58 [9] kg) were enrolled and completed the study. Each treatment group comprised 25 patients. No significant differences in the demographic characteristics were observed among the 6 groups. The overall incidence of pain on injection of propofol was 92% (23 of 25 patients) in the control group versus 60% (15/ 25) in the flurbiprofen group (P = 0.009); 84% (21/25) in the tourniquet control group versus 32% (8/25) in the tourniquet flurbiprofen group (P = 0.001); and 92% (23/25) in the mixed control group versus 80% (20/25) in the mixed flurbiprofen group (P = NS). The median pain score was significantly lower in the flurbiprofen group (1) compared with the control group (2) (P = 0.002); this score was significantly lower in the tourniquet flurbiprofen group (0) compared with the tourniquet control group (2) (P = 0.001); the score was comparable between the mixed control and mixed flurbiprofen groups (2 vs 2, respectively; P = NS). The incidence and severity of pain on injection of propofol were significantly less in the tourniquet flurbiprofen group compared with the flurbiprofen group (both, P < 0.05). No AEs at the injection site were observed or reported. CONCLUSION: In this study of adult Japanese surgical patients, pretreatment with flurbiprofen axetil 50 mg preceded by venous occlusion was found to be more effective in reducing pain on injection of propofol than the other flurbiprofen axetil administration strategies tested. PMID- 19446146 TI - Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI 528, a monoclonal antibody against interleukin-9, in healthy adult volunteers. AB - BACKGROUND: Interleukin-9 (IL-9) is involved in pathogenic aspects of the asthmatic response, including induction of the proliferation of T-helper type 2 lymphocytes, mucus production, and mast-cell differentiation, proliferation, and recruitment to the lung. In preclinical studies in mice, inhibition of IL-9 through neutralizing monoclonal antibody (mAb) treatment partially reduced airway hyperresponsiveness and mast-cell progenitor migration to the lung. OBJECTIVE: The goal of the present studies was to determine the safety and pharmacokinetic profiles and immunogenicity of MEDI-528, a humanized immunoglobulin G1k anti-IL-9 mAb, in healthy adult volunteers. METHODS: In separate open-label, Phase I dose escalation studies, single doses of MEDI-528 0.3, 1.0, 3.0, or 9.0 mg/kg were administered as an intravenous infusion (20 mg/min administered over 1-40 minutes, depending on dose) and by subcutaneous injection. All subjects were followed for 84 days. Any laboratory test value outside the normal reference range was considered an adverse event (AE). RESULTS: Twenty-four subjects were enrolled in the intravenous study, and 29 subjects were enrolled in the subcutaneous study. No deaths or serious or severe AEs occurred in either study. The most frequently reported AEs in the intravenous study were laboratory test abnormalities; the most frequently reported AEs in the subcutaneous study were pharyngolaryngeal pain, palpable lymph nodes, and laboratory test abnormalities. The single-dose pharmacokinetics of MEDI-528 were linear and dose proportional over the dose range studied with both routes of administration. The mean t((1/2)) after intravenous administration was approximately 26 days (range, 25-28 days); the mean t((1/2)) after subcutaneous administration ranged from 33 to 87 days across doses. A low titer (1:80) of antibodies to MEDI-528 was detected on day 84 in a single volunteer receiving intravenous MEDI-528 3.0 mg/kg. No antibody titers were detected in any of the volunteers receiving subcutaneous MEDI-528. CONCLUSIONS: Administered intravenously or subcutaneously, MEDI-528 had an acceptable safety profile and exhibited linear pharmacokinetics over the dose range studied in healthy adults in these Phase I studies. The findings support further investigation of MEDI-528 in multiple-dose trials in patients with asthma. ClinicalTrials.gov Identification numbers: NCT00192296 (intravenous study); NCT00116168 (subcutaneous study). PMID- 19446147 TI - A comparison of a standard-dose prednisone regimen and mycophenolate mofetil combined with a lower prednisone dose in Chinese adults with idiopathic nephrotic syndrome who were carriers of hepatitis B surface antigen: a prospective cohort study. AB - BACKGROUND: When receiving immunosuppressive therapy, patients with idiopathic nephrotic syndrome who are also carriers of hepatitis B virus (HBV) surface antigen (HBsAg) are at risk for reactivation of HBV. OBJECTIVE: This study compared the effectiveness and tolerability of a standard-dose prednisone regimen with those of the combination of mycophenolate mofetil (MMF) and a lower prednisone dose for the treatment of idiopathic nephrotic syndrome characterized by minimal-change nephropathy or slight mesangial proliferative glomerulonephritis in Chinese adults who were also carriers of HBsAg, a combination here termed MSNS-HBV. METHODS: This was a prospective, open-label cohort study in Chinese adults with MSNS-HBV. Patients were self-assigned to 1 of 2 treatment groups: the standard prednisone regimen of 1 mg/kg daily or oral MMF 0.5 to 1.0 g BID combined with the lower prednisone dose of 0.5 mg/kg daily. The planned duration of treatment was 36 weeks, with an additional 60 weeks of follow up. The primary outcome measures were rates of complete remission of idiopathic nephrotic syndrome (a decrease in daily proteinuria to within the normal range [<0.3 g]) and rates of HBV reactivation (detectable serum HBV DNA). Secondary outcome measures included relapse rates (>1+ albuminuria on dipstick urinalysis on 3 consecutive days), alanine aminotransferase (ALT) elevations (>50 U/L), use of lamivudine 100 mg/d (added if HBV DNA titers reached >or=10(5) copies/mL), and adverse effects. RESULTS: The intent-to-treat population included 41 patients (22 prednisone, 19 MMF). In patients who completed the study, rates of complete remission after 24 weeks of treatment were 78.9% (15/19) in the prednisone group and 76.5% (13/17) in the MMF group; 2 and 3 patients in the respective groups had a partial remission, and 2 and 1 patient had no response. HBV reactivation occurred in 63.6% (14/22) and 36.8% (7/19) of patients (P = 0.047). The only significant difference in the study was in the probability of HBV reactivation between groups (P = 0.043, log-rank test). During follow-up, at least 1 relapse occurred in 46.7% (7/15) and 30.8% (4/13) of patients. Elevations in ALT were observed in 36.4% (8/22) and 26.3% (5/19) of patients, and the addition of lamivudine was required in 40.9% (9/22) and 21.1% (4/19) of patients. The most frequent adverse effects in both groups were infections (27.3% and 26.3%), followed by gastrointestinal symptoms (13.6% and 21.1%). Two MMF patients developed leukopenia. One patient in the prednisone group discontinued treatment because of severe hepatitis, and 1 patient in the MMF group discontinued because of severe pulmonary infection. CONCLUSIONS: Among the adult Chinese patients with MSNS-HBV who completed this study, there were no significant differences in remission rates of idiopathic nephrotic syndrome between the standard prednisone regimen and the combination of MMF and a reduced prednisone dose. Rates of HBV reactivation, however, were significantly lower in the combination-therapy group. PMID- 19446148 TI - Efficacy and tolerability of once-monthly oral ibandronate (150 mg) and once weekly oral alendronate (70 mg): additional results from the Monthly Oral Therapy With Ibandronate For Osteoporosis Intervention (MOTION) study. AB - BACKGROUND: The MOTION (Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention) study reported that once-monthly ibandronate was noninferior to once-weekly alendronate in terms of increasing bone mineral density (BMD) at the lumbar spine and total hip over 12 months. On analysis of secondary and exploratory end points in MOTION, which included trochanter and femoral neck BMD, monthly ibandronate was found to be noninferior to weekly alendronate. The coprimary, secondary, and exploratory BMD end points from MOTION have been previously reported. OBJECTIVE: This report presents additional results from the MOTION study, including response rates in terms of lumbar spine and total hip BMD gains above baseline; findings from a comparison of serum concentrations of bone turnover markers; and tolerability analysis, including adverse events that led to withdrawal and gastrointestinal (GI) adverse events. METHODS: MOTION was a 12 month (with 15-day follow-up), randomized, multinational, multicenter, double blind, double-dummy, parallel-group, noninferiority study in postmenopausal women aged 55 to <85 years with osteoporosis. Patients were randomly assigned to receive 150-mg-monthly oral ibandronate and weekly alendronate-matched placebo, or 70-mg-weekly oral alendronate and monthly ibandronate-matched placebo, for 12 months. At baseline, day 7 of treatment, 3 and 6 months, 6 months + 7 days, and 12 months, serum concentrations of markers of bone resorption (C-telopeptide of the a chain of type 1 collagen [sCTX]) and bone formation (serum N-terminal propeptides of type 1 collagen) were measured in a subset of the total trial population. At baseline and month 12, BMD was measured using dual-energy x-ray absorptiometry. Exploratory analyses of patients whose spine, total hip, and trochanter BMD at 12 months were above baseline (responders) were also performed. RESULTS: A total of 1760 women were enrolled (ibandronate, 887 patients; alendronate, 873). The median changes in the trough concentrations of sCTX were 75.5% with monthly ibandronate and -81.2% with weekly alendronate. The percentage of patients with mean lumbar spine and total hip BMD gains above baseline (responders) were 90% and 87%, respectively, for ibandronate and 92% and 90%, respectively, for alendronate. GI adverse events were reported in 200 mg/dL. However, due to persistent blood glucose concentration fluctuations, a continuous insulin infusion (0.05 U/kg/h) was started on DOL 7. Because subcutaneous insulin injections could not be administered by the parents outside of the hospital, oral sulfonylurea therapy was attempted. A glyburide oral suspension, prepared by dissolving half of a 1.25-mg tablet in 1 mL of preservative-free, sterile water, was started at 0.2 mg/kg/d in 2 divided doses. The suspension was prepared immediately prior to each dose and was administered via syringe during feedings. On DOL 21, the patient's NDM was managed solely with an oral sulfonylurea, target blood glucose concentrations of 150 to 250 mg/dL were achieved with glyburide 0.7 mg/kg/d in 2 divided doses, and insulin administration was no longer required. On DOL 25, the glyburide dosage was decreased to 0.5 mg/kg/d in 2 divided doses. On DOL 27, the patient was discharged on the same dosage. The patient's NDM subsequently resolved by DOL 49. CONCLUSION: An oral sulfonylurea was a useful treatment option in the management of TNDM in this patient. PMID- 19446155 TI - Standing on the shoulders of Mark H. Beers: more than a giant in geriatric medicine. PMID- 19446156 TI - Differences in annual medication costs and rates of dosage increase between tumor necrosis factor-antagonist therapies for rheumatoid arthritis in a managed care population. AB - BACKGROUND: Tumor necrosis factor (TNF) antagonists are commonly used to treat rheumatoid arthritis (RA). Differences in the dosage and mode of administration of these agents may result in differential rates of dosage adjustment and costs of care. OBJECTIVE: This study compared dosing patterns and annual costs associated with the use of the subcutaneous TNF antagonists adalimumab and etanercept, and the intravenous TNF antagonist infliximab. METHODS: A large managed care database (PharMetrics) was used to identify patients with RA who newly initiated TNF-antagonist therapy with adalimumab, etanercept, or infliximab on or after January 1, 2003, and had at least 6 months of continuous health plan enrollment before initiation of therapy and 12 months of continuous enrollment after initiation. The patients were followed over 12 months of enrollment. Annual pharmacy, inpatient, and outpatient costs were estimated based on plan reimbursements and were compared between cohorts. The average daily dosage (ADD) between prescription refills was used to compare the percentages of patients with greater-than-expected dosing (GTED), defined as 2 consecutive increases in ADD relative to the patient's established maintenance dosage. RESULTS: A total of 2382 patients (568 adalimumab, 1181 etanercept, 633 infliximab) were included in the analysis. Significantly more patients had GTED with infliximab compared with adalimumab and etanercept (32.1%, 8.5%, and 4.7%, respectively; both comparisons, P < 0.05). For patients with a dosage increase, the mean time to the first GTED was significantly shorter for infliximab compared with adalimu-mab and etanercept (154.5, 173.3, and 167.9 days; both, P < 0.05). The mean annual costs of anti-TNF therapy, adjusted for baseline differences, were significantly greater for infliximab compared with adalimumab and etanercept ($15,617, $12,200, and $12,146; both, P < 0.05). There were also significant differences between infliximab relative to adalimumab and etanercept in total RA-related medication costs ($16,280, $12,989, and $12,794; P < 0.05) and total pharmacy costs ($17,854, $14,805, and $14,398; P < 0.05). CONCLUSION: Patients initiating TNF antagonist treatment for RA with infliximab incurred annual medication costs that were nearly 30% greater than costs in those initiating therapy with adalimumab or etanercept, in part because of the significantly greater rate of GTED in infliximab recipients. PMID- 19446157 TI - Time to psychiatric hospitalization in patients with bipolar disorder treated with a mood stabilizer and adjunctive atypical antipsychotics: a retrospective claims database analysis. AB - OBJECTIVE: This study compared the time to psychiatric hospitalization in commercially insured patients with bipolar disorder who were treated with a mood stabilizer plus adjunctive aripiprazole versus adjunctive ziprasidone, olanzapine, quetiapine, or risperidone. METHODS: This was a retrospective, propensity score-matched cohort study using the Ingenix I3/LabRx integrated insurance claims data set. Patients with bipolar disorder were included if they had >or=180 days of pre-index enrollment in the health plan without atypical antipsychotic exposure. Patients received mood stabilizers and subsequently received adjunctive atypical antipsychotic agents; they were then monitored for up to 90 days after the index antipsychotic prescription. The primary analysis was a Cox proportional hazards analysis to evaluate the time until psychiatric hospitalization comparing adjunctive aripiprazole with ziprasidone, olanzapine, quetiapine, or risperidone after adjusting for age, sex, and preindex hospitalization. RESULTS: Adjunctive aripiprazole was associated with a longer time until hospitalization than adjunctive ziprasidone, olanzapine, quetiapine, or risperidone (hazard ratios 1.7, 1.6, 1.5, and 1.5, respectively; all, P < 0.05). Mean initial and maximum doses of all drugs were below those recommended by the package insert or clinical practice guidelines. Sensitivity analyses suggested the robustness of the results in the general population of patients with bipolar disorder recently treated with atypical antipsychotics. CONCLUSIONS: This retrospective claims-data analysis suggests that in these adults with bipolar disorder treated with mood stabilizers, the addition of adjunctive aripiprazole was associated with a longer time to hospitalization than adjunctive ziprasidone, olanzapine, quetiapine, or risperidone during a 90-day follow-up period. PMID- 19446158 TI - Gastroprotective drugs in Australia: utilization patterns between 1997 and 2006 in relation to NSAID prescribing. AB - BACKGROUND: In Australia, the prescribing of proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H(2)RAs) for defined gastrointestinal disorders is approved for subsidy by the universal Australian Pharmaceutical Benefits Scheme. These agents also may be used with NSAIDs, but this prescribing is not approved for subsidy. PPI prescribing increased in Australia between 1997 and 2006, and some authorities are concerned that this increase may be due to prescriptions outside the approved indications. OBJECTIVES: The aims of this study were to quantify gastroprotective drug consumption in Australia between 1997 and 2006 and to investigate the relationship over time between this prescribing and NSAID prescribing. METHODS: Data from concession beneficiaries (seniors and welfare recipients) were included. Data on PPIs, H(2)RAs, NSAIDs, and cyclooxygenase (COX)-2 inhibitors dispensed between 1997 and 2006 were gathered from Medicare Australia and are expressed as defined daily doses (DDDs) per 1000 concession beneficiaries per day (CBPDs). Gastroprotective drugs were defined using the World Health Organization Anatomical Therapeutic Chemical classification of 2006. Drug utilization 90% and expenditures in Australian dollars (AUD $, not normalized to an index year) were calculated. RESULTS: H(2)RA prescribing was stable between 1997 and 2001, at approximately 60 DDDs/1000 CBPDs. Dispensation of H(2)RAs began to decrease in 2001 to 20 DDDs/ 1000 CBPDs in 2006. PPI consumption increased consistently, with a sharp change beginning in 2001 (from about 45 to 140 DDDs/1000 CBPDs between 2001 and 2006). The government expenditure for PPIs per concession beneficiary per year also increased from about AUD $26 in 1997 to almost AUD $74 in 2006, whereas the expenditure for H2RAs decreased from about AUD $24 to about AUD $5. Nonselective NSAID prescribing decreased with the introduction of COX-2 inhibitors in 2000. COX-2 inhibitors increased the overall consumption of total NSAIDs in the first 4 years (2000-2003) after their introduction. CONCLUSIONS: The prescribing of H(2)RAs decreased, whereas the prescribing of PPIs increased, between 1997 and 2006 in this population of concession beneficiaries in Australia. During the same period, nonselective NSAID prescribing decreased while COX-2 inhibitor prescribing increased. PMID- 19446159 TI - Model-based simulation to explore the cost-effectiveness of following practice guidelines for triglyceride and low-density lipoprotein cholesterol control among patients with diabetes mellitus and mixed dyslipidemia. AB - BACKGROUND: The National Cholesterol Education Program Adult Treatment Panel III guidelines recommend maintaining lipid levels within particular targets to reduce the risk of coronary heart disease (CHD) events. OBJECTIVE: The objective of this simulation study was to evaluate the cost-effectiveness of following guideline recommended care compared with current practice or usual care for patients with diabetes mellitus (DM) and mixed dyslipidemia (ie, high low-density lipoprotein cholesterol [LDL-C] and triglyceride [TG] levels). METHODS: A simulation model using a US health care payer perspective was designed to predict changes in lipid levels (LDL-C, TG, high-density lipoprotein cholesterol, and total cholesterol) and long-term CHD risk. Data about patients with DM and uncontrolled TG and/or LDL-C were taken from an electronic medical records database to develop the description of current care (eg, statin, fibrate, or no medication) and cholesterol levels. Patients with uncontrolled lipid levels who were not following guideline recommendations were assumed to be receiving combination treatment (ie, coadministration of statin and fibrate) or monotherapy for the uncontrolled lipids under guideline care. Results from a previous study were used to project incremental benefits of combination treatment compared with monotherapy. CHD events were predicted based on risk equations. A 20-year model of direct costs and quality-adjusted life-years (QALYs) was created. RESULTS: Among patients switched to guideline therapy, the model predicted 72% achieved 2 lipid targets and 44% achieved 3 lipid targets in 1 year. Over 20 years, in a modeled sample of 1000 patients, 176 myocardial infarction and angina events would be avoided by following guideline care. Total present value of costs for drug treatment and medical care for CHD events would be $33,626 per patient for guideline treatment versus $25,264 per patient for current care. The discounted QALY gain would be 0.18 per patient for an incremental cost per QALY of $50,315. CONCLUSIONS: The results of this model simulation suggest that for patients with DM and mixed dyslipidemia, following treatment guidelines rather than current practice (including combination therapy rather than monotherapy) would result in more patients achieving lipid targets, fewer CHD events, and more QALYs gained at a reasonable cost (less than $109,000) per QALY. PMID- 19446160 TI - The financial implications for Medicare of greater use of peritoneal dialysis. AB - BACKGROUND: Although annual per-person health care costs for patients with end stage renal disease (ESRD) on in-center hemodialysis greatly exceed those for patients on peritoneal dialysis (PD), which is a home dialysis therapy, current use of PD remains low. In April 2008, the Centers for Medicare & Medicaid Services issued a new Dialysis Conditions of Coverage final rule underscoring its intent to promote use of home dialysis whenever appropriate. OBJECTIVES: The objectives of this paper were to provide context for the use of in-home versus in center dialysis, to describe factors that influence patterns of dialysis utilization in the United States, and to explore the magnitude of the potential savings that might result from broader use of home dialysis therapies. METHODS: A 5-year budget-impact analysis was performed using data from the 2007 Annual Data Report of the United States Renal Data System. Scenarios were developed in which the PD share of total dialysis was varied to estimate the impact on total Medicare dialysis costs. This study took the perspective of Medicare, the main payer for dialysis in the United States. RESULTS: If the PD share of total dialysis were to decrease from the current 8% to 5%, Medicare spending for dialysis would increase by an additional $401 million over a 5-year period. Alternatively, if the PD share of total dialysis were to increase to 15%, Medicare could realize potential savings of >$1.1 billion over 5 years. CONCLUSIONS: Similar to the conclusion articulated in the Dialysis Conditions of Coverage final rule, increasing clinically appropriate use of PD would be associated with considerable savings to Medicare and to the taxpayers who fund Medicare. These savings could be used to offset part of the financial burden of ESRD care on Medicare and to help legislators meet ever-tightening budgetary constraints. PMID- 19446161 TI - Modified visual analog scale symptom-intensity and overall-bother measures for the assessment of symptoms in studies of pharmacologic stress agents. AB - BACKGROUND: Drugs used to induce stress for cardiac imaging studies often cause discomfort. Patient-reported intensity of discomfort should be considered when comparing such agents. OBJECTIVE: The purpose of this study was to assess the psychometric properties of a modified visual analog scale (VAS) symptom-intensity measure and an overall-bother measure adapted to assess patient-reported intensity of the adverse events (AEs) associated with pharmacologic stress testing with adenosine, a pharmacologic stress myocardial perfusion imaging (PS MPI) agent. METHODS: Data were based on 2 complementary, open-label, multicenter, naturalistic, observational studies among patients completing a PS-MPI procedure. Content, concurrent, and discriminant validity was examined by correlating modified VAS symptom-intensity scores obtained from patients with investigator rated intensity at time of event, overall bother, and patient-reported measures obtained during a structured interview. Test-retest reliability of the overall bother measure was examined using 1- and 2-hour assessments, and concurrent validity was assessed by correlating counts of symptoms and other patient reported measures. Responsiveness was examined by calculating change scores of the VAS symptom-intensity measures from baseline to 1 hour among patients who reported symptoms during the 1-hour monitoring period after PS infusion. Low to moderate correlation was defined as a coefficient between 0.3 and 0.5. RESULTS: A total of 324 patients enrolled in the 2 studies. Content validity of the VAS symptom-intensity and overall-bother measures was established, with nearly all patients reporting that they were a useful way to rate symptom intensity and overall bother. VAS ratings were moderately to highly correlated with physician rated AE intensity, and patient-reported assessments of symptom intensity, discomfort, and concern (r(s) = 0.21 r(s) = 0.84). Findings to support discriminant validity were inconclusive because of small sample size. Responsiveness was demonstrated with VAS symptom-intensity change scores ranging from 2.8 for headache to 4.9 for chest pain; effect sizes for these differences were large, ranging from 1.6 to 7.3, respectively. CONCLUSION: Findings support the validity, reliability, and responsiveness of the modified VAS symptom intensity measure, and the reliability and validity of the overall-bother measure for use in patients completing PS procedures. PMID- 19446162 TI - Interpreting treatment-effect estimates with heterogeneity and choice: simulation model results. AB - BACKGROUND: Researchers using observational data in health-services research use various treatment-effect estimators to reduce the bias associated with unmeasured confounding variables and have focused on estimate differences to indicate the relative ability of these estimators to mitigate bias. However, available estimators may identify different treatment-effect concepts; if treatment effects are heterogeneous across patients and treatment choice reflects "sorting on the gain," then treatment-effect estimates should differ regardless of confounding. Risk-adjustment approaches yield estimates of the average treatment effect on the treated (ATT), whereas instrumental variable approaches yield estimates of a local average treatment effect (LATE). OBJECTIVE: The goal of this article was to use simulation methods to illustrate the treatment-effect concepts that are identified using observational data with various estimators. METHODS: We simulated patient treatment choices based on expected treatment valuation to observe estimates of both ATT and LATE. Different model scenarios were run to isolate the effects of both treatment-effect heterogeneity and unmeasured confounding on treatment-effect concept estimation. Models were estimated using standard linear and nonlinear estimation methods. RESULTS: We show that the true values of the underlying treatment concepts differ if patients (with the help of their health care providers) make treatment choices based on expected gains, and that distinct estimators produce estimates of distinct concepts. In scenarios without unmeasured confounding, both linear and nonlinear estimation models produced estimates close to the true value of the concept identified by each estimator. However, nonlinear models suggested additional treatment-effect heterogeneity that does not exist in these scenarios. CONCLUSIONS: Our results suggest that, to ensure clarity and correctness of treatment-effect estimate interpretation, it is important for researchers to state the treatment-effect concept that they are trying to identify before beginning estimation. In addition, theoretical models of treatment choice are needed to provide the foundation linking treatment-effect estimates to treatment-effect concepts and to justify instrument selection. PMID- 19446180 TI - Africa, a reservoir of new virulent strains of Newcastle disease virus? PMID- 19446181 TI - Credibility of polio data from India. PMID- 19446182 TI - National immunization advisory committees of the World Health Organization's European Region. AB - This study sought to understand the prevalence, structure and decision-making process of national immunization advisory committees (IACs) among the 53 member countries of the World Health Organization (WHO)'s European region. Of the 47 countries responding to the electronically administered questionnaire, 37 (72%) have an IAC. The majority of committees have a legislative basis while just over half have formal terms of reference. Fewer than half have experts in health economics. The vast majority of countries do not allow the public to attend committee meetings nor distribute publicly the minutes of their meetings. Countries should partner with financial experts early in the process of immunization policy decision-making and should examine their policies regarding conflicts of interest and public access to meetings, as financial strategy and public trust are essential to the successful implementation of new vaccines. PMID- 19446183 TI - Antigen processing of glycoconjugate vaccines; the polysaccharide portion of the pneumococcal CRM(197) conjugate vaccine co-localizes with MHC II on the antigen processing cell surface. AB - Pneumococcal (Pn) polysaccharides (PS) are T-independent (TI) antigens and do not induce immunological memory or antibodies in infants. Conjugation of PnPS to the carrier protein CRM(197) induces PS-specific antibody in infants, and memory similar to T-dependent (Td) antigens. Conjugates have improved immunogenicity via antigen processing and presentation of carrier protein with MHC II and recruitment of T cell help, but the fate of the PS attached to the carrier is unknown. To determine the location of the PS component of PnPS-CRM(197) in the APC, we separately labeled PS and protein and tracked their location. The PS of types 14-CRM(197) and 19F-CRM(197) was specifically labeled by Alexa Fluor 594 hydrazide (red). The CRM(197) was separately labeled red in a reaction that did not label PS. Labeled antigens were incubated with APC which were fixed, permeabilized and incubated with anti-MHC II antibody labeled green by Alexa Fluor 488, followed by confocal microscopy. Labeled CRM(197) was presented on APC surface and co-localized with MHC II (yellow). Labeled unconjugated 14 or 19F PS did not go to the APC surface, but PS labeled 14-CRM(197) and 19F-CRM(197) was internalized and co-localized with MHC II. Monoclonal antibody to type 14 PS bound to intracellular type 14 PS and PS-CRM(197). Brefeldin A and chloroquine blocked both CRM(197) and PS labeled 14-CRM(197) and 19F-CRM(197) from co localizing with MHC II. These data suggest that the PS component of the CRM(197) glycoconjugate enters the endosome, travels with CRM(197) peptides to the APC surface and co-localizes with MHC II. PMID- 19446184 TI - Investigation of the biological indicator for vaccine efficacy against highly pathogenic avian influenza (HPAI) H5N1 virus challenge in mice and ferrets. AB - To investigate the biological indicator for vaccine efficacy against HPAI H5N1 virus challenge of varying clades, two inactivated whole-virus H5N1 vaccines containing the hemagglutinin (HA) and neuraminidase (NA) genes of either clade 2.2 A/EM/Korea/W149/06 (RgKoreaW149/06 x PR8) or clade 2.5 A/Ck/Korea/ES/03 (RgKoreaES223N/03XPR8) virus in the background of A/PR/8/34 (H1N1) were generated by reverse genetics. Administration of the vaccines (2-dose 1.77, 3.5, 7.5 or 15microg of HA) elicited high HI titers in a dose-dependent manner. Mice immunized with RgKoreaW149/06 x PR8 were completely protected from challenge against wild-type A/EM/Korea/W149/06 without clinical signs of infection. RgKoreaES223N/03XPR8 could not protect mice at 1.77microg while all immunized ferrets were completely protected. Two-dose (7.5microg) vaccinated mice (HI titer > or =320) and triple dose (7.5 microg) vaccinated ferrets with RgKoreaES223N/03xPR8 (HI titer > or =640) protected vaccine recipients from mortality, inhibited nasal virus shedding and limited influenza virus tropism. Thus, these vaccines provided cross-protectivity in both models. More importantly, these results collectively suggested a positive correlation between vaccine-induced HI titers and inhibition of virus shedding including block of viral proliferation in major organs against a heterologous HPAI H5N1 virus. Although developing technologies or methods that will enable the reduction of administration dose/frequency remains to be resolved, our study demonstrated a considerable biological marker (> or =640 HI titer) for full protection of the vaccinated hosts that could provide a preliminary basis for the assessment of complete immunization. PMID- 19446185 TI - Cross-antigenicity among EV71 strains from different genogroups isolated in Yamagata, Japan, between 1990 and 2007. AB - We isolated and identified six subgenogroups (B2, B4, B5, C1, C2, and C4) of enterovirus 71 (EV71) between 1990 and 2007 in Yamagata, Japan. We measured neutralizing antibody (NT Ab) titers against those subgenogroup strains and the BrCr reference strain for antigenic analysis. Serological analysis of 83 residents in Yamagata in 2004 showed that differences in the NT Ab titer of each individual against the different subgenogroups were mostly within 4-fold. Furthermore, sera from guinea pigs, immunized with the B2 and C1 strains indicated cross-antigenicity among the seven different subgenogroups. In conclusion, our results showed that cross-antigenicity exists among EV71 strains from different subgenogroups circulating in the community through genomic evolution. Our results also suggest that eliciting neutralizing antibodies against one genotype is likely to confer cross-neutralization against other genotypes. PMID- 19446186 TI - Age, revaccination, and tolerance effects on pneumococcal vaccination strategies in the elderly: a cost-effectiveness analysis. AB - Optimal pneumococcal polysaccharide vaccination (PPV) policy is unknown for cohorts aged > or =65 years. Using a Markov model, we estimated the cost effectiveness of single- and multiple-dose PPV strategies in 65-, 75-, and 80 year-old cohorts. PPV at age 65 cost $26,100 per QALY (quality adjusted life years) gained. Vaccination at ages 75 and 80 cost $71,300-75,800 per QALY; revaccination strategies cost more. When prior vaccination and loss of vaccine effectiveness due to tolerance are assumed, cost-effectiveness ratios increase substantially. Single-dose PPV is worth considering in patients aged 65-80 from clinical and economic standpoints. Revaccination strategies for the elderly are less cost-effective, particularly when prior vaccination and vaccine tolerance are considered. PMID- 19446187 TI - Multimeric soluble CD40 ligand (sCD40L) efficiently enhances HIV specific cellular immune responses during DNA prime and boost with attenuated poxvirus vectors MVA and NYVAC expressing HIV antigens. AB - The attenuated poxvirus vectors MVA and NYVAC are now in clinical trials against HIV/AIDS. Due to the vectors restricted replication capacity in human cells, approaches to enhance their immunogenicity are highly desirable. Here, we have analyzed the ability of a soluble form of hexameric CD40L (sCD40L) to stimulate specific immune responses to HIV antigens when inoculated in mice during priming with DNA and in the booster with MVA or NYVAC, expressing the vectors HIV-1 Env, Gag, Pol and Nef antigens from clade B. Our findings revealed that sCD40L in DNA/poxvirus combination enhanced the magnitude about 2-fold (DNA-B/MVA-B) and 4 fold (DNA-B/NYVAC-B), as well as the breath of the HIV antigen specific cellular immune responses. sCD40L was necessary in both prime and boost inoculations triggering a potent polarization of the Th response towards a Th1 type. In DNA B/NYVAC-B regime the addition of sCD40L significantly enhanced the humoral immune response against HIV gp160, but not in DNA-B/MVA-B combination. These findings provided evidence for the immunostimulatory benefit of sCD40L when DNA and the poxvirus vectors MVA and NYVAC are used as immunogens. PMID- 19446188 TI - Relationship between tightness of binding and immunogenicity in an aluminum containing adjuvant-adsorbed hepatitis B vaccine. AB - Phospholipid-containing antigens, such as Hepatitis B Surface Antigen (HBsAg), adsorb to aluminum-containing adjuvants by ligand exchange of a phosphate group for a hydroxyl group on the adjuvant surface. In this study, a tightness of binding (TOB) assay was developed to characterize the strength of binding between HBsAg and aluminum hydroxyphosphate sulfate adjuvant containing two levels of phosphate. Antigen desorption was induced using either fluoride or phosphate as a competing ion. HBsAg, formulated as a monovalent or combination vaccine, showed decreased tightness of binding when the amount of phosphate in the adjuvant composition increased, indicating that there was less ligand exchange between HBsAg and the adjuvant. Furthermore, the physicochemical property of TOB was related to enhanced immunogenicity in a murine model. These data show that tightness of binding can be a useful characterization tool, and potential predictor of immunogenicity, during development of vaccines that adsorb to aluminum adjuvants via ligand exchange. PMID- 19446189 TI - Intranasal immunization with a mixture of PspA and a Toll-like receptor agonist induces specific antibodies and enhances bacterial clearance in the airways of mice. AB - To develop an effective nasal vaccine for Streptococcus pneumoniae, the effects of a panel of Toll-like receptor (TLR) agonists in combination with pneumococcal surface protein A (PspA) on induction of PspA-specific antibodies and bacterial clearance were compared in mice. Mice were nasally immunized with 10 microg of TLR agonist (TLR 2-4 and 9) and 2.5 microg of PspA once per week for 3 weeks. Significantly increased levels of PspA-specific immunoglobulin G (IgG) and IgA in the airways and PspA-specific IgG in plasma were found in mice administered PspA plus each TLR agonist, compared with mice administered PspA alone. In a sub lethal pneumonia model using a serotype 3 pneumococcal strain, bacterial density in the lungs of mice was significantly reduced in mice administered PspA plus each TLR agonist, compared with mice administered either PspA alone or phosphate buffered saline alone 3h after bacterial challenge. Similarly, enhanced bacterial clearance was found in the nasopharynx of mice administered PspA plus each TLR agonist 1 day after infection with a serotype 19F strain. Our data suggest that PspA-specific antibody induced by nasal immunization with PspA plus TLR agonist is capable of reducing the bacterial load in both the nasopharynx and lungs after challenge with pneumococci with different serotypes. Despite the skewed Th1/Th2 immune responses, the effects of nasal immunization with PspA plus each TLR agonist on bacterial clearances from the lungs 3h after infection and from nasopharynx 1 day after infection in mice were equivalent. PMID- 19446190 TI - Novel use of a N2-specific enzyme-linked immunosorbent assay for differentiation of infected from vaccinated animals (DIVA)-based identification of avian influenza. AB - Proper vaccination with validated companion differentiation of infected from vaccinated animals (DIVA) tests using a vaccine containing a heterologous neuraminidase to the field virus can be effective to control avian influenza (AI). However, indirect immunofluorescent assay, the only field validated DIVA test, has limitations to be set up as high throughput screening test and the assay requires subjective interpretation of the results. To apply the DIVA strategy to the Korean H9N2 low pathogenic AI (LPAI) vaccine program and overcome these limitations, we generated a reassortant H9N8 virus (rgH9N8) vaccine using plasmid-based reverse genetics and developed a novel N2-specific enzyme-linked immunosorbent assay (N2-ELISA). The rgH9N8 vaccine showed adequate immunogenicity and protection, and the optimized N2-ELISA showed that the sensitivity was 97.0% and specificity was 96.4% compared with a hemagglutination inhibition test. In vaccination-challenge experiments in specific pathogen-free chickens, the sera of chickens vaccinated with rgH9N8 vaccine and uninfected were negative by the N2 ELISA (S/P< or =0.4), whereas infected sera with H9N2 were positive (S/P>0.4). These results suggest that the rgH9N8 vaccine and the companion DIVA test, N2 ELISA, allow the utilization of the DIVA strategy for the control of H9N2 LPAI infections in Korea. PMID- 19446191 TI - Human papillomavirus (HPV) vaccine availability, recommendations, cost, and policies among health departments in seven Appalachian states. AB - Telephone interviews of health department personnel in six states and review of an immunization database from one state were conducted to assess human papillomavirus (HPV) vaccine availability, recommendations, cost, policies, and educational materials in health departments in seven Appalachian states. Most (99.1%) health departments (n=234) reported receiving patient requests for the HPV vaccine, and only two (1%) health departments reported that they did not provide the vaccine for patients. HPV vaccine supply was reported to not meet the demand in 10.5% (24/228) of health departments due to high costs. Level (state, region, county) at which policy about the HPV vaccine was determined, vaccine recommendations, costs, and available educational materials varied among states. This study documented variation in vaccine availability, recommendations, cost, policies, and educational materials in Appalachian health departments that could significantly affect vaccine distribution. Findings highlight the need for more comprehensive and consistent policies that maximize accessibility of the HPV vaccine to women, especially those in underserved areas. PMID- 19446192 TI - Comparison of the efficacy of rotavirus VLP vaccines to a live homologous rotavirus vaccine in a pig model of rotavirus disease. AB - Rotavirus-like particles (VLPs) have shown promise as rotavirus vaccine candidates in mice, rabbits and pigs. In pigs, VLP vaccines reduced rotavirus shedding and disease but only when used in conjunction with live attenuated human rotavirus. Using a porcine rotavirus pig model, rotavirus antigen shedding was reduced by up to 40% after vaccination with VLPs including the neutralizing antigens VP7 and VP8* when used in combination with the adjuvant polyphosphazene poly[di(carbozylatophenoxy)phoshazene] (PCPP). In contrast, complete protection from rotavirus antigen shedding and disease was induced by vaccination with the virulent porcine rotavirus PRV 4F. This is the first study to demonstrate some post-challenge reductions in rotavirus antigen shedding in a pig model of rotavirus disease after vaccination with VLPs without combining with infectious rotavirus. PMID- 19446193 TI - Immunogenicity and safety of diphtheria-tetanus vaccine in pre-adolescent and adolescent South Koreans. AB - This study was conducted to compare the immunogenicity and safety of diphtheria tetanus (Td) vaccine between pre-adolescents aged 11-12 years and adolescents aged 13-18 years. A total of 277 subjects (132 pre-adolescents and 145 adolescents) participated. After vaccination, all subjects (100%) in both groups exhibited seroprotective antibody levels (> or =0.1I U/mL) against diphtheria or tetanus toxoids. Although local adverse events following vaccination were more frequently observed in the pre-adolescent group than in the adolescent group (p=0.006), these events resolved within 7 days. Our study shows Td vaccination at age 11-12 years to be immunogenic and tolerable. PMID- 19446194 TI - Pneumococcal serotype 3 otitis media, limited effect of polysaccharide conjugate immunisation and strain characteristics. AB - BACKGROUND: In contrast to the other vaccine serotypes, no protection could be demonstrated in the POET study against serotype 3 acute otitis media (AOM) following primary and booster vaccination with a multi-valent pneumococcal conjugate vaccine. METHODS: AOM efficacy and immunogenicity data were reviewed. Pheno- and genotypic characteristics of different serotype 3 strains including efficacy study AOM isolates were evaluated. RESULTS: Evaluation of vaccine efficacy before and after booster vaccination indicated that lack of efficacy against serotype 3 pneumococci might have been due to declined protection following the booster dose. However, although atypical immunogenicity was observed for serotype 3 in the second year of life, the capacity to respond to serotype 3 plain polysaccharide was not impaired. All but one of the serotype 3 strains examined had abundant polysaccharide capsules. Comparison of serotype 3 capsular polysaccharide biosynthesis gene sequences found no relevant differences between any of the serotype 3 strains, but mRNA transcript levels were lower for the less densely encapsulated strain. CONCLUSION: Lack of clinical efficacy against serotype 3 AOM following pneumococcal conjugate vaccination may be due to an impaired induction of immune memory. A possible alternative explanation may lie with the atypically abundant expression of capsular polysaccharide which could make serotype 3 strains less susceptible to anti-polysaccharide antibody defence mechanisms in the middle ear. The occurrence of acapsular forms during biofilm growth may also play a role. Clinical impact against otitis media, of vaccines containing pneumococcal serotype 3 components, remains unclear until further investigations have demonstrated the value. PMID- 19446195 TI - Analysis of mortality following a mass immunization campaign with serogroup C meningococcal conjugate vaccine: methodological difficulties and imperfect solutions. AB - BACKGROUND: In 2001, a mass immunization campaign was implemented in the province of Quebec, Canada, using a new serogroup C meningococcal conjugate vaccine (C MCV). OBJECTIVE: To describe methodological difficulties in the investigation of the mortality risk associated with administration of C-MCV using large administrative databases, and to present possible solutions. MATERIALS AND METHODS: The study population included approximately 1.9 million residents in Quebec aged 2 months to 20 years. Death certificates in 2001 and 2002 were linked with vaccination registry data. Age-specific and age-adjusted mortality rates were compared between 1.4 million persons who had been vaccinated with C-MCV, and a mixed control group including 0.5 million individuals. In the C-MCV group, deaths within the 6-month period after vaccination were analyzed to identify any clustering, using the exponentially weighted moving average technique. RESULTS: All cause mortality was more than three times higher in the control group than in the C-MCV group, and the excess was seen for all major categories of causes. Two time-clusters were detected in the C-MCV group, but none of them appeared to be plausibly related to the administration of C-MCV. In the C-MCV group, there was no death caused by meningococcal disease, Guillain-Barre syndrome, anaphylactic shock, or a complication of vaccination. CONCLUSION: Data concerning the safety of C-MCV are reassuring. However, the very strong "healthy vaccinee" effect limits our ability to detect any excess mortality risk in the vaccinated cohort and there is no perfect method to overcome this problem. PMID- 19446196 TI - Laboratory diagnosis of measles and rubella infection. AB - Current diagnostic laboratory tests were summarized. Measles outbreak was noted in Japan 2007 and large proportion of the patients was high school, college students, and adult patients, caused by D5 Bangkok type. Through molecular epidemiological study, drastic changes in circulating genotypes were demonstrated since 1984 to present, in Japan. PMID- 19446197 TI - Development of measles vaccines in Japan. AB - Studies on measles vaccine development started in 1950s in Japan. After 3-year studies on development of further attenuated live measles vaccines by Japan Measles Vaccine Research Commission, two kinds of vaccines of different strains were licensed for optional use in 1971. In 1978, periodical immunization against measles was started using BIKEN CAM-70 vaccine, Takeda Schwarz-FF8 vaccine and Kitasato AIK-C vaccine. Combined measles and rubella vaccines (MR vaccine) were licensed in 2005. Periodical immunization with MR vaccines of BIKEN and Takeda Pharmaceutical Co. Ltd. to eliminate measles together with rubella from Japan by 2012 was started for children 1- and 6 (5-7)-year of age in 2006. PMID- 19446198 TI - Fellowships: the third wave. PMID- 19446199 TI - Metastatic ameloblastoma to the cervical lymph nodes: a case report and review of literature. PMID- 19446200 TI - Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. AB - PURPOSE: The aim of this study was to determine, in a clinical setting, the effectiveness of the C-terminal cross-linking telopeptide test (CTX) test in the prevention and management of osteonecrosis of the jaws (ONJ) in patients taking bisphosphonates. PATIENTS AND METHODS: A total of 348 patients underwent a fasted morning CTX test. Of these, 222 were patients at risk of ONJ who had been referred for extractions, 15 had ONJ, and 113 were controls. RESULTS: The 215 patients taking long-term oral bisphosphonates were older (71 +/- 11.6 years), were predominantly women with osteoporosis, and were medically compromised. The average CTX value was 238 +/- 144 pg/mL, with 98 having a value less than 200 pg/mL. One patient with a CTX value of 126 pg/mL developed ONJ after an extraction. Seven intravenous bisphosphonate patients underwent extractions with no cases of ONJ developing. The CTX value was 329 +/- 354, with 4 less than 200 pg/mL. Fifteen patients developed ONJ, 12 after extractions and 3 spontaneously. Of these, 7, who were still taking a bisphosphonate at presentation, had a CTX value of 116 pg/mL. A CTX value of less than 150 pg/mL did not correlate with the clinical risk factors of age, gender, comorbidities, bone disease, or bisphosphonate duration. A statistically significant difference in the CTX value was found for those taking alendronate compared with those taking risedronate (P < .0001). If the bisphosphonate was ceased, the CTX value increased at approximately 25 pg/mL per month. CONCLUSIONS: The CTX test is not predictive of the development of ONJ for an individual patient but does identify those in the "risk zone," which is a value of less than 150 pg/mL to 200 pg/mL. If medically appropriate, the bisphosphonate can be ceased so that the CTX value increases to bring the patient out of the "risk zone." PMID- 19446201 TI - Comparison of vascularized osteoperiosteal femur flaps and nonvascularized femur grafts for reconstruction of mandibular defects: an experimental study. AB - PURPOSE: The aim of this study was to compare the vascularized osteoperiosteal femur flaps (VFFs) and the nonvascularized femur grafts (NVFGs) for reconstruction of the mandibular defects of pigs. MATERIALS AND METHODS: Eight adult domestic pigs were used. The defects created in the mandibular angle were reconstructed with VFFs in 4 pigs (group 1) and NVFGs in the other 4 pigs (group 2). All the pigs were killed after 3 months of healing. Undecalcified and decalcified sections were prepared for histomorphometric analysis and histologic examination. Radiodensitometric absorptiometry was used to assess the differences in bone mineral density between the 2 groups. RESULTS: The bone volume to the total measured volume, trabecular thickness, and trabecular number were significantly greater in the VFF group than in the NVFG group (P < .05). However, the trabecular separation was significantly lower in the VFF group than the NVFG group (P = .029). Although the VFF group had a greater bone mineral density value than the NVFG group, the difference was not statistically significant (P = .057). In histologic examination, the viability of bone in the VFF group, enchondral bone healing, and lamellar bone formation in the NVFG group were apparent. CONCLUSIONS: The results of this study suggest that NVFGs have a greater bone resorption rate than do VFFs. Furthermore, the histomorphometric results imply that reconstruction of the mandibular defects with vascularized osteoperiosteal femur flaps will provide greater strength. PMID- 19446202 TI - Histologic study of adhesions in the upper joint compartment of the temporomandibular joint. AB - PURPOSE: The aim of this study was to observe the histologic characteristics of adhesions in the upper joint compartment of the temporomandibular joint and investigate the mechanism of genesis. PATIENTS AND METHODS: During arthroscopic surgery, we obtained 42 biopsy specimens of different grades of adhesions, ranging from grade I to grade IV, from 21 joints in 21 patients with internal derangement. Two biopsy specimens from each temporomandibular joint were obtained in this study; one was immediately fixed in 4% formalin and examined under a light microscope, and the other was fixed in 2% glutaraldehyde solution and examined under a transmission electron microscope. RESULTS: Different grades of adhesions had uniform dense connective tissue under the light microscope, and a number of fibrocytic cells were scattered within the extracellular matrix. However, in grade II adhesions, synovial membrane and some elastic fibers were shown. Under the transmission electron microscope, orderly arranged collagen bundles were prominent in grade I and grade III adhesions. Elastic fibers were abundant in grade II adhesions with orderly arranged collagen bundles; a small number of inactive fibroblasts were scattered about these adhesions. Randomly arranged collagen bundles and elastic fibers were also observed in grade IV adhesions, in which synovial membrane cells and cartilaginoid cells were detected. In addition, fibroblasts with active secretion were observed, and a considerable amount of rough endoplasmic reticulum was noted. CONCLUSIONS: Different arrangements of collagen fibers with or without elastic fibers were observed in the 4 types of adhesions. These findings could enable further exploration into the mechanism of adhesion formation. PMID- 19446203 TI - Parotid duct repair with suturing and anastomosis using tissue adhesive, evaluated by sialography: an experimental study in the dog. AB - PURPOSE: The most common method of parotid duct anastomosis is suturing. In addition to the postoperative complications in suturing (ie, anastomosis leakage, fistula formation, and infection of maxillofacial spaces), the surgical duration and suturing difficulties arise as major problems. The efficacy of fibrin glue in parotid duct anastomosis was evaluated and compared with suturing in 15 dogs. MATERIALS AND METHODS: Fifteen dogs (of the same breed and gender) were studied in this experimental trial. Intravenous cephalothin (1 g) and intramuscular dexamethasone (8 mg) were administered preoperatively for all cases, but no drug was administered postoperatively. Extraoral transverse incisions were made in buccal regions bilaterally to expose parotid ducts and transection was performed in similar areas (right and left). Next, the right transected duct was repaired with 7-0 nylon sutures, and then the left anastomosis was performed, using fibrin glue. At 10 days after the operation, clinical evaluations and sialography were used to evaluate the quality of the anastomosis repair, ductal leakage, and fistula. RESULTS: The ductal fistula was found on the right in 2 cases (13.33%) and on the left (20%) in 3 cases. Aspiration was positive in the right parotid duct in 2 cases (13.33%) and in the left parotid duct (33.33%) in 5 cases. Also, right ductal leakage was seen in 4 cases (26.66%) and left ductal leakage in 7 cases (46.66%), using sialography. CONCLUSIONS: The results of this study suggest that the efficacies of fibrin glue and suturing in parotid duct anastomosis are similar, but the use of fibrin glue had a number of advantages, including shortening of the operative time and the possibility of stent removal intraoperatively. PMID- 19446204 TI - Lateral lip-splitting approach for total and subtotal maxillectomy. AB - PURPOSE: This study reviewed our patients who underwent maxillectomy by the lateral lip-splitting approach and evaluated postoperative outcomes. PATIENTS AND METHODS: Thirty-six patients with diseases in the maxilla, maxillary gingiva, and hard palate who underwent total or subtotal maxillectomy by the lateral lip splitting approach. The marginal mandibular branch of facial nerves were dissected and preserved before and after the procedure to split the lateral lower lip in all patients. Seventeen patients were reconstructed with free vascularized flaps. Postoperative radiotherapy was administered in 26 patients. The patient's self-assessment and examiner's evaluation were included in the postoperative assessment. The patient's self-assessment included answering a questionnaire, that included evaluation of buccal scar, symmetry of cheilion, lower lip movement, oral incontinence, and lower lip sensation. The examiner's evaluation included assessment of the functions of the facial nerve. RESULTS: All tumors were removed en bloc with sufficient safety margins except 1 adenoid cystic carcinoma in maxilla. The average mouth opening was 3.81 cm. According to the results classified as good, fair, and poor by questionnaires, most of the 36 patients thought their results were good or fair. Most of the patients were high scores, according to the examiner's evaluation. The overall 5-year survival and local control rates for patients with malignant tumors were 76.7% and 85.8%, respectively. The local and regional recurrent and distant metastasis rate was 12.9%, 6.5%, and 19.4%, respectively. CONCLUSIONS: The lateral lip-splitting approach is an acceptable and optional approach for maxillectomy because of wide exposure, satisfied function, inconspicuous scar, and preservation of facial nerve. PMID- 19446205 TI - Assessment of combined local anesthesia and ketamine for pain, swelling, and trismus after surgical extraction of third molars. AB - PURPOSE: The aim of this study was to assess the clinical efficacy of combined treatment with local anesthetic and subanesthetic ketamine for the relief or prevention of postoperative pain, swelling, and trismus after the surgical extraction of third molars. PATIENTS AND METHODS: Fifty patients undergoing the extraction of impacted mandibular third molars were included in the study. The patients were randomly divided into 2 groups: local anesthetic alone (LAA) and local anesthetic plus ketamine (LAK). The patients in the LAA group received 5 mL of a local anesthetic and saline combination comprising 2 mL of local anesthetic and 3 mL of saline. The patients in the LAK group received 5 mL of a local anesthetic, ketamine, and saline combination comprising 2 mL of local anesthetic and 0.3 mg/kg ketamine and saline. RESULTS: Facial swelling on postoperative days was significantly lower in the LAK group than in the LAA group (P = .0001). The mouth opening on the postoperative days was significantly greater in the LAK group than in the LAA group (P = .0001). The pain scores on the VAS at 30 minutes and 1, 4, 12, and 24 hours after surgery were significantly higher in the LAA group than in the LAK group (P = .0001, P = .005). CONCLUSION: The combination of a local anesthetic and subanesthetic doses of ketamine during surgical extraction of third molars can produce good local anesthesia while affording a comfortable procedure for the surgeon and patient and providing good postoperative analgesia with less swelling and significantly less trismus. PMID- 19446206 TI - Clinical experiences with resorbable ultrasonic-guided, angle-stable osteosynthesis in the panfacial region. AB - PURPOSE: In this study we report our experiences with the treatment of midfacial fractures and various other indications in regions with low load bearing (eg, dysmorphias) using the biodegradable Osteosynthesis System (SonicWeld Rx by KLS Martin, Tuttlingen, Germany), comprising biomechanical and histological aspects. PATIENTS AND METHODS: Seventy-five patients were included in this study. We describe the application of this system for the treatment of fractures of the zygomamaxillary complex, frontal bone impression fractures, surgical treatment of mukocele in the frontal sinus, isolated fractures of the orbital floor, complex midfacial trauma and bone cap fixation, craniosynostoses, and fixation of a distracted bone fragment. RESULTS: The pin insertion could be finished with a total failure rate of lower than 5%. In 3 patients, soft tissue swellings in regions with less subcutaneous fat were observed 6 to 8 months postoperatively. No fracture dislocations occurred. Scanning electron micrograph of the experimentally acquired connection between the resorbable plate and 2 pins clearly demonstrates a tight and reliable fusion to bone, both at the cortical as well as at the spongy compartment. Conventional histology leads to corresponding findings as scanning electron micrography, and shows a close fusion between all components. CONCLUSION: This retrospective study shows the general feasibility, sufficient mechanical stability, and efficient intraoperative handling of this angle-stable, ultrasonic-guided resorbable Osteosynthesis System (ResorbX and SonicWeld Rx) for a wide variety of indications in craniomaxillofacial surgery. PMID- 19446207 TI - Barrier membranes used for ridge augmentation: is there an optimal pore size? AB - PURPOSE: To identify the optimal pore size of barrier membranes for successful alveolar ridge reconstruction procedures, to determine if cortical perforations have any effect on bone regeneration, and to reiterate that bone graft containment is an important parameter for successful regeneration. MATERIALS AND METHODS: This was a prospective, randomized, controlled study performed on hound dogs. Corticocancellous tibial bone grafting was performed to the lateral border of the mandible and protected with barrier membranes (meshes). The experiment analyzed three different pore sized meshes, compared with controls without the mesh. Two meshes (macroporous and microporous) were made of titanium, and one was a resorbable mesh. Meshes were preformed into the shape of a cube with one face open. Each side of the cube measured approximately 10 mm. Cubes were open-faced on one side, to facilitate packing of the graft material. The dogs received bilateral ramus grafts. Cortical perforations were created on the left ramus of all the dogs and compared with the right side, which did not have perforations. The dogs were randomly divided into 3 groups and sacrificed at intervals of 1, 2, and 4 months. Before sacrifice, all dogs received 2 doses of tetracycline as a marker for new bone formation. Histomorphometry was performed by using Bioquant image-analysis software. Areas of new bone and soft tissue were measured. The rate of mineral apposition was also calculated. All values obtained via histomorphometry were statistically analyzed with a t test. RESULTS: Thirty-one experimental sites were evaluated. The amount of new bone growth into the macroporous mesh was significantly higher than in the other groups. The mean area of new bone formation in large and small meshes was 66.26 +/- 13.78 mm(2) and 52.82 +/- 24.75 mm(2), respectively. In the resorbable mesh group, the mean area of new bone formed was 46.76 +/- 21.22 mm(2). The amount of new bone formed in the control group was 29.80 +/- 9.35 mm(2). There was no significant difference in amount of bone formation between left and right sides (P = .3172). Resorbable meshes had significant soft tissue ingrowth (23.47 mm(2)) compared with macroporous mesh (16.96 mm(2)) and microporous mesh (22.29 mm(2)). Controls had the least amount of soft tissue ingrowth (9.41 mm(2)). Mineral apposition rate was found to be higher in the resorbable group (2.41 microm/day), and the rate was lowest (1.09 microm/day) in the large pore mesh group. CONCLUSION: Macroporous membranes facilitated greater bone regeneration compared with microporous and resorbable membranes. Macroporous mesh also prevented significant soft tissue ingrowth compared with other meshes. Containment of a bone graft is the most critical parameter in successful bone regeneration. Cortical perforations did not have any effect on the quantity of regenerated bone. Further research should be directed toward identifying a critical pore size and manufacturing a reliable mesh that would prevent excessive soft tissue ingrowth in ridge augmentation procedures. PMID- 19446208 TI - Midface reconstruction with various flaps based on the angular artery. AB - PURPOSE: Although several methods can be used to perform midface reconstruction, difficulties exist in selecting the appropriate method because of anatomic and functional complexities, donor site morbidities, and poor esthetic results. The purpose of this study was to develop an alternative reconstructive method for the midface using various flaps based on the angular artery. MATERIALS AND METHODS: We investigated the relation between the angular artery and its surrounding structures through cadaveric studies and then applied the findings clinically. As a result, we were able to perform reconstruction with a retroangular flap for defects of the lower half of the nose and the lower eyelid. In addition, defects of the upper half of the nose and the medial canthal area were reconstructed by use of island composite nasal flaps. RESULTS: The angular artery was reliable as a pedicle whether it was used in an antegrade or retrograde manner. All the wounds were successfully closed, with the exception of minor complications such as partial skin necrosis and flap bulkiness. The esthetic outcomes for the donor and recipient sites were acceptable. CONCLUSION: The angular artery has diverse relations with its surrounding structures according to its course of travel, and if the surgeon has a precise understanding of its anatomic location, we believe that retroangular flaps and island composite nasal flaps may prove useful for the treatment of midface defects. PMID- 19446209 TI - A preferable technique for protecting the inferior alveolar nerve: coronectomy. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of coronectomy for teeth whose root apices are very close to the inferior alveolar canal. PATIENTS AND METHODS: The 43 patients of this study needed removal of their lower third molar, whose root apices were very close to the inferior alveolar canal. These patients underwent 47 coronectomies. RESULTS: The mean follow-up period was 9.3 months (range, 1 to 48 months). The mean total amount of root movement was 3.4 mm at 6 months, 3.8 mm at 12 months, and 4.0 mm at 24 months. CONCLUSIONS: The technique of coronectomy is defined as removing the crown of a tooth but leaving the roots untouched, so that the possibility of nerve damage is reduced. Coronectomy is a preferable technique for patients who run a risk of injury to the inferior alveolar nerve during third molar surgery. PMID- 19446210 TI - Management of parapharyngeal-space tumors. AB - PURPOSE: This study evaluated parapharyngeal-space (PPS) tumors in regard to clinical pathological features, preoperative assessment, surgical approaches, perioperative complications, and patterns of recurrence. PATIENTS AND METHODS: We performed a retrospective review of patients with PPS tumors referred to the stomatological hospitals of Sichuan University and Xi'an Jiaotong University between 1990 and 2004. RESULTS: Beginning in 1990 and ending in 2004, 162 patients with PPS tumors were evaluated in our unit. The gender distribution was 94 (58.08%) males and 68 (41.98%) females. The median age was 36.4 years. The main presenting symptom was neck swelling. All cases were evaluated with at least a computed tomography scan. The most common class of lesion was salivary-gland neoplasm, accounting for 74 cases (45.68%). The next most common group of tumors was neurogenic, representing 68 cases (41.98%). Only 22 patients (13.58%) presented with malignant disease. Three surgical approaches were commonly used in the management of these lesions: transcervical-transparotid in 93 patients (57.41%), transcervical in 51 patients (31.48%), and transcervical transmandibular in 18 patients (11.11%). Twenty patients with malignant disease underwent adjuvant chemotherapy and/or radiotherapy. All cases were followed for a mean of 36 months. There was no perioperative mortality. Two patients suffered local failure, and 4 patients developed distant metastasis during the observation period. CONCLUSIONS: Surgery is the mainstay treatment for PPS tumors. Surgical approaches were dictated by size of the tumor, its location, its relationship to the great vessels, and suspicion of malignancy. The most common approach was transcervical-transparotid for benign tumors. PMID- 19446211 TI - Remifentanil decreases mandibular bone marrow blood flow during propofol or sevoflurane anesthesia in rabbits. AB - PURPOSE: The purpose of this study was to investigate the effect of remifentanil on the blood flow in rabbit oral tissues during propofol or sevoflurane anesthesia. MATERIALS AND METHODS: Thirty-two male tracheotomized Japanese white rabbits were anesthetized with propofol (P group) or sevoflurane (S group) under mechanical ventilation. Animals were further divided into 4 groups: adenosine triphosphate (ATP) treatment in the P group (P-ATP) (n = 8), remifentanil treatment in the P group (P-Remi) (n = 8), ATP treatment in the S group (S-ATP) (n = 8), and remifentanil treatment in the S group (S-Remi) (n = 8). Blood pressure, heart rate, common carotid artery blood flow (CABF), lingual mucosal blood flow (LMBF), and mandibular bone marrow blood flow (BMBF) were measured during each period before and during infusion of ATP or remifentanil. RESULTS: Mean arterial pressure (MAP), CABF, LMBF, and BMBF showed a significant decrease in all 4 groups during infusion of the drug. Similarly, LMBF and BMBF showed significant decreases in both the ATP and remifentanil groups, whereas the decreases in MAP and CABF measured as percent change were greater in the ATP groups than in the remifentanil groups. A significant correlation was observed between CABF and BMBF in the S-Remi group. In both the P and S groups, the correlations between MAP and LMBF or BMBF were relatively strong when ATP was administered. CONCLUSIONS: Our findings suggest that infusion of remifentanil during propofol or sevoflurane anesthesia reduces BMBF and LMBF, as does deliberate hypotension by use of ATP, without a major decrease in MAP. PMID- 19446212 TI - Five-year retrospective study of mandibular fractures in Freiburg, Germany: incidence, etiology, treatment, and complications. AB - PURPOSE: To evaluate current trends in maxillofacial trauma, a retrospective review of mandibular fractures at a German university hospital was carried out. PATIENTS AND METHODS: In this retrospective study, records of 444 patients with mandibular fractures between 2000 and 2005 at the Department of Oral and Maxillofacial Surgery, University Hospital of Freiburg, Germany, were reviewed. A total of 444 patients presented with 696 mandibular fractures. RESULTS: Three hundred twenty-nine (74%) of the fractures occurred in male and 115 (26%) in female patients (2.9:1). One hundred forty-two fractures (32%) resulted from road traffic accidents, 126 from fights (28%), and 116 from falls (26%). Forty-four fractures were caused by sport accidents (10%) and 16 by pathologic fractures (4%). The mandibular condyle area was the most common fracture site, with 291 fractures (42%), followed by 144 fractures of the symphyseal and parasymphyseal area (21%) and 141 angle fractures (20%). Combined fractures were found in nearly half of the cases. Five hundred seventy-nine (83%) of patients with mandibular fractures were treated by surgical intervention, 117 (17%) of patients conservatively. Regarding the surgical treatment, 561 (65%) miniplates, 247 (29%) locking plates, and 51 (6%) lag screws were used. Complications, such as postoperative infections, abscesses, and osteomyelitis appeared in 66 (9%) cases. CONCLUSION: We concluded that osteosynthesis of mandibular fractures by miniplates and locking plates are both reliable. PMID- 19446213 TI - Constitutive release of cytokines by human oral keratinocytes in an organotypic culture. AB - PURPOSE: The Food and Drug Administration requires an accurate determination of the dose and potency of tissue-engineered or combination products as is required for drugs. This needs to be done as a rapid, quantitative, and noninvasive measurement of biologic function/activity in a way so as not to perturb the tissue-engineered product being developed. The aim of this study was to correlate constitutive release of cytokine(s) from unstimulated cells, at different stages of development, within a 3-dimensional (3D) organotypic ex vivo produced oral mucosa equivalent (EVPOME) to be used for intraoral grafting, with oral keratinocyte cell viability of the EVPOME. MATERIALS AND METHODS: Tissue culture medium was assayed with an enzyme-linked immunosorbent assay from monolayer culture of oral keratinocytes and a 3D EVPOME to determine the constitutive release of interleukin (IL) 1alpha, IL-6, IL-8, and vascular endothelial growth factor (VEGF). VEGF messenger ribonucleic acid expression by oral keratinocytes within the 3D EVPOME was detected by in situ hybridization at days 4, 7, and 11. The number of viable oral keratinocytes within the EVPOME was extrapolated from VEGF release by use of a modified MTT assay. RESULTS: Both VEGF release level and the number of viable cells in the monolayer cultures and 3D EVPOME as measured by MTT assay significantly increased in a time-dependent manner (P < .001, r = 0.743). CONCLUSION: These results suggest that the increasing detectable levels of VEGF associated with the increasing number of viable cells in the EVPOME may provide a useful noninvasive/nondestructive means of assessing both cellular viability (dose) and biologic function/activity (potency) of a combination cell based device such as the EVPOME. PMID- 19446214 TI - Iatrogenic subcutaneous emphysema of dental and surgical origin: a literature review. AB - PURPOSE: Subcutaneous emphysema arises when air is forced beneath the tissue, leading to swelling, crepitus on palpation, and potential to spread along the fascial planes. The goal of this literature review is to alert the oral and maxillofacial surgeon to the inciting factors, diagnosis, and management of subcutaneous emphysema. PATIENTS AND METHODS: A comprehensive search of the medical and dental literature from 1993 to 2008 was performed using PubMed, and yielded 32 case reports of subcutaneous emphysema. Only cases associated with dental or surgical procedures were included. Cases of trauma were excluded. RESULTS: Sixteen of the 32 cases were linked to the use of air-driven handpieces. Other cases involved a CO(2) laser, a NO(2) cryomachine, an air abrasive system, endotracheal intubation/ventilation, and patient activities after surgical procedures. Of the cases reviewed, 5 resulted in significant complications after subcutaneous emphysema. CONCLUSION: Although rare, iatrogenic subcutaneous emphysema can have serious and potentially life-threatening effects. Care should be taken when using air-driven handpieces or performing endotracheal intubation/ventilation. Additionally, instructions should be given to patients after procedures violating the epithelium to reduce the incidence of subcutaneous emphysema. When subcutaneous emphysema does arise, it must be quickly diagnosed and properly managed to reduce further complications. PMID- 19446215 TI - Intraoperative and perioperative complications in anterior maxillary osteotomy: a retrospective evaluation of 103 patients. AB - PURPOSE: To study the intraoperative and perioperative complications associated with anterior maxillary osteotomy (AMO), and assess its safety and predictability in orthognathic surgery. PATIENTS AND METHODS: We performed a retrospective evaluation of 103 patients undergoing AMO as a single procedure, or in combination with other osteotomies over a period of 5 years, with a mean follow up of 3 years. RESULTS: Twenty-seven (26.2%) patients in our series of 103 had complications of varying severity: 43.3% of these were soft tissue-related, and 36.6% were attributable to dental causes. All other complications accounted for the remaining 20%. CONCLUSION: Although its indications are limited, AMO is a safe and reliable procedure in routine orthognathic surgery. PMID- 19446216 TI - Surgically assisted palatine expansion in adult patients: evaluation of a conservative technique. AB - PURPOSE: This study was conducted to assess a conservative technique for surgically assisted palatine expansion (SAPE) done under local anesthesia and conscious sedation in adults. Dental inclination, uniformity of expansion, and satisfaction of orthodontist were evaluated. PATIENTS AND METHODS: Twenty-seven consecutive patients, ranging in age from 25 to 42 years, underwent SAPE under local anesthesia. The surgical procedure involved osteotomy of the lateral wall of the maxilla, from the maxillary tuberosity to the nasal cavity, with the nasal septum and the ptyerigoid plates left intact. Cast models were obtained before surgery and 1 year after surgery. Cuspid inclinations were assessed, with intercanine distance in 2 points, the incisal and cervical borders, measured before and after surgery. Molar inclination was obtained by measuring intermolar distance at the cervical margin and occlusal table. The results were statistically analyzed by analysis of variance. A questionnaire with 4 questions was addressed to the orthodontists to evaluate the level of satisfaction with the procedure. RESULTS: Cuspid and molar inclination occurred, but there was no statistically significant difference (P < .05) in dental inclination before and after surgery. The expansion was greater at the molar level than at the canine level, but this difference also was not statistically significant (P > .05). According to the questionnaire, 100% of the procedures allowed the expansion, 100% of the orthodontists were satisfied, and 68.75% observed dental inclination, but this inclination was not excessive in 100% of the cases. CONCLUSIONS: The proposed technique is a safe, predictable, and reliable method for SAPE in adult patients. Although ptyerigoid plate and nasal septum fractures were not performed, the maxillary bone exhibited uniform expansion. Dental inclination was not significant, either clinically or during cast model analysis. Orthodontists could achieve treatment objectives with this surgical procedure. PMID- 19446217 TI - Maxillary ridge augmentation with fresh-frozen bone allografts. AB - PURPOSE: The present investigation clinically and histologically evaluated the use of fresh-frozen bone in the reconstruction of maxillary alveolar ridges to confirm the effective bone fill and support for the placement of dental implants. PATIENTS AND METHODS: Fifteen patients who had atrophic maxillary ridge necessitating bone block grafts prior to implant placement were submitted to maxillary reconstructions performed with human block grafts of tibia fresh-frozen chips. Nine months later the re-entry procedures were carried out and at this time a bone core was removed from the grafts for histological analysis. RESULTS: Thirty-four blocks were placed, and the number of blocks each patient received ranged from 1 to 4. During the re-entry procedures, all of the grafts were found to be firm in consistency, well-incorporated, and vascularized. A total of 51 implants were placed over the grafts with a minimum of 40-Newton torque in all cases. None of the implants were lost. The follow-up period ranged from 24 to 35 months. The histological analysis revealed a living bone that showed features characteristic of mature and compact osseous tissue surrounded by marrow spaces. CONCLUSION: Bone allografts can be successful as graft material for the treatment of maxillary ridge defects. If adequate surgical techniques are adopted, this type of bone graft can be safely used in regions of implant placement as a suitable alternative to autogenous grafts. PMID- 19446218 TI - Immediate loading of immediate mandibular implants with a full-arch fixed prosthesis: a preliminary study. AB - PURPOSE: To determine the survival of immediate dental implants with immediate loading in the partially edentulous mandible, by use of a full-arch screw retained provisional restoration. MATERIALS AND METHODS: Patients who were partially edentulous in the mandible with indications for extraction of the remaining teeth and with a minimum follow-up of 12 months after implant placement were included in the study. They were treated in chronologic order by the insertion of 6 Defcon dental implants (Impladent, Sentmenat, Spain) subjected to immediate loading (4 interforaminal and 2 posterior placements). Implants with a minimum primary stability of 60 implant stability quotient were loaded. All resin screw-retained prostheses were inserted and loaded with fully functional occlusion within 24 hours of implant placement. RESULTS: Eleven patients were treated with immediate implants, although 2 patients were excluded from the study for having an implant stability quotient value below 60 in at least one of the implants after surgery and did not undergo restoration with immediate loading. Fifty-four implants were placed in 9 partially edentulous patients with immediate loading with a full-arch screw-fixed prosthesis. The patients wore this provisional prosthesis during the healing period (2 months) without complication and with a high level of comfort. The survival rate of the implants was 100% at 12 months of follow-up. CONCLUSION: Immediate mandibular loading with immediate full-arch implant-supported and screw-retained restorations is a viable treatment alternative, yielding a 100% success rate in this small series of patients. PMID- 19446219 TI - Intrasocket reactive soft tissue for primary closure after augmentation of extraction sites with severe bone loss before implant placement. AB - PURPOSE: The normal bone resorption after tooth extraction can be significantly aggravated in the case of pre-existing severe bone loss and chronic infection. Bone augmentation procedures have been proposed, but they require adequate closure of soft tissues. We propose the use of intrasocket reactive tissue to cover extraction sites augmented by bovine bone mineral graft to promote the success of the graft procedure. PATIENTS AND METHODS: The study included 24 patients with severe bone loss and chronic pathology in 27 sites. The intrasocket reactive soft tissue was elevated from the bony walls in a subperiosteal plane. Porous bovine or allograft bone mineral was placed in the extraction site without membranes, and the intrasocket reactive soft tissue was sutured over the grafting material to seal the coronal portion of the socket. Twenty-seven implants were placed 6 months after bone augmentation. RESULTS: Healing progressed uneventfully. Postoperative morbidity was minimal. There was no leakage or infection of the grafting material. The mean time to implant placement was 7.8 months. Supplemental augmentation was not needed. There were no implant failures. Follow-up ranged from 6 to 36 months (mean, 15 months). All implants were rehabilitated with fixed prostheses. CONCLUSIONS: Intrasocket reactive soft tissue can be used predictably to obtain primary closure of augmented extraction sites with severe bone loss with minimal postoperative morbidity. PMID- 19446220 TI - Deep-frozen allogeneic onlay bone grafts for reconstruction of atrophic maxillary alveolar ridges: a preliminary study. AB - PURPOSE: The purpose of this article was to evaluate the suitability of deep frozen allograft for ridge augmentation procedures in severely atrophic maxillae and to evaluate the clinical success of dental implants inserted after grafting and before prosthetic rehabilitation. PATIENTS AND METHODS: This study included 13 patients (3 men and 10 women) aged 36 to 65 years. All the patients selected for this study required bone augmentation procedures because of severe alveolar ridge atrophy and were scheduled for onlay bone allograft and titanium implants in a 2-stage procedure. The dental implants were inserted 5 months after grafting. The follow-up period for the implants was 6 months after placement at the second stage of implant surgery. RESULTS: A total of 24 onlay block allografts were used to augment atrophic maxillae in 13 patients. Of the 24 onlay block allografts, 5 were scheduled for vertical alveolar ridge augmentation and the remaining 19 for horizontal alveolar ridge augmentation. Early exposure of the onlay bone graft was observed in 2 patients. All the block grafts showing early exposure had to be completely removed because of infection. All the observed complications were associated with onlay bone grafts placed to increase the vertical dimension of the alveolar ridges. Thirty-eight implants ranging in length from 10 to 15 mm were placed in the area of bone augmentation. All implants inserted achieved satisfactory primary stability. Two implants failed to integrate 6 months after placement during the second stage of surgery. The failed implants were successfully replaced without any need for additional bone grafting. CONCLUSIONS: The use of block allografts to treat maxillary atrophy yielded successful outcomes. Moreover, the augmentation procedure allowed the insertion of implants in the grafted area 5 months after surgery. Therefore, on the basis of this preliminary study, deep-frozen bone allograft can be considered a promising treatment for severe maxillary atrophy, with more extensive follow-up studies being needed to confirm these preliminary data. PMID- 19446221 TI - Mucocele in posterior dorsal surface of tongue: an extremely rare location. PMID- 19446222 TI - Pathological fractures in patients caused by bisphosphonate-related osteonecrosis of the jaws: report of 3 cases. PMID- 19446223 TI - Removal of a maxillary third molar accidentally displaced into the infratemporal fossa via intraoral approach under local anesthesia: report of a case. PMID- 19446224 TI - Horner syndrome after temporomandibular joint arthroscopy: a new complication. PMID- 19446225 TI - Giant pedunculated fibrolipoma arising from right facial and cervical region. PMID- 19446226 TI - Severe glossal edema after primary palatoplasty. PMID- 19446227 TI - Giant submandibular sialolith of remarkable size in the comma area of Wharton's duct: a case report. PMID- 19446228 TI - Breast cancer metastatic to the mandible misdiagnosed as parotitis: report of a case. PMID- 19446229 TI - Obstructive sialadenitis of submandibular gland due to foreign body successfully treated by sialoendoscopic intervention. PMID- 19446230 TI - Angiolipoma of the upper lip: report of a case. PMID- 19446231 TI - Clear-cell odontogenic carcinoma: a new case and long-term follow-up of an old case, and review of the literature. PMID- 19446232 TI - Extended vertical lower trapezius island myocutaneous flap for repairing extensive oropharyngeal defects. PMID- 19446233 TI - Oral bisphosphonates and dental implants. PMID- 19446234 TI - Increased risk for bisphosphonate-related osteonecrosis of the jaws in patients wearing dentures could be attributable to impaired mucosal cell wound healing. PMID- 19446235 TI - Citation error. PMID- 19446236 TI - Sometimes the old is still gold. PMID- 19446237 TI - Platelet-rich plasma: an adjunctive treatment modality for bisphosphonate osteonecrosis? PMID- 19446238 TI - The effect of informed consent on stress levels. PMID- 19446239 TI - Relationship between human paraoxonase-1 activity and PON1 polymorphisms in Mexican workers exposed to organophosphate pesticides. AB - Paraoxonase-1 (PON1) is a serum enzyme which catalyzes the hydrolysis of organophosphate pesticides. In this study we conducted a cross-sectional study and reported on the distribution of three common genetic polymorphisms of the PON1 gene in a population of floriculture workers from Mexico as well as the association between those polymorphisms and other predictors with serum PON1 activity on paraoxon, diazoxon and phenylacetate. The genotype frequencies at position PON1(55) were 89% (LL), 10% (LM) and 0.6% (MM), at position PON1(192) they were 16% (QQ), 47% (QR) and 37% (RR), and 26% (TT), 42% (TC) and 32% (CC) at position PON1(-108). Thus, the frequencies of alleles L, Q and T were 0.94, 0.40 and 0.47, respectively. The PON1(55) polymorphism had no significant effect on serum PON1 activity on any substrate. We found a significant association between the PON1(192) polymorphism and PON1 activity towards paraoxon and diazoxon, which increased in genotypes as follows: 192RR>192QR>192QQ for paraoxonase activity and, inversely, 192QQ>192QR>192RR for diazoxonase activity. The PON1(-108) polymorphism also had a significant effect on PON1 activity level towards paraoxon in the following order among the genotype groups: -108CC>-108TC>-108TT. Serum PON1 activity towards diazoxon was not associated with the PON1(-108) polymorphism but it was influenced by the intensity exposure to pesticides at the floriculture industry and the years of the occupational exposure to pesticides. No polymorphism significantly influenced serum PON1 activity on phenylacetate. PMID- 19446240 TI - Scoring multiple toxicological endpoints using a toxicogenomic database. AB - As information regarding microarray data sets and toxicogenomic biomarkers grows rapidly, the process of analyzing data and interpreting the results is increasingly complicated. To facilitate data analysis, a simple expression ratio based scoring method called the TGP1 score was previously proposed [Kiyosawa, N., Shiwaku, K., Hirode, M., Omura, K., Uehara, T., Shimizu, T., Mizukawa, Y., Miyagishima, T., Ono, A., Nagao, T., Urushidani, T., 2006. Utilization of a one dimensional score for surveying chemical-induced changes in expression levels of multiple biomarker gene sets using a large-scale toxicogenomics database. J. Toxicol. Sci. 31, 433-448]. Although the TGP1 score has demonstrated its efficacy for rapid comprehension of large-scale toxicogenomic data sets, inclusion of low quality gene expression data in the biomarker gene set produced flaws in the calculated score. To overcome this shortcoming, we tested a new scoring method called the differentially expressed gene score (D-score), where Detection Call as well as signal log ratios generated by MAS5 algorithm on Affymetrix GeneChip data were considered for the calculation. Four prototypical toxicants, namely acetaminophen, phenobarbital, clofibrate and acetamidofluorene, were used for detailed analysis. A toxicogenomics database (TG-GATEs) was utilized as a reference data set. The D-score successfully alleviated the effects of low quality data on the score calculation, and captured the overall direction of expression changes as well as the magnitude of expression change level of a set of genes, highlighting the affected toxicological endpoints elicited by chemical treatment. The D-score will be useful for high-throughput toxicity screening using a toxicogenomic database and biomarkers. PMID- 19446241 TI - In vitro to in vivo concordance of a high throughput assay of bone marrow toxicity across a diverse set of drug candidates. AB - The development of predictive toxicology assays is necessary to optimize the drug candidate selection process. The colony forming assay (CFA) is used routinely to assess bone marrow toxicity and represents a viable tool for the discovery toxicologist, but the assay is not widely accepted as a standard screening tool due to technical challenges. A higher throughput and standardized version of the assay recently was developed such that the proliferative capacity of a cell lineage is measured indirectly via ATP levels, replacing the cumbersome identification and enumeration of specific colonies. In this study, a high throughput assay of bone marrow toxicity prediction using the granulocyte, erythrocyte, monocyte, and macrophage (GEMM) progenitor cell lineage was evaluated using a training set of 56 structurally diverse compounds with known in vivo bone marrow effects. In general, compounds identified as toxic in vivo had lower IC(50) values, whereas those identified as non-toxic had higher IC(50) values. Concordance (i.e., predictive accuracy) to in vivo bone marrow toxicity results was 82% when an in vitro toxicity threshold of 20 microM was used. Additional experiments in other hematopoietic lineages were conducted to determine if predictivity of several false positive and negative compounds in the GEMM lineage could be improved; however an increase in sensitivity or specificity was not observed. The high-throughput GEMM assay has good concordance to in vivo bone marrow toxicity results and, with the high-throughput and standardized format, can be incorporated readily into the pharmaceutical toxicological screening paradigm, aiding in the early identification of compounds that eventually may fail due to bone marrow toxicity. PMID- 19446242 TI - UV-enhanced cytotoxicity of thiol-capped CdTe quantum dots in human pancreatic carcinoma cells. AB - Quantum dots (QDs) have been gaining popularity due to their potential application in cellular imaging and diagnosis, but their cytotoxicity under light illumination has not been fully investigated. In this study, green and red mercaptopropionic acid capped CdTe quantum dots (MPA-CdTe QDs) were employed to investigate their cytotoxicity in human pancreatic carcinoma cells (PANC-1) under UV illumination. MPA-CdTe QDs exhibited excellent photostability under UV illumination and could be easily ingested by cells. The cytotoxicity of MPA-CdTe QDs was significantly enhanced under UV illumination, which was determined by changes in cell morphology as well as by decreases in the metabolic activity and cell counting. Our results indicated that green and red QDs had different cellular distribution and exhibited distinct UV-enhanced cytotoxicity. UV illumination enhanced the generation of reactive oxygen species (ROS) in cells containing QDs, and NAC antioxidant could reduce their damage to cells under UV illumination. Moreover, the influences of different UV illumination conditions on the viability of cells containing QDs were examined and discussed in detail. PMID- 19446243 TI - Size-dependent toxicity of metal oxide particles--a comparison between nano- and micrometer size. AB - Toxicological studies have shown increased toxicity of nanoparticles (<100 nm) compared to micrometer particles of the same composition, which has raised concern about the impact on human health from nanoparticles. However, if this is true for a wide range of particles with different chemical composition is not clear. The aim of this study was to compare the toxicity of nano- and micrometer particles of some metal oxides (Fe(2)O(3), Fe(3)O(4), TiO(2) and CuO). The ability of the particles to cause cell death, mitochondrial damage, DNA damage and oxidative DNA lesions were evaluated after exposure of the human cell line A549. This study showed that nanoparticles of CuO were much more toxic compared to CuO micrometer particles. One key mechanism may be the ability of CuO to damage the mitochondria. In contrast, the micrometer particles of TiO(2) caused more DNA damage compared to the nanoparticles, which is likely explained by the crystal structures. The iron oxides showed low toxicity and no clear difference between the different particle sizes. In conclusion, nanoparticles are not always more toxic than micrometer particles, but the high toxicity of CuO nanoparticles shows that the nanolevel gives rise to specific concern. PMID- 19446244 TI - Dermal penetration and metabolism of p-aminophenol and p-phenylenediamine: application of the EpiDerm human reconstructed epidermis model. AB - To address the provision of the 7th Amendment to the EU Cosmetics Directive banning the use of in vivo genotoxicity assays for testing cosmetic ingredients in 2009, the 3D EpiDerm reconstructed human skin micronucleus assay has been developed. To further characterise the EpiDerm tissue for potential use in genotoxicity testing, we have evaluated the dermal penetration and metabolism of two hair dye ingredients, p-aminophenol (PAP) and p-phenylenediamine (PPD) in this reconstructed epidermis model. When EpiDerm tissue was topically exposed to PAP or PPD for 30 min (typical for a hair dye exposure), the majority (80->90%) of PAP or PPD was excluded from skin tissue and removed by rinsing. After a 23.5h recovery period, the PAP fraction that did penetrate was completely N-acetylated to acetaminophen (APAP). Similarly, 30 min topical application of PPD resulted in the formation of the N-mono- and N,N'-diacetylated metabolites of PPD. These results are consistent with published data on the dermal metabolism of these compounds from other in vitro systems as well as from in vivo studies. When tissue was exposed topically (PAP) or via the culture media (PPD) for 24h, there was good batch-to-batch and donor-to-donor reproducibility in the penetration and metabolism of PAP and PPD. Overall, the results demonstrate that these two aromatic amines are biotransformed in 3D EpiDerm tissue via N-acetylation. Characterising the metabolic capability of EpiDerm tissue is important for the evaluation of this model for use in genotoxicity testing. PMID- 19446245 TI - Effects of low concentrations of benzene on human lung cells in vitro. AB - Exposure to benzene causes health hazards to humans. The airway epithelium is a physical barrier to inhaled toxicants and particulates. This is an in vitro basic science study to evaluate the effects of benzene on lung cells without the inflammatory responses triggered by inhalation. Dose-response cytotoxicity was assessed using two cell lines: alveolar derived (A549) human epithelial adenocarcinoma and human lung (LL24) fibroblast. A549 cells were more resistant than LL24 fibroblast lung cells to benzene. LL24 cells demonstrated enhanced proliferation with diluted benzene solutions. Moreover, low concentrations of benzene enhanced telomerase activity in LL24 cells while no effects were observed in the adenocarcinoma cells. Proteolysis of lung matrix by matrix metalloproteinases (MMPs) is an early event observed in lung pathologies. Benzene increased MMP-2 and MMP-3 mRNA. Using the ratio (MMP-1+MMP-2+MMP-3)/(TIMP-1+TIMP 2), as an index of prodestructive activity, we observed a dose-dependent increase. The overall higher expression levels of MMPs in benzene treated cells did not appear to be controlled by TIMPs, which are negatively correlated. Comparing different cell lines, we demonstrated how crucial is the target's susceptibility. Our observations may represent early functional alterations that occur in the airways of exposed people. PMID- 19446246 TI - Anabolic and androgenic activity of 19-norandrostenedione after oral and subcutaneous administration--analysis of side effects and metabolism. AB - One of the most frequently misused steroid precursors (prohormones) is 19 norandrostenedione (estr-4-ene-3,17-dione, NOR). Recently we have show that NOR stimulates skeletal muscle growth after s.c. administration in a highly selective manner but exhibits only weak androgenic activity in rats. Because most abusers take NOR orally, the aim of this study was to compare the anabolic and androgenic potency of NOR between s.c. and oral application. Orchiectomised rats were treated with NOR either s.c. (1 mg/kg BW/day) or orally (0.1, 1 and 10 mg/kg BW/day). The tissue weights of the levator ani, the seminal vesicle and the prostate were analysed to determine the anabolic and androgenic activity. Heart and liver wet weights were examined to identify side effects. Serum concentrations of NOR and its metabolite nandrolone (NT) were determined. GCMC analysis revealed that free and glucuronidated NOR and NT were detectable in the serum after oral and s.c. administration and that NOR was converted to NT in comparable amounts independent of the route of administration. In agreement to our previous study s.c. application of NOR stimulates skeletal muscle growth but has only weak androgenic effects. In contrast, after oral administration of NOR neither stimulation of the prostate nor the levator ani could be observed in the doses administered in this study. Interestingly, and in contrast to s.c. treatment, oral administration of NOR resulted in a dose-dependent decrease of body weight. In summary, oral administration of NOR, at least in the rat, seems to be a very ineffective strategy for stimulating skeletal muscle mass increases but may be associated with side effects. PMID- 19446247 TI - Mechanisms of thiosulfinates from Allium tuberosum L.-induced apoptosis in HT-29 human colon cancer cells. AB - This study was performed to elucidate the apoptotic pathways by thiosulfinates, major biologically active components of Allium tuberosum L., in HT-29 human colon cancer cells. Thiosulfinates significantly induced cell death in dose- and time dependent manners in HT-29 cells, which is associated with apoptosis. Thiosulfinates activated the initiator caspase-8, and -9, and the effector caspase-3. In the present study, thiosulfinates were found to stimulate Bid cleavage, indicating that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. Thiosulfinates down-regulated the expression of the anti-apoptotic protein Bcl-2, and up-regulated the expression of the pro-apoptotic protein Bax. We also found that thiosulfinates increased the expression of AIF, a caspase-independent mitochondrial apoptosis factor, and induced DNA fragmentation and chromatin condensation in HT-29 cells. These results indicate that thiosulfinates from A. tuberosum L. inhibited cell proliferation and activated both the caspase-dependent and caspase-independent apoptotic pathways in HT-29 cells. PMID- 19446248 TI - Paraquat induces alternation of the dopamine catabolic pathways and glutathione levels in the substantia nigra of mice. AB - The herbicide paraquat (PQ) is a strong redox agent that participates in the formation of reactive oxygen species (ROS) and induces toxicity in the nigrostriatal dopaminergic system. In this study, we investigated the effect of PQ on dopamine (DA) and glutathione levels in the substantia nigra (SN) of mice. Male C57BL/6 mice (aged 7 weeks and 23-25 g) were used for this study. The mice were treated with normal saline (vehicle) and PQ (10 mg/kg, i.p.) twice weekly for three consecutive weeks. We measured changes in tyrosine hydroxylase (TH) immunoreactivity, DA and its metabolites, and glutathione (reduced and oxidized) in the SN. After repeated PQ administration, the density of TH-positive neurons in the substantia nigra pars compacta (SNpc) decreased as compared to the control. Levels of DA and homovanillic acid (HVA) decreased significantly in the PQ-treated mice (p<0.05), but levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) did not change. The rate of DA oxidation increased significantly in the SNpc, whereas the O-methylation pathway remained unchanged. Levels of reduced glutathione (GSH) in the SNpc decreased more in the PQ group than in the control group, while levels of oxidized glutathione (GSSG) increased in same region. We propose that repeated PQ injection induces dopaminergic neurotoxicity through generation of oxidative stress, and that this toxicity is related to the decline of GSH in the SNpc. The neurotoxic mechanism may specifically involve enhancement of the oxidative pathway of DA metabolism through coupling with the antioxidant GSH system of the SN. PMID- 19446249 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits neurite outgrowth in differentiating human SH-SY5Y neuroblastoma cells. AB - TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a highly toxic environmental pollutant, is known to induce neurodevelopmental and neurobehavioral deficits. However, the underlying mechanism of TCDD-mediated neurotoxicity has remained unclear. We have studied TCDD inhibition of neurite outgrowth using human SH-SY5Y neuroblastoma cells induced to differentiate by all-trans-retinoic acid (RA). TCDD, at concentrations of 3 nM or 5 nM, had no significant effect on the viability of either undifferentiating or differentiated SH-SY5Y cells. However, differentiating SH-SY5Y cells exhibited a distinct decrease of neurite outgrowth 48 h after TCDD treatment in a dose-dependent manner. TCDD treatment 12h or 24h after RA stimulation did not elicit a significant inhibition of neurite outgrowth, whereas TCDD cotreatment with RA or TCDD treatment at 6h after RA stimulation significantly inhibited neurite outgrowth. Western blot analysis of cell extracts of RA-stimulated differentiating SH-SY5Y cells showed increased level of cross reactivities with tissue glutaminase (TGase) antibody compared to control extracts, in a time-dependent manner. By contrast, treatment of differentiating SH-SY5Y cells with 1-5 nM TCDD resulted in decreased level of cross-reactivities with TGase antibody in a dose-dependent manner. The results indicate that TCDD is able to inhibit neurite outgrowth by differentiating SH SY5Y cells and that this effect might result from reduced levels of TGase. PMID- 19446250 TI - Cell death and production of reactive oxygen species by murine macrophages after short term exposure to phthalates. AB - The effects of four phthalates, i.e., di-2-ethylhexyl phthalate (DEHP), butyl benzyl phthalate (BBP), dibutyl phthalate (DBP) and diisobutyl phthalate (DIBP) on necrotic and apoptotic cell death, and production of reactive oxygen species (ROS) were studied on mouse macrophage cell line RAW 264.7. All the phthalates caused negligible and non-dose-dependent ROS production compared to control experiment. DEHP and BBP did not cause significant necrotic nor apoptotic cell death at any of the studied doses. Both DIBP and DBP caused dose-dependent necrotic cell death at the two highest concentrations (100 microM and 1 mM). Both doses (500 microM and 1 mM) of DIBP increased apoptosis by 31- and 60-fold, respectively, whereas the increase in apoptotic cell death caused by DBP was only two and fourfold, that however, was not statistically significant. In conclusion, DIBP caused a substantially different apoptotic cell death effect on murine macrophages from the three other phthalates, and this effect was not related to ROS production. Thus, toxicological and health risks of DIBP and DBP should be assessed separately in the future. PMID- 19446251 TI - Effects of penicillin-induced developmental epilepticus on hippocampal regenerative sprouting, related gene expression and cognitive deficits in rats. AB - For the purpose of investigating the long-term effects of seizures in developmental rats on spatial learning ability and hippocampal mossy fiber sprouting related gene expressions in adult rat brain, a seizure was induced by penicillin quaque die alterna in Sprague-Dawley rats from postnatal day 29 (P29). Rats were assigned into the recurrent seizure group (RS, seizures were induced in 11 consecutive days) and the control group. During P51-P56, P81-P84 and P92-P95, the rats were tested for spatial learning ability with the Morris water maze task. On P95, the authors examined mossy fiber sprouting and gene expression of zinc transporters 1 and 3 (ZnT-1, ZnT-3), calcium/calmodulin-dependent protein kinase IIalpha (CaMK-IIalpha), NMDA receptor 2C (NR2C) and glutamate receptor 2 (GluR2) in hippocampus by Timm staining and real-time RT-PCR analysis. The escape latencies from the water maze of the rats in the RS group were significantly longer than those of the control rats at d5 of the first test, at d1 of the second test, and at d2 of the third test. In the spatial probe test, the ratio between the swim time in the third quadrant and the total swim time in control group was significantly higher than RS group (p<0.05) in the entire three probe tests. The Timm scores in CA3 and dentate gyrus in the RS animals were significantly higher than that in the control. Compared with the control rats, the expressions of ZnT-1, CaMK-IIalpha and GluR2 transcripts in the hippocampus of the RS group was significantly decreased while unchanged in transcriptional levels of ZnT-3 and NR2C. There were positive linear correlations among ZnT-3, CaMKIIalpha, and NR2C in control group and among CaMKIIalpha, ZnT-1 and GluR2 in RS group. The results suggest that recurrent seizures induced in developmental rats could cause long-term disturbance on the hippocampal mossy fiber sprouting related gene expressions, which might play an important role in long-term cognitive deficit and hippocampal aberrant mossy fiber sprouting. PMID- 19446252 TI - Drug interaction between ethanol and 3,4-methylenedioxymethamphetamine ("ecstasy"). AB - Alcohol (ethanol) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are frequently co-abused, but recent findings indicate a harmful drug interaction between these two agents. In our previous study, we showed that MDMA exposure inhibits the activity of the acetaldehyde (ACH) metabolizing enzyme, aldehyde dehydrogenase2 (ALDH2). Based on this finding, we hypothesized that the co administration of MDMA and ethanol would reduce the metabolism of ACH and result in increased accumulation of ACH. Rats were treated with MDMA or vehicle and then administered a single dose of ethanol. Liver ALDH2 activity decreased by 35% in the MDMA-treated rats compared to control rats. The peak concentration and the area under the concentration versus time curve of plasma ACH were 31% and 59% higher, respectively, in the MDMA-ethanol group compared to the ethanol-only group. In addition, the MDMA-ethanol group had 80% higher plasma transaminase levels than the ethanol-only group, indicating greater hepatocellular damage. Our results not only support a drug interaction between MDMA and ethanol but a novel underlying mechanism for the interaction. PMID- 19446253 TI - Preface: peptic ulcer disease. PMID- 19446254 TI - The role of proton pump inhibitors in the management of upper gastrointestinal bleeding. AB - Pre-endoscopic administration of PPIs in patients with nonvariceal upper GI bleeding is still of controversial efficacy. It downstages the severity of the endoscopic signs of recent bleeding and may reduce the requirement for endoscopic hemostatic therapy at index endoscopy. However, there is no evidence of an effect on mortality, rebleeding, or surgical intervention rates. In contrast, the efficacy of PPIs in endoscopically diagnosed peptic ulcer bleeding is supported by high-quality evidence from numerous RCTs and meta-analyses of RCTs. PPIs compared with H2RAs or placebo consistently reduce rebleeding rates regardless of dose, route of administration, application or not of endoscopic hemostatic treatment, and geographic location. Surgical intervention rates and the need for further endoscopic hemostatic treatment are also reduced by PPI treatment, although the results are not as robust as those for rebleeding. There is no evidence of an overall effect of PPI treatment on all-cause mortality. However, all-cause mortality is reduced among patients with high-risk endoscopic signs and among trials that had been conducted in Asia. The optimal dose and route of PPI administration has yet to be determined. PMID- 19446255 TI - Predicting poor outcome from acute upper gastrointestinal hemorrhage. AB - In conclusion, numerous prediction models identified pre-endoscopic and endoscopic risk factors for adverse clinical outcomes in patients with acute upper GI hemorrhage. The risk factors for mortality are different from those of rebleeding. Predictors for rebleeding are usually related to the severity of the bleeding and characteristics of the ulcer, whereas advanced age, physical status of the patient, and comorbidities are important predictors for mortality in addition to those for rebleeding. Future studies should focus on validation of these predictors in a prospective cohort and application of these prediction models to guide clinical management in patients with acute upper GI hemorrhage. PMID- 19446256 TI - Management of massive peptic ulcer bleeding. AB - Massive bleeding from a peptic ulcer remains a challenge. A multidisciplinary team of skilled endoscopists, intensive care specialists, experienced upper gastrointestinal surgeons, and intervention radiologists all have a role to play. Endoscopy is the first-line treatment. Even with larger ulcers, endoscopic hemostasis can be achieved in the majority of cases. Surgery is clearly indicated in patients in whom arterial bleeding cannot be controlled at endoscopy. Angiographic embolization is an alternate option, particularly in those unfit for surgery. In selected patients judged to belong to the high-risk group--ulcers 2 cm or greater in size located at the lesser curve and posterior bulbar duodenal, shock on presentation, and elderly with comorbid illnesses--a more aggressive postendoscopy management is warranted. The optimal course of action is unclear. Most would be expectant and offer medical therapy in the form of acid suppression. Surgical series suggest that early elective surgery may improve outcome. Angiography allows the bleeding artery to be characterized, and coil embolization of larger arteries may further add to endoscopic hemostasis. The role of early elective surgery or angiographic embolization in selected high-risk patients to forestall recurrent bleeding remains controversial. Prospective studies are needed to compare different management strategies in these high-risk ulcers. PMID- 19446257 TI - Stress-induced ulcer bleeding in critically ill patients. AB - Increased knowledge of risk factors and improved ICU care has decreased the incidence of stress-related bleeding. Not all critically ill patients need prophylaxis for SRMD and withholding such prophylaxis in suitable low-risk candidates is a reasonable and cost-effective approach. Mechanical ventilation for more than 48 hours and coagulopathy are the main risk factors for stress induced upper GI bleeding. Although intravenous H2RAs can prevent clinically important bleeding, their benefits seem to be limited by the rapid development of tolerance. The availability of intravenous formulations of PPIs makes it possible to critically compare their prophylactic efficacy and safety to different classes of acid-suppressive agents, such as H2RAs, in critically ill patients. The appropriate dose of PPI and the role of newer PPI formulations need to be further defined along with proposed guidelines for the use of intravenous and oral/enteral formulations of PPIs in patients at risk for stress-related mucosal damage. PMID- 19446258 TI - Refractory peptic ulcer disease. AB - Refractory PUD is a diagnostic and therapeutic challenge. Optimal management of severe or refractory PUD requires a multidisciplinary team approach, using primary care providers, gastroenterologists, and general surgeons. Medical management has become the cornerstone of therapy. Identification and eradication of H pylori infection combined with acid reduction regimens can heal ulceration and also prevent recurrence. Severe, intractable or recurrent PUD and associated complications mandates a careful and methodical evaluation and management strategy to determine the potential etiologies and necessary treatment (medical or surgical) required. PMID- 19446259 TI - Management of patients with high gastrointestinal risk on antiplatelet therapy. AB - Increasing use of antiplatelet therapies is associated with increasing GI complications, such as ulceration and GI bleeding. Identification of high-risk patients and, in such patients, incorporation of strategies to reduce their GI risk would be clinically prudent. After assessment and treatment of H pylori in patients with prior ulcer or GI bleeding histories, further reduction in GI risk in other high-risk patients who require antiplatelet agents is primarily accomplished by prescribing drugs that when coadministered with antiplatelet agents protect against mucosal ulceration, primarily proton pump inhibitors (PPIs). However, observational studies indicate a higher cardiovascular event rate in patients taking PPIs along with clopidogrel and aspirin compared with that of patients undergoing dual antiplatelet therapy without PPIs. Whether concurrent use of a PPI with clopidogrel represents a safety concern or not is currently being evaluated by the US Food and Drug Administration. Until more specific regulatory guidance is available, current recommendations are that patients taking both PPIs and clopidogrel concurrently should probably continue to do so until more data become available. PMID- 19446260 TI - Balancing risks and benefits of cyclooxygenase-2 selective nonsteroidal anti inflammatory drugs. AB - Choosing NSAID therapy remains confusing and controversial-the challenge for the clinician is to sum all the risks as well as analgesic and anti-inflammatory efficacy. COX-2 inhibitors are an important scientific advance in pain therapy, and using them in a safe and cost-effective manner is possible when all the competing risks are carefully weighed. PMID- 19446261 TI - Prevention of nonsteroidal anti-inflammatory drug-induced ulcer: looking to the future. AB - The great challenge for those attempting to develop safer NSAIDs is shifting from a focus on GI toxicity to the increasingly more appreciated cardiovascular toxicity. At present, coxib shows an unmatched GI safety and appears to be a rational choice for patients at a low cardiovascular risk who have had serious GI events. In these patients, however, a cost-effective alternative is the use of tNSAIDs associated with comedication with a low-cost PPI or PN400. Because it seems prudent to avoid coxibs in patients who have cardiovascular disease or who are at risk for it, naproxcinod will be an appealing alternative to coxibs and tNSAIDs. However, because naproxcinod carries a significant risk of GI bleeding, a comedication therapy with a PPI inhibitor will be required if these patients also present risk factors for GI events. Although the development of H2S releasing anti-inflammatory drugs is in its infancy, the preclinical data available thus far provide cause for optimism. The quest for the development of NSAIDs devoid of cardiovascular toxicity and that spare the gastric mucosa to the same extent as that of a coxib, however, is still open. PMID- 19446262 TI - Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. AB - In addition to the upper GI tract, NSAIDs can damage the small bowel and the colon. NSAID enteropathy is frequent and may be present in more than 60% of patients taking these drugs long term. In most cases, damage is subclinical, including increased mucosal permeability, inflammation, erosions, ulceration, but other more serious clinical outcomes such as anemia, and overall bleeding, perforation, obstruction, diverticulitis and deaths have also been described. The magnitude of these serious outcomes from the lower GI tract is not well defined, but recent data suggest that they may be as frequent and severe as upper GI complications. Contrary to what happens in the upper GI tract, treatment and prevention of NSAID enteropathy is difficult, since the pathogenic mechanisms are different and not well understood. Among other options, misoprostol, antibiotics, and sulphasalazine have been proved to be effective in animal models, but they have not been properly tested in humans. Selective COX-2 inhibition is emerging as a potential alternative to tNSAIDs in the prevention of damage in the lower GI tract in rheumatologic patients. Preliminary studies in healthy volunteers have shown that these drugs are associated with no or less small bowel damage than tNSAIDs plus PPI, although their long-term effects in patients need to be properly tested. Post hoc analysis of previous outcome studies focused on complications of upper GI tract or cardiovascular events have shown contradictory results. Data from one ongoing trial comparing celecoxib versus diclofenac plus PPI and examining serious outcomes from the whole GI tract will probably provide new insights in this area. PMID- 19446263 TI - Helicobacter pylori-negative nonsteroidal anti-inflammatory drug-negative ulcer. AB - The most important clinical point for dyspeptic H pylori-negative NSAID-absent negative ulcers is to adequately ensure that these common risk factors are indeed absent. Once that is done, further investigations to include the rare causes of ulcer disease need to be performed and exclusion of underlying malignancy ensured. The possibility of the Zollinger Ellison syndrome should be considered, remembering that proton pump inhibitor therapy will mitigate its classical, clinical features. PMID- 19446264 TI - Differences in peptic ulcer between the East and the West. AB - PUD affects both the East and the West. The magnitude of the problem, however, varies within these regions. The study of peptic ulcer epidemiology is impeded by the paucity of general population-based data, invasiveness of diagnostic tests, and variable access to testing facilities. As such, direct comparisons of PUD epidemiology between the East and the West are difficult. The prevalence rates of H pylori are highly variable and depend greatly on the local sanitation conditions. The use of NSAIDs and aspirin is ubiquitous and increasing especially for the antiplatelet activity of aspirin in the prophylaxis of cardiovascular events. There is evidence that pharmacogenetics play a role in susceptibility to the ulcerogenic properties of NSAIDs. The prevalence of PUD parallels the risk factors, but emerging in both the East and the West is idiopathic PUD, now a substantial proportion of ulcers in areas of declining H pylori infection. Genetic polymorphisms affect the efficacy of treatment using PPIs. Local H pylori resistance rates also influence the eradication success rates. PMID- 19446265 TI - Chagas disease: the forgotten American neuroinfection. PMID- 19446266 TI - ACTIVE A: balancing the benefits and risks of clopidogrel and aspirin. PMID- 19446267 TI - Is antiviral medication for severe Bell's palsy still useful? PMID- 19446270 TI - EAYNT: promoting training in neuro-rehabilitation. PMID- 19446271 TI - Health-care reform in Obama's first 100 days. PMID- 19446272 TI - Bengt Winblad: coaching the team in Alzheimer's disease. PMID- 19446274 TI - Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. AB - Disease-modifying drugs (DMDs) for relapsing-remitting multiple sclerosis (RRMS) are only partly effective -- breakthrough disease commonly occurs despite treatment. Breakthrough disease is predictive of continued disease activity and a poor prognosis. Availability of several DMDs offers the possibility of tailoring treatment to individual patients with RRMS and altering treatment in patients with breakthrough disease. However, no biological or imaging markers have been validated to guide initial treatment, markers of individual responsiveness to DMDs are scarce, and there is no class 1 evidence to guide alternative therapy in patients with breakthrough disease. In this Review, we discuss proposed strategies to monitor patients with RRMS being treated with DMDs, outline approaches to identifying therapeutic response in individual patients, review MRI and biological markers of treatment response, and summarise the role of antibodies in biological therapies. We also outline possible strategies for the management of patients with breakthrough disease and highlight areas in which research is needed. PMID- 19446275 TI - Advanced neuroimaging of migraine. AB - Advanced neuroimaging has helped to increase our knowledge about migraine pathophysiology. Our perception of migraine has transformed from a vascular, to a neurovascular, and most recently, to a CNS disorder. Functional imaging has confirmed the importance of cortical spreading depression (CSD) as the pathophysiological mechanism of migraine aura in human beings, whereas novel animal studies are unravelling the mechanistic underpinnings of CSD. Altered cerebral blood flow and neurotransmitter systems have been identified during and between headaches in migraine with and without aura. Advanced neuroimaging has identified mechanisms involved in the transformation of migraine from an episodic disorder to one with near continuous symptomatology. Questions regarding the secondary effects of migraine on brain structure and function, possibly related to attack frequency and duration of illness, have been raised. New imaging techniques could lead to novel diagnostic and therapeutic interventions that will help to improve the lives of millions of patients with migraine. In this Review, we summarise the most important findings from current imaging studies of migraine. PMID- 19446276 TI - Carotid-artery imaging in the diagnosis and management of patients at risk of stroke. AB - Carotid atherosclerotic disease is one of the major preventable causes of ischaemic strokes. In clinical practice, decision making with regard to carotid endarterectomy or stenting is still primarily based on the extent of luminal stenosis. In most centres worldwide, luminal stenosis is now mainly assessed with non-invasive techniques, such as Doppler ultrasound, magnetic resonance angiography, and CT angiography, either alone or in combination. Although intra arterial digital subtraction angiography remains the historical gold standard, it has now mostly been replaced by these non-invasive techniques. Moreover, in addition to luminal stenosis, certain morphological features of carotid plaques, such as large lipid cores, intraplaque haemorrhage, or thin or ruptured fibrous caps, are increasingly believed to be associated with heightened risk of stroke. In this Review, we discuss current state-of-the-art non-invasive diagnostic imaging strategies for luminal stenosis and describe the most promising novel imaging techniques, such as high-resolution MRI and CT combined with PET imaging, which can be used to characterise vulnerable carotid-plaque features in vivo. PMID- 19446277 TI - Therapeutic challenges in primary CNS lymphoma. AB - Optimum treatment for patients with primary CNS lymphoma remains challenging because there have not been any large randomised clinical trials of this rare tumour. Drugs used in treating systemic non-Hodgkin lymphoma have mostly proven ineffective because of difficulties crossing the blood-brain barrier. The recognition of the efficacy of high-dose methotrexate was a substantial therapeutic breakthrough and further advances, such as the development of polychemotherapy regimens, have built on this. Whole-brain radiotherapy can consolidate response to chemotherapy, but the associated toxic effects of chemoradiation can be unacceptable. Other effective approaches include disruption of the blood-brain barrier and the use of high-dose chemotherapy. Recently, there have been attempts to optimise multi-drug chemotherapy regimens by focusing on improving survival and reducing toxic effects. A promising area of research is the incorporation of novel targeted drugs into standard treatment frameworks. In the future, greater cooperation between research groups should hopefully lead to further therapeutic advances. PMID- 19446278 TI - In search of the magic bullet. PMID- 19446280 TI - Low-dose aspirin has no impact on systemic level of serine protease inhibitors in healthy volunteers. AB - Low-dose aspirin (100 mg/day) was recently found to increase serum levels of alpha-1 protease inhibitor (A1-PI). Here, we studied the serum levels of 2 major serine protease inhibitors, A1-PI and serine leukocyte protease inhibitor (SLPI), in 10 Helicobacter pylorinegative healthy volunteers (HVs) treated with low-dose aspirin alone and in combination with other drugs.(1) Neither the treatment with low-dose aspirin alone or in combination altered serum levels of both serine protease inhibitors. The previously described increase of A1-PI levels by low dose aspirin was most likely caused by multiple endoscopies within a few days, which caused a systemic stress response. PMID- 19446279 TI - Role of endothelin-1 in acute lung injury. AB - The alveolar-capillary membrane serves as a barrier that prevents the accumulation of fluid in the alveolar space and restricts the diffusion of large solutes while facilitating an efficient gas exchange. When this barrier becomes dysfunctional, patients develop acute lung injury (ALI), which is characterized by pulmonary edema and increased lung inflammation that leads to a life threatening impairment of gas exchange. In addition to the increase of inflammatory cytokines, plasma levels of endothelin-1 (ET-1), which is a primarily endothelium-derived vasoconstrictor, are increased in patients with ALI. As patients recover, ET-1 levels decrease, which suggests that ET-1 may not only be a marker of endothelial dysfunction but may have a role in the pathogenesis of ALI. While pulmonary edema accumulates, alveolar fluid clearance (AFC) is of critical importance, as failure to return to normal clearance is associated with poor prognosis in patients with pulmonary edema. AFC involves active transport mechanisms where sodium (Na(+)) is actively transported from the alveolar airspaces, across the alveolar epithelium, and into the pulmonary circulation, which creates an osmotic gradient that is responsible for the clearance of lung edema. In this article, we review the relevance of ET-1 in the development of ALI, not only as a vasoconstrictor molecule but also by inhibiting AFC via the activation of endothelial ET-B receptors and generation. Furthermore, this review highlights the therapeutic role of drugs such as beta-adrenergic agonists and, in particular, of endothelin receptor antagonists in patients with ALI. PMID- 19446281 TI - Novel insulin-like growth factor-methotrexate covalent conjugate inhibits tumor growth in vivo at lower dosage than methotrexate alone. AB - The insulin-like growth factor receptor is overexpressed on many types of cancer cells and has been implicated in metastasis and resistance to apoptosis. We report here the development of a novel covalent conjugate that contains the antifolate drug methotrexate coupled to an engineered variant of insulin-like growth factor-1 (IGF-1), long-R3-IGF-1, which was designed to target methotrexate to tumor cells that overexpress the membrane IGF-1 receptor. The IGF-methotrexate conjugate was found to contain at least 4 methotrexate molecules per IGF-1 protein. The IGF-methotrexate conjugate bound to MCF7 breast cancer cells with greater than 3.3-fold higher affinity than unconjugated long-R3-IGF-1 in a competition binding assay against radiolabeled wild-type IGF-1. Compared with free methotrexate, the IGF-methotrexate conjugate required slightly higher concentrations to inhibit the in vitro growth of the human prostate cancer cell line LNCaP. In vivo, however, in a mouse xenograft model using LNCaP cells, the IGF-methotrexate conjugate was more effective than free methotrexate even at a 6.25-fold lower molar dosage. Similarly, MCF7 xenografts were inhibited more effectively by the IGF-methotrexate conjugate than free methotrexate, even at a 4 fold lower molar dosage. Our results suggest that the targeting of the IGF receptor on tumor cells and tumor-related tissues with IGF-chemotherapy conjugates may substantially increase the specific drug localization and therapeutic effect in the tumor. PMID- 19446283 TI - Lipid profile and inflammatory markers associated with estrogen receptor alpha PvuII and XbaI gene polymorphisms. AB - Estrogen is established to influence lipoprotein metabolism and inflammatory markers. Alternations in estrogen receptor alpha (ESR1) expression and function may affect the role of estrogen in this regard. The aim of this study was to determine whether ESR1 PvuII and XbaI gene polymorphisms have effects on lipoprotein (a) as well as inflammatory variables in an Iranian population. Three hundred and ninety seven consecutive participants (228 men, 57.4%) who were admitted at our center for elective coronary angiography because of symptoms related to coronary artery disease (CAD) were enrolled in our study. Total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglyceride levels were determined by standard methods using commercial kits. Low-density lipoprotein (LDL)-cholesterol was calculated according to the Friedewald formula. The lipoprotein (a) levels were measured by ELISA method using Biopool kit, and the CRP concentrations were determined by Latex Immunoturbidometry. The presence of PvuII and XbaI polymorphisms within the ESR gene were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR RFLP). The frequency of homozygous and heterozygous were 25.9% and 50.1%, for PvuII genotypes, and the frequency was 23.7% and 48.6%, for XbaI genotypes, respectively. After adjusting for CAD and age, no impacts of ESR1 PvuII and XbaI polymorphisms were found on lipid profile, lipoprotein (a) level, and quantitative CRP either in total population or in subgroups stratified by gender. In conclusion, our data demonstrate that ESR1 PvuII and XbaI gene polymorphisms did not seem to have an effect on lipoprotein metabolism or on inflammatory variables such as CRP. PMID- 19446282 TI - Effect of heme oxygenase-1 on the kidney during septic shock in rats. AB - The aim of this study was to clarify the effect of heme oxygenase (HO)-1 on the kidney during septic shock in rats. Eighty healthy and clean Sprague-Dawley rats were randomly divided into 4 groups: control group (group C) , septic shock group (group SS) , lipopolysaccharide plus ZnPP-IX group (group LZ) , and ZnPP-IX (group Z) . The plasma levels of COHb, Cr, and BUN; the urine levels of gamma GTP, alpha1-MG, RBP, and NAG; and MDA content, SOD activity; HO-1mRNA; HO-2mRNA; HO-1 protein; and HO-2 protein from kidney were measured. The plasma levels of Cr and BUN; the urine levels of gamma-GTP, alpha1-MG, RBP, and NAG; and MDA content from kidney in group SS were obviously higher than in group C and Z (both P < 0.05), respectively, but lower than in group LZ (both P < 0.05), respectively. In contrast, the plasma levels of COHb and SOD activity from kidney in group SS were obviously lower than those in group C and Z (both P < 0.05), respectively, but higher than in group LZ (both P < 0.05), respectively. The HO-1mRNA and HO-1 protein of nephridial tissue in group LZ were obviously higher than in group C and Z, respectively (both P < 0.05), but lower than in group SS, respectively (both P < 0.05). There were no significant differences of HO-2mRNA and HO-2 protein among these 4 groups (both P > 0.05). It is concluded that upregulation of the HO-1 protein might contribute to the protection of kidney during septic shock in rats. PMID- 19446284 TI - Effect of abdominal surgery on the intestinal absorption of lipophilic drugs: possible role of the lymphatic transport. AB - Although abdominal surgery is a routine procedure in clinical practice and in preclinical investigation, little is known regarding its effect on the intestinal absorption of drugs. The aim of this study was to investigate the effect of abdominal surgery on the intestinal absorption of highly lipophilic compounds with different absorption mechanisms following oral administration. The 2 compounds that were tested were biopharmaceutical classification system (BCS) class 2 model lipophilic cannabinoid derivatives, dexanabinol and PRS-211,220. Although dexanabinol is mostly absorbed via passive diffusion to the portal blood, PRS-211,220 is absorbed mostly via lymphatic transport. In this work, we compared the absorption of these compounds after abdominal surgery in rat with the absorption data obtained from naive animals. The outcomes of this investigation showed that the abdominal surgery mostly affected the absorption process on the preenterocyte level, as indicated by the 2-fold increase in the extent of intestinal absorption of dexanabinol, which is a compound with a low degree of intestinal lymphatic transport. However, the lymphatic transport was not affected by the surgical procedure as evident by the absence of change in the extent of absorption of PRS-211,220, which is transported to the systemic circulation mainly by intestinal lymphatics. In conclusion, abdominal surgery can significantly affect the intestinal absorption of lipophilic drugs; however, intestinal lymphatic transport seems to be less affected by the abdominal surgery. PMID- 19446285 TI - The use of viral load as a surrogate marker in predicting disease progression for patients with early invasive cervical cancer with integrated human papillomavirus type 16. AB - OBJECTIVE: The purpose of this study was to assess the effectiveness of the use of human papillomavirus type 16 (HPV16) physical status and viral load in combination to predict clinical outcome during cervical development. STUDY DESIGN: A follow-up study was monitored in association with HPV integration and viral load in 121 cervical samples with the use of multiplex quantitative polymerase chain reaction. RESULTS: A significant increase of viral load was found earlier from preinvasive to invasive groups compared with normal groups, except with clinical staging and clinical outcome. High occurrence of integrated HPV16 was observed in preinvasive (27/44 samples) and invasive cervical carcinoma (40/68 samples). Cervical progression was observed significantly in most preinvasive (18/27 samples) and invasive cases (25/40 samples) that were infected with integrated HPV. Integrated HPV16 with significant viral load can be used as a predictive marker for tumor progression in the early stage of invasive cervical carcinoma. CONCLUSION: Integrated HPV16 in combination with viral load is a predictive indicator for tumor progression in early invasive stage but not in preinvasive and advanced invasive stage. PMID- 19446286 TI - Influence of topical anaesthesia on the corticomotor response to tongue training. AB - OBJECTIVES: The aim of this experimental study was to investigate if perturbation of somatosensory function would change corticomotor excitability of the tongue musculature in relation to a novel tongue training task. MATERIALS AND METHODS: Sixteen healthy volunteers participated in two randomized and double-blind sessions separated by two weeks, in which topical anaesthetics or placebo cream were applied to the tongue during a standardized tongue training task. Corticomotor excitability was assessed by changes in motor evoked potentials (MEPs) in the tongue musculature evoked by transcranial magnetic stimulation (TMS) before and after training. RESULTS: The success rate of the training task increased in both sessions (relative increase: topical anaesthetics = 53 +/- 53%; placebo = 50 +/- 48%; P = 0.713). The MEP amplitudes increased with stimulation intensity (P < 0.026) in both sessions and there were significantly higher MEP amplitudes on the contralateral tongue muscle compared to the ipsilateral tongue (P < 0.019). There were no differences in MEP amplitudes between the topical anaesthetic and placebo session and there were no main effects of the tongue training task. However, there were significant correlations between increases in success rate and facilitation of the MEP amplitudes in the tongue muscles. CONCLUSION: Topical anaesthesia has no major effects on corticomotor excitability of tongue musculature and there appears to be a strong individual variation in the effects of a tongue training task on MEP amplitudes. PMID- 19446287 TI - A systematic review and meta-analysis of cognitive-behavioural interventions to reduce problem gambling: hedging our bets? AB - Problem gambling is of serious public, social and clinical concern, especially so because ease of access to different types of gambling is increasing. A systematic review and meta-analysis was carried out to determine whether Cognitive Behavioural Therapies (CBT) were effective in reducing gambling behaviour. Twenty five studies which met the inclusion criteria were identified. Overall, there was a highly significant effect of CBT in reducing gambling behaviours within the first three months of therapy cessation regardless of the type of gambling behaviour practiced. Effect sizes were also significant at six, twelve and twenty four month follow-up periods. Sub-group analysis suggested that both individual and group therapies were equally as effective in the 3 month time window, however this equivalence was not clear at follow-up. All variants of CBT (cognitive therapy, motivational interviewing and imaginal desensitization) were significant, although there was tentative evidence that when different types of therapy were compared cognitive therapy had an added advantage. Meta-regression analyses showed that the quality of the studies influenced the effect sizes, with those of poorer quality having greater effect sizes. These results give an optimistic message that CBT, in various forms, is effective in reducing gambling behaviours. However, caution is warranted because of the heterogeneity of the studies. Evaluation of treatment for problem gambling lags behind other fields and this needs to be redressed in the future. PMID- 19446288 TI - Postoperative evaluation platform of female breast implant surgery with breast configuration indicator. AB - The purpose of this study is to establish an optimal module of breast configuration, under normal seating state, for postoperative evaluation of a female breast implant surgery. The analytical parameters of breast configuration, such as the breast position, size and shape, can be derived from a three dimensional (3D), full-sized image process under non-radiation condition. This optimal module converts the breast position, size and shape to the breast configuration indicator consisting of three components or indices-the breast position, volume and breast congruence rate. In conjunction with the continuity analysis, the breast configuration indicator would allow a surgeon to practically grasp the progress during the postsurgery revisits. In addition, the module derived from the proposed computer-aided breast configuration indicator could be of great use as a tool of communication between patients and surgeons. PMID- 19446289 TI - Appearance and location of secondary ossification centres may be explained by a reaction-diffusion mechanism. AB - We present here a mathematical model of chondrocytes hypertrophy, regulated by molecular factors, able to predict the onset of secondary ossification centres during long bones development. From the results obtained, we can conclude that the chemical feedback between two reactive molecular factors through a reaction diffusion mechanism could explain the stable spatial pattern found in the origination of secondary ossification centres, as well as the dependency of such a pattern on the size and shape of the bone head, in line with what has been observed in different animals. PMID- 19446290 TI - Hyperreactio luteinalis with both markedly elevated human chorionic gonadotropin levels and an imbalance of angiogenic factors subsequently developed severe early onset preeclampsia. AB - OBJECTIVE: To report a case of hyperreactio luteinalis (HL) with elevated levels of human chorionic gonadotropin (hCG) and a severe imbalance of angiogenic factors, which developed into severe, early onset preeclampsia (PE). DESIGN: Case report. SETTING: University perinatal center. PATIENT(S): A 32-year-old primigravida woman with HL, high hCG levels, and severe imbalance of angiogenic factors who subsequently developed severe PE. INTERVENTION(S): Emergent cesarean section due to nonreassuring fetal status. MAIN OUTCOME MEASURE(S): Severe, early onset PE. RESULT(S): A case of HL was referred to our hospital for remarkably elevated hCG levels and bilaterally enlarged multicystic ovaries in the first trimester; the patient subsequently developed severe, early onset PE with a severe imbalance of angiogenic factors. Emergency cesarean section was performed, and she delivered a premature female infant weighing 1818 g at 32 week's gestational age. During her next pregnancy, the circulating levels of hCG and angiogenic factors remained normal, and she did not develop either PE or HL. CONCLUSION(S): Although HL complicated with PE is very rare, our case suggests that HL associated with both an elevated hCG level and an imbalance of angiogenic factors might be a risk/predictive factor for severe, early onset PE. PMID- 19446292 TI - Chymase activity is closely related with plaque vulnerability in a hamster model of atherosclerosis. AB - OBJECTIVE: To test the hypothesis that stimulation of chymase secretion may contribute to plaque vulnerability and inhibition of chymase activity may enhance plaque stability. METHODS AND RESULTS: Sixty eight-week-old male Syrian golden hamsters were randomly divided into normal control group, high-cholesterol (HC) treated group, HC+ovalbumin treated group and HC+tranilast treated group. The normal control group received a normal diet while the other three intervention groups received a high-cholesterol diet for 15 weeks. Hamsters in the HC+ovalbumin treated group underwent transcatheter pharmacological triggering at the end of week 15 after antigen sensitization and those in the HC+tranilast treated group were given tranilast intragastrically for 3 weeks before euthanasia. Serological, ultrasonographic, pathologic, immunohistochemical, and gene expression studies were performed in all animals. The total number of mast cells, proportion of degranulated mast cells and the number of extracellular granules in plaques, the apoptosis rate of vascular smooth cells, the local activities of chymase, the concentration of Ang II and the expression levels of inflammatory markers as well as plaque vulnerability index all increased significantly in HC+ovalbumin treated group, but remarkably decreased in HC+tranilast treated group, in comparison with the HC treated group. These results suggest that stimulation of chymase secretion contributes to plaque vulnerability while inhibition of chymase activity enhances plaque stability. We conclude that chymase activity provides a promising therapeutic target in the stabilization of atherosclerotic plaques. PMID- 19446293 TI - Relation of baseline plasma phospholipid transfer protein (PLTP) activity to left ventricular systolic dysfunction in patients referred for coronary angiography. AB - Phospholipid transfer protein (PLTP) is an important modulator of phospholipid transfer and exchange among proteins. It also plays a role in inflammation and oxidative stress. Accordingly, PLTP has been implicated in the development of atherosclerosis. Left ventricular (LV) systolic dysfunction is common in patients with atherosclerosis, and both inflammation and oxidative stress have also been implicated in its development and progression. The goal of the present study was to examine the relation between plasma PLTP activity and LV systolic function. Baseline plasma PLTP activity was measured in 389 male patients referred for coronary angiography for a variety of indications. Detailed clinical, angiographic and laboratory characteristics were available for the patients. Compared to those patients with normal LV function (defined as an ejection fraction of >or=55% on ventriculography), patients with any degree of LV dysfunction had elevated PLTP activity (median PLTP 17.8 pmol/microl/h versus 15.9 pmol/microl/h, p=0.0038). Using multivariate analysis, and adjusting for a variety of confounding variables known to affect both LV function and PLTP activity, PLTP activity was an independent predictor of the presence of any left ventricular systolic dysfunction in the entire population (OR 1.47, 95% CI 1.12 1.93, p=0.0052). Furthermore, PLTP activity was an independent predictor of the presence of LV dysfunction in both patients with and without myocardial infarction on presentation (OR 2.39, 95% CI 1.18-4.86, p=0.0161 and OR 1.41, 95% CI 1.05-1.89, p=0.0206, respectively). In conclusion, PLTP activity may represent a novel marker of LV systolic dysfunction in patients with known or suspected coronary artery disease. PMID- 19446294 TI - Is slow walking more stable? AB - Several efforts have been made to study gait stability using measures derived from nonlinear time-series analysis. The maximum finite time Lyapunov exponent (lambda(max)) quantifies how a system responds to an infinitesimally small perturbation. Recent studies suggested that slow walking leads to lower lambda(max) values, and thus is more stable than fast walking, but these studies suffer from methodological limitations. We studied the effects of walking speed on the amount of kinematic variability and stability in human walking. Trunk motions of 15 healthy volunteers were recorded in 3D during 2 min of treadmill walking at different speeds. From those time series, maximum Lyapunov exponents, indicating short-term and long-term divergence (lambda(S-stride) and lambda(L stride)), and mean standard deviation (MeanSD) were calculated. lambda(S-stride) showed a linear decrease with increasing speed for forward-backward (AP) movements and quadratic effects (inverted U-shaped) for medio-lateral (ML) and up down (VT) movements. lambda(L-stride) showed a quadratic effect (inverted U shaped) of walking speed for AP movements, a linear decrease for ML movements, and a linear increase for VT movements. Moreover, positive correlations between lambda(S) and MeanSD were found for all directions, while lambda(L-stride) and MeanSD were correlated negatively in the AP direction. The different effects of walking speed on lambda(S-stride) and lambda(L-stride) for the different planes suggest that slow walking is not necessarily more stable than fast walking. The absence of a consistent pattern of correlations between lambda(L-stride) and MeanSD over the three directions suggests that variability and stability reflect, at least to a degree, different properties of the dynamics of walking. PMID- 19446295 TI - Adaptive glenoid bone remodeling simulation. AB - Glenoid prosthesis loosening is the most common cause for revision total shoulder arthroplasty. Stress-induced bone remodeling may compromise long-term prosthesis fixation and significantly contribute to loosening. Realistic, robust analysis of bone-prosthesis constructs need to look beyond initial post-implantation mechanics provided by static finite element (FE) simulation. Adaptive bone remodeling simulations based on Wolff's law are needed for evaluating long-term glenoid prostheses fixation. The purpose of this study was to take a first step towards this goal and create and validate two-dimensional FE simulations, using the intact glenoid, for computing subject-specific adaptive glenoid remodeling. Two-dimensional glenoid FE models were created from scapulae computed tomography images. Two distinct processes, "element" and "node" simulations, used the forward-Euler method to compute bone remodeling. Initial bone density was homogeneous. Center and offset load combinations were iteratively applied. To validate the simulations we performed location-specific statistical comparisons between predicted and actual bone density, load combinations, and "element" and "node" processes. Visually and quantitatively "element" simulations produced better results (p>0.22), and correlation coefficients ranged 0.51-0.69 (p<0.001). Having met this initial work's goals, we expect subject-specific FE glenoid bone remodeling simulations together with static FE stress analyses to be effective tools for designing and evaluating glenoid prostheses. PMID- 19446296 TI - Offering proper feedback to control for out-of-plane lumbar moments influences the activity of trunk muscles during unidirectional isometric trunk exertions. AB - The assessment of trunk muscle activation and coordination using dynamometric measurements made in one anatomical plane has hardly minimized the production of out-of-plane coupled moments (CMs). This absence of control may add much variability in moment component partition as well as in recorded muscle activation. The aim of the study was to assess whether providing these CMs as visual feedback efficiently reduces them and whether this feedback influences trunk muscle activation. Twenty men performed five 5-s static ramp submaximal contractions, ranging from 0% to 55% of the maximal voluntary contraction (MVC), in six different directions while standing in a static dynamometer measuring L5/S1 moments. For each direction, four feedback conditions were offered, ranging from simple 1D-feedback in the primary plane of exertion, to full 3D-feedback. Surface electromyographic signals were collected for eight back and six abdominal muscles. Muscle activation amplitudes and CMs were extracted at each 10% force level from 10% to 50% maximum voluntary contraction (MVC). Providing 3D-feedback significantly reduced the CMs, at 50% MVC, by about 1-6%, 1-8% and 2-10% MVC in the sagittal, frontal and transverse planes, respectively. Providing 3D-feedback produced relatively small systematic effects (2-7%) on trunk muscle activation. However, the subjects responded differently to adequately control the coupled moments, leading in some cases to relatively high inter-individual differences in muscle activation. Interestingly, the statistical differences, and size of the effects, were mainly observed when the primary exertions were performed in the frontal and transverse planes. The implications of these findings are discussed. PMID- 19446297 TI - Maximum allowable force on a safety harness cable to discriminate a successful from a failed balance recovery. AB - A safety harness system is essential to ensure participant safety in experiments at the threshold of balance recovery where avoiding a fall is not always possible. The purpose of this study was to propose a method to determine the maximum allowable force on a safety harness cable to discriminate a successful from a failed balance recovery. Data from 12 younger adults, who participated in experiments to determine the maximum forward lean angles that participants could be suddenly released from and still recover balance using three different limits on the number of steps, were used. For each participant, the coefficients of an asymptotic exponential regression, between the maximum vertical force on the safety harness cable and the initial lean angle at each trial, were evaluated by a least squares method. A proposed threshold for the maximum allowable vertical force of five force constants ensured that the initial lean angle reached 99% of its steady state value with respect to its initial value. It should thus discriminate well a successful (below the threshold) from a failed (above the threshold) balance recovery. Furthermore, although the amplitude of the horizontal forces should not be neglected in safety harness system designs, the contributions of the medial-lateral and anterior-posterior forces can be neglected in experiments at the threshold of balance recovery. Finally, although our five force constants method could be used, the actual value obtained for the maximum allowable vertical force may vary with other safety harness systems and postural perturbations. PMID- 19446298 TI - Pre-staining paper chromatography method for quantification of gamma-aminobutyric acid. AB - The routine method of paper chromatography includes five steps: spotting, separating, drying, spraying/immersing and color development. In this paper, a pre-staining paper chromatography which only consisted of spotting, separating and color development was developed for quantitative analysis of gamma aminobutyric acid. Compared to the routine paper chromatography, the improved method is clean, rapid, inexpensive and reproducible. The effects of ninhydrin concentration, color temperature, color time and Cu(2+) concentration on the color yield in the ninhydrin reaction were optimized. And then the pre-staining paper chromatography coupled with vis spectrophotometry was applied to gamma aminobutyric acid quantification. The results indicated that the limit of detection was 0.05 mg mL(-1) and the linear range was from 0.5 to 20.0 mg mL(-1). Furthermore, an excellent correlation coefficient was observed with an R(2)=0.998. The method is accurate (RSD<2.64%), and has good recoveries (102.7 103.9%). The validation of the modified technique was verified by a HPLC method. PMID- 19446299 TI - Analysis of formose sugar and formaldehyde by high-performance liquid chromatography. AB - Formose sugar and formaldehyde (HCHO) were analyzed using high-performance liquid chromatography (HPLC) utilizing a CarboPac PA1 column (Dionex) and pulsed amperometric detection. This HPLC system was unsuitable for the analysis of formose sugar and HCHO and thus reducing sugars and unconverted HCHO were determined by endowing them with charges through a derivatization method using 2,4-dinitrophenylhydrazine. The separation and detection of compounds were performed by three Chromolith RP-C18 columns (Merck) and diode array detection, at a wavelength of 360 nm ultraviolet light, respectively. Lower sugars (except HCHO) showed some instabilities when the derivatized samples were kept for the extended periods of time. For C(5) and consecutive higher sugars, a certain derivatization time was necessary. In the present case (formose reaction with partial HCHO conversion), approximately 18 h may be a reasonable compromise for the derivatization reaction. A derivatization agent to compound mole ratio of up to 100:1 was required to complete the derivatization of C(4) and higher sugars. However, the analysis of C(4) and consecutive higher sugars is problematic for example due to overlapping of peaks or branched-chain sugars. PMID- 19446300 TI - Brains of apolipoprotein E deficient mice fed vitamin E deficient diets show alteration in handling alpha tocopherol injected into the cerebral ventricles. AB - Abnormal function of apolipoprotein E (apoE) has been implicated in the incidence of some neurological disorders including dementia. Our recent experiments have shown that apoE deficiency alters the dynamics of alpha tocopherol (vitamin E) handling by brain. In the current investigation, we examined the uptake and retention of tritium-labeled alpha tocopherol that was injected into the lateral cerebral ventricles of apoE-deficient and wild type mice that were fed vitamin E deficient diet. Eighteen weeks-old, male mice were fed vitamin E-deficient diets for 28 weeks. Labeled cholesterol was injected with the radioactive tocopherol and the cholesterol counts were used as internal standard. After an equilibration time of 48 h, radioactive alpha tocopherol levels in most brain regions were higher in apoE deficient animals when compared with the wild type. Along with our other data, this suggests that the clearance of vitamin E is slower in apoE deficient brains. Nearly all of the injected alpha tocopherol was unchanged in the brains of both apoE-deficient and wild type animals (even with the additional dietary stress of vitamin E deficiency) suggesting low turnover rate of tocopherol in brain. The data strongly suggest that apoE is a key protein involved with the transport and/or retention of alpha tocopherol in brain. PMID- 19446301 TI - [Towards a better prevention of venous thromboembolism]. PMID- 19446302 TI - [Venous thromboembolism risk and antithrombotic prophylaxis among patients admitted to Spanish hospitals (ENDORSE study)]. AB - BACKGROUND AND OBJECTIVES: The proportion of patients at risk of venous thromboembolism (VTE) in Spanish hospitals and, among those, the proportion who receive prophylaxis are not well known. The objective of this study was to obtain this information by means of the analysis of data from the Spanish centres that participated in the international ENDORSE study. METHODS: Cross-sectional study in 20 Spanish hospitals. VTE risk factors and VTE prophylaxis were assessed in all hospital inpatients, aged 18 years or over, admitted to a surgical ward, and 40 years or over admitted to a medical ward. The 7th Conference of the American College of Chest Physicians (ACCP) guidelines and recommendations were used as a reference to assess risk categories and the prophylaxis given to patients. RESULTS: 6.554 hospital beds were assessed, and 3.809 inpatients were enrolled; 2.069 (67,5%) were medical and 996 (32,5%) surgical. Based on the ACCP criteria, 1.878 (61,3%) were at risk for VTE, 1.140 (55,1%) were medical and 738 (74,1%) were surgical. According to the ACCP guidelines and recommendations, 731 medical patients at risk of VTE (64,1%, 95% CI 61,3%-66,9%) received appropriate prophylaxis, as compared to 605 (82%; 95% CI 79,2%-84,8%) surgical patients (p<0,001). CONCLUSIONS: VTE prophylaxis in the Spanish centres was more common in surgical patients than in medical patients. Nevertheless, it is still necessary to extend the VTE prophylaxis to a significant number of patients (29%) at high risk of VTE, particularly in medical wards. PMID- 19446303 TI - Benefits and risks from the national strategy for improvement of iodine nutrition in Bulgaria: study on schoolchildren living in a rural area. AB - OBJECTIVES: To assess the effectiveness of iodine prophylaxis in schoolchildren, living in a rural area in South Bulgaria, after the introduction of salt iodization. STUDY DESIGN: The study subjects were 114 schoolchildren (59 boys and 55 girls), aged 11-14 years, living in a rural area in Bulgaria. Urinary iodine concentration was used as an index of iodine intake. The iodine level in table salt used in the children's households was also monitored. METHODS: Iodine concentration was measured by the Sandell-Kolthoff reaction. The iodine content of samples of table salt was determined by redox titration. RESULTS: The median urinary iodine concentration of the inspected schoolchildren was >200 microg/l, which indicates that iodine intake is more than adequate. An unfavourable result of the study was that 52.6% of the schoolchildren had more than adequate or excessive iodine intake. The hypothesis that this iodine overload may be due to poorly controlled salt iodization was confirmed by monitoring the iodine content in samples of table salt; three of six specimens contained iodine above the recommended level. DISCUSSION: Although the results indicated that the national strategy has had a positive effect on iodine-deficiency disorders, excessive iodization during the production of table salt and excessive consumption may be potential risks for the development of thyroid-related diseases. PMID- 19446304 TI - Accumulation of a 5' proximal subgenomic RNA of Citrus tristeza virus is correlated with encapsidation by the minor coat protein. AB - During replication, Citrus tristeza virus (CTV) produces large amounts of two unusual subgenomic (sg) RNAs that are positive-stranded and 5' coterminal. Although these RNAs are produced in similar amounts and are similar in size, with LMT1 ( approximately 750 nt) only slightly larger than LMT2 ( approximately 650), we found that the similar sgRNAs are produced differently. We previously showed that the LMT1 RNA is produced by premature termination during genomic RNA synthesis. However, LMT2 production was found to correlate with virion assembly instead of RNA replication. The time course of accumulation of the LMT2 RNA occurred late, coinciding with virion accumulation. The long flexuous virions of CTV contain two coat proteins that encapsidate the virions in a polar manner. The major coat protein encapsidates approximately 97% of the virion, while the minor capsid protein encapsidates the remainder of the genome beginning in the 5' non translated region with the transition zone at approximately 630 nucleotides from the 5' end. The section of the virion RNA that was encapsidated by CPm was identical in size to the LMT2 RNA, suggesting that the LMT2 RNA represented a portion of the viral RNA protected by CPm encapsidation. Mutations that abrogated encapsidation by CPm also abolished the accumulation of LMT2 RNA. Thus, these two unusual but similar RNAs are produced via different pathways, one from RNA replication and one processed by the virion assembly process. To our knowledge, this represents the first evidence of a viral RNA processed by the assembly mechanism. PMID- 19446306 TI - Size and shape variation in the proximal femur of Australopithecus africanus. AB - Aside from use as estimates of body mass dimorphism and fore to hind limb joint size comparisons, postcranial elements have not often contributed to assessments of variation in Australopithecus africanus. Meanwhile, cranial, facial, and dental size variation is interpreted to be high or moderately high. Further, the cranial base and face express patterns of structural (shape) variation, which are interpreted by some as evidence for the presence of multiple species. Here, the proximal femur is used to consider postcranial size and shape variation in A. africanus. Original fossils from Makapansgat and Sterkfontein, and samples from Homo, Pan, Gorilla, and Pongo were measured. Size variation was assessed by comparing the A. africanus coefficient of variation to bootstrapped distributions of coefficient of variation samples for each taxon. Shape variation was assessed from isometrically adjusted shape variables. First, the A. africanus standard deviation of log transformed shape variables was compared to bootstrapped distributions of logged standard deviations in each taxon. Second, shape variable based Euclidean distances between fossil pairs were compared to pairwise Euclidean distance distributions in each reference taxon. The degree of size variation in the A. africanus proximal femur is consistent with that of a single species, and is most comparable to Homo and Pan, lower than A. afarensis, and lower than some estimates of cranial and dental variation. Some, but not all, shape variables show more variation in A. africanus than in extant taxa. The degree of shape difference between some fossils exceeds the majority of pairwise differences in the reference taxa. Proximal femoral shape, but not size, variation is consistent with high estimates of A. africanus cranial variation. PMID- 19446305 TI - Altered interactions between stem-loop IV within the 5' noncoding region of coxsackievirus RNA and poly(rC) binding protein 2: effects on IRES-mediated translation and viral infectivity. AB - Coxsackievirus B3 (CVB3) is a causative agent of viral myocarditis, meningitis, pancreatitis, and encephalitis. Much of what is known about the coxsackievirus intracellular replication cycle is based on the information already known from a well-studied and closely related virus, poliovirus. Like that of poliovirus, the 5' noncoding region (5' NCR) of CVB3 genomic RNA contains secondary structures that function in both viral RNA replication and cap-independent translation initiation. For poliovirus IRES-mediated translation, the interaction of the cellular protein PCBP2 with a major secondary structure element (stem-loop IV) is required for gene expression. Previously, the complete secondary structure of the coxsackievirus 5' NCR was determined by chemical structure probing and overall, many of the RNA secondary structures bear significant similarity to those of poliovirus; however, the functions of the coxsackievirus IRES stem-loop structures have not been determined. Here we report that a CVB3 RNA secondary structure, stem-loop IV, folds similarly to poliovirus stem-loop IV and like its enterovirus counterpart, coxsackievirus stem-loop IV interacts with PCBP2. We used RNase foot-printing to identify RNA sequences protected following PCBP2 binding to coxsackievirus stem-loop IV. When nucleotide substitutions were separately engineered at two sites in coxsackievirus stem-loop IV to reduce PCBP2 binding, inhibition of IRES-mediated translation was observed. Both of these nucleotide substitutions were engineered into full-length CVB3 RNA and upon transfection into HeLa cells, the specific infectivities of both constructs were reduced and the recovered viruses displayed small-plaque phenotypes and slower growth kinetics compared to wild type virus. PMID- 19446307 TI - Late Pleistocene human evolution in Sicily: comparative morphometric analysis of Grotta di San Teodoro craniofacial remains. AB - The paleoanthropological remains from Grotta di San Teodoro near Acquedolci (province of Messina, Italy) represent the oldest and largest skeletal collection yet found documenting human settlement of Sicily. The sample, attributed to the Late Epigravettian (between 14,000 and 10,000 years B.P.), consists of seven variously complete adult individuals (San Teodoro 1-7). We compare the cranial sample to an array of both prehistoric and recent samples using multivariate techniques including D(2) distance analysis, canonical variate analysis, cluster analysis, and multidimensional scaling. Overall, the San Teodoro cranial sample displays a morphometric pattern close to Western European groups of similar antiquity, in particular those from Central and Southern Italy. The morphometric affinities indicate that these people probably came from peninsular Italy by sea during the Late Epigravettian epoch. An alternative hypothesis is that they descended from immigrants that arrived by land during a low sea level episode corresponding to the maximum Wurmian regression, about 18,000 years B.P, with gene flow accounting for the morphological homogeneity with the populations of peninsular Italy. The San Teodoro skeletal sample provides the first reliable evidence for human settlement of Sicily. PMID- 19446308 TI - Sexual difference in PCB concentrations of walleyes (Sander vitreus) from a pristine lake. AB - We determined polychlorinated biphenyl (PCB) concentrations in 15 adult female walleyes (Sander vitreus) and 15 adult male walleyes from South Manistique Lake (Michigan, United States), a relatively pristine lake with no point source inputs of PCBs. By measuring PCB concentration in gonads and in somatic tissue of the South Manistique Lake fish, we also estimated the expected change in PCB concentration due to spawning for both sexes. To determine whether gross growth efficiency differed between the sexes, we applied bioenergetics modeling. Results showed that, on average, adult males were 34% higher in PCB concentration than adult females in South Manistique Lake. Results from the PCB determinations of the gonads and somatic tissues revealed that shedding of the gametes led to 1% and 5% increases in PCB concentration for males and females, respectively. Therefore, shedding of the gametes could not explain the higher PCB concentration in adult male walleyes. Bioenergetics modeling results indicated that the sexual difference in PCB concentrations of South Manistique Lake walleyes was attributable, at least in part, to a sexual difference in gross growth efficiency (GGE). Adult female GGE was estimated to be up to 17% greater than adult male GGE. PMID- 19446309 TI - Emission reduction from diesel engine using fumigation methanol and diesel oxidation catalyst. AB - This study is aimed to investigate the combined application of fumigation methanol and a diesel oxidation catalyst for reducing emissions of an in-use diesel engine. Experiments were performed on a 4-cylinder naturally-aspirated direct-injection diesel engine operating at a constant speed of 1800 rev/min for five engine loads. The experimental results show that at low engine loads, the brake thermal efficiency decreases with increase in fumigation methanol; but at high loads, it slightly increases with increase in fumigation methanol. The fumigation method results in a significant increase in hydrocarbon (HC), carbon monoxide (CO), and nitrogen dioxide (NO(2)) emissions, but decrease in nitrogen oxides (NO(x)), smoke opacity and the particulate mass concentration. For the submicron particles, the total number of particles decreases. In all cases, there is little change in geometrical mean diameter of the particles. After catalytic conversion, the HC, CO, NO(2), particulate mass and particulate number concentrations were significantly reduced at medium to high engine loads; while the geometrical mean diameter of the particles becomes larger. Thus, the combined use of fumigation methanol and diesel oxidation catalyst leads to a reduction of HC, CO, NO(x), particulate mass and particulate number concentrations at medium to high engine loads. PMID- 19446310 TI - Degradation of C2-C15 volatile organic compounds in a landfill cover soil. AB - The composition of non-methane volatile organic compounds (hereafter VOCs) in i) the cover soil, at depths of 30, 50 and 70 cm, and ii) gas recovery wells from Case Passerini landfill site, (Florence, Italy) was determined by GC-MS. The study, based on the analysis of interstitial gases sampled along vertical profiles within the cover soil, was aimed to investigate the VOC behaviour as biogas transits from a reducing to a relatively more oxidizing environment. A total of 48 and 63 different VOCs were identified in the soil and well gases, respectively. Aromatics represent the dominant group (71.5% of total VOC) in soil gases, followed by alkanes (6.8%), ketones (5.7%), organic acids (5.2%), aldehydes (3.0%), esters (2.6%), halogenated compounds (2.1%) and terpenes (1.3%). Cyclics, heterocyclics, S-bearing compounds and phenols are 6 months after treatment. With a median follow-up of 31.5 months (range 5.9-57.3), estimated median survival was 52.0 months and median progression-free survival 25.74 (8.4-57.3) months (95% CI, 21.2-30.3). Overall and complete response rates were 92.1% and 64.1% respectively. CONCLUSION: Weekly carboplatin and paclitaxel as the initial chemotherapy for EOC is a feasible and well tolerated regimen and should be further evaluated in a larger phase III study. PMID- 19446319 TI - Multicenter analysis of recurrence and survival in stage IIIA endometrial cancer. AB - OBJECTIVE: To determine factors related to recurrence and survival in women with stage IIIA endometrial cancer; to examine outcomes of women with IIIA1 disease. METHODS: Multi-institutional analysis of women with stage IIIA endometrial carcinoma undergoing hysterectomy, bilateral salpingo-oophorectomy, lymphadenectomy, and pelvic cytology between 1980 and 2008. Overall survival (OS) and recurrence-free disease specific survival (RFDSS) were compared using Kaplan Meier method, univariate and multivariate analyses. RESULTS: 98 women underwent surgical staging for stage IIIA endometrial carcinoma. Pelvic washings were positive in 53%, serosa in 18%, and adnexae in 45%. Forty were IIIA1; 58 were IIIA2 (adnexal/serosal involvement). Median number of lymph nodes was 19 (range 1 73). Adjuvant treatment was given to 88%: radiotherapy--21%, chemotherapy - 19%, chemotherapy and radiotherapy--19%, hormonal therapy--16%, and intraperitoneal P 32 - 11%. Five-year OS and RFDSS for IIIA1 were 77% and 76%, respectively; and for IIIA2 were 75% and 73%, respectively (p=NS for both). Patients with IIIA1 disease were less likely to receive chemotherapy or radiotherapy than those with IIIA2 disease (p=0.0035). Older age (Hazard ratio 1.24; 95% CI 1.00-1.54), non Caucasian race (HR 5.35; 95% CI 1.96-14.5), and cervical metastases (HR 3.3; 95% CI 1.3-8.7) predicted lower RFDSS in multivariate analysis. Among 24 patients meeting NCCN's observation criteria (IIIA1, non-serous, and FIGO grade 1-2), 0/12 receiving adjuvant treatment recurred, while 1/12 not receiving adjuvant treatment recurred. CONCLUSIONS: Surgically assessed stage IIIA endometrial adenocarcinoma recurs in approximately 20-25% of cases. A subset of stage IIIA1 with very low risk factors may be appropriate candidates for observation. PMID- 19446320 TI - Topotecan combined with carboplatin in recurrent epithelial ovarian cancer: results of a single-institutional phase II study. AB - OBJECTIVE: The aim of this trial was to investigate the efficacy and toxicity of a relative high-dose of topotecan combined with carboplatin in recurrent or persistent epithelial ovarian cancer (EOC). METHODS: Patients participating in this phase II trial received topotecan at a dose of 1.0 mg/m(2)/day intravenously (IV) on days 1 to 5 in combination with carboplatin AUC 5 IV on day 5, every 21 days. The primary outcome was response rate (RR) and the toxicity. The secondary measurements were duration of response, time to progression (TTP) and overall survival (OS). RESULTS: Fifty-nine patients entered the study and 53 were assessable for response. For this study, 260 courses of topotecan and carboplatin were given (median, 4 per patient; range, 1-8). The overall RR was 26.4%. The median duration of response and TTP were 7 and 6 months, respectively. The median OS was 19 months with a median follow-up period of 14 months. Initial platinum sensitivity and treatment free interval (TFI) >or=6 months were associated with RR and OS. In the platinum-sensitive group, RR and OS were 40.0% and 25 months, whereas in the platinum-resistant group, these were 8.7% and 11 months, respectively. Grade 4 neutropenia occurred in 40.7% of the patients, and grade 4 thrombocytopenia was seen in 32.2% with a bleeding event in two patients. Nonhematologic toxicities were mild. There were no drug-related toxic deaths. CONCLUSION: The relative high-dose of topotecan combined with carboplatin was feasible and produced modest activity in recurrent or persistent EOC. The RR and survival data appear promising for the initially platinum-sensitive cohort and thus this regimen may be considered for further development in this patient. PMID- 19446321 TI - DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. AB - The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival. PMID- 19446322 TI - Multiple assembly chaperones govern biogenesis of the proteasome regulatory particle base. AB - The central protease of eukaryotes, the 26S proteasome, has a 20S proteolytic core particle (CP) and an attached 19S regulatory particle (RP). The RP is further subdivided into lid and base subcomplexes. Little is known about RP assembly. Here, we show that four conserved assembly factors govern biogenesis of the yeast RP base. Nas2 forms a complex with the Rpt4 and Rpt5 ATPases and enhances 26S proteasome formation in vivo and in vitro. Other RP subcomplexes contain Hsm3, which is related to mammalian proteasome subunit S5b. Hsm3 also contributes to base assembly. Larger Hsm3-containing complexes include two additional proteins, Nas6 and Rpn14, which function as assembly chaperones as well. Specific deletion combinations affecting these four factors cause severe perturbations to RP assembly. Our results demonstrate that proteasomal RP biogenesis requires multiple, functionally overlapping chaperones and suggest a model in which subunits form specific subcomplexes that then assemble into the base. PMID- 19446323 TI - Multiple proteasome-interacting proteins assist the assembly of the yeast 19S regulatory particle. AB - The 26S proteasome is a highly conserved multisubunit protease that degrades ubiquitinated proteins in eukaryotic cells. The 26S proteasome consists of the proteolytic core particle (CP) and one or two 19S regulatory particles (RPs). Although the mechanisms of CP assembly are well described, the mechanism of RP assembly is largely unknown. Here, we show that four proteasome-interacting proteins (PIPs), Nas2/p27, Nas6/gankyrin, Rpn14/PAAF1, and Hsm3/S5b, bind specific Rpt subunits of the RP and interact each other genetically. Lack of these PIPs resulted in defective assembly of the 26S proteasome at an early stage, suggesting that these proteins are bona fide RP chaperones. Each of the RP chaperones formed distinct specific subassemblies of the base components and escorted them to mature RPs. Our results indicate that the RP assembly is a highly organized and elaborate process orchestrated by multiple proteasome dedicated chaperones. PMID- 19446324 TI - Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. AB - BACKGROUND: Long-term complications of critical illness include intensive care unit (ICU)-acquired weakness and neuropsychiatric disease. Immobilisation secondary to sedation might potentiate these problems. We assessed the efficacy of combining daily interruption of sedation with physical and occupational therapy on functional outcomes in patients receiving mechanical ventilation in intensive care. METHODS: Sedated adults (>/=18 years of age) in the ICU who had been on mechanical ventilation for less than 72 h, were expected to continue for at least 24 h, and who met criteria for baseline functional independence were eligible for enrolment in this randomised controlled trial at two university hospitals. We randomly assigned 104 patients by computer-generated, permuted block randomisation to early exercise and mobilisation (physical and occupational therapy) during periods of daily interruption of sedation (intervention; n=49) or to daily interruption of sedation with therapy as ordered by the primary care team (control; n=55). The primary endpoint-the number of patients returning to independent functional status at hospital discharge-was defined as the ability to perform six activities of daily living and the ability to walk independently. Therapists who undertook patient assessments were blinded to treatment assignment. Secondary endpoints included duration of delirium and ventilator-free days during the first 28 days of hospital stay. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00322010. FINDINGS: All 104 patients were included in the analysis. Return to independent functional status at hospital discharge occurred in 29 (59%) patients in the intervention group compared with 19 (35%) patients in the control group (p=0.02; odds ratio 2.7 [95% CI 1.2-6.1]). Patients in the intervention group had shorter duration of delirium (median 2.0 days, IQR 0.0-6.0 vs 4.0 days, 2.0-8.0; p=0.02), and more ventilator-free days (23.5 days, 7.4-25.6 vs 21.1 days, 0.0-23.8; p=0.05) during the 28-day follow-up period than did controls. There was one serious adverse event in 498 therapy sessions (desaturation less than 80%). Discontinuation of therapy as a result of patient instability occurred in 19 (4%) of all sessions, most commonly for perceived patient-ventilator asynchrony. INTERPRETATION: A strategy for whole-body rehabilitation-consisting of interruption of sedation and physical and occupational therapy in the earliest days of critical illness-was safe and well tolerated, and resulted in better functional outcomes at hospital discharge, a shorter duration of delirium, and more ventilator-free days compared with standard care. FUNDING: None. PMID- 19446325 TI - Could the UK lead the world in medical education and training? PMID- 19446326 TI - Statistical reporting in Chinese biomedical journals. PMID- 19446327 TI - Physical and occupational therapy during sedation stops. PMID- 19446328 TI - Improving social policy and practice: knowledge matters. PMID- 19446329 TI - The in vivo performance of biomagnetic hydroxyapatite nanoparticles in cancer hyperthermia therapy. AB - Hyperthermia therapy for cancer has drawn more and more attention these days. In this study, we conducted an in vivo cancer hyperthermia study of the new magnetic hydroxyapatite nanoparticles by a mouse model. The magnetic hydroxyapatite nanoparticles were first made by co-precipitation method with the addition of Fe(2+). Then, magnetic-HAP powder (mHAP) or pure HAP powder (HAP) was mixed with phosphate buffer solution (PBS), respectively. The mixture was injected around the tumor. In order to achieve hyperthermia, the mice were placed into an inductive heater with high frequency and alternating magnetic field. Only the mice which were injected with mHAP and had been treated inside the magnetic field showed dramatic reduction of tumor volume, in the 15-day observation period. No local recurrence was noted. The blood test of mice proved that mHAP powders possessed good biocompatibility and little toxicity when injected subcutaneously. Therefore, our new magnetic hydroxyapatite nanoparticles have demonstrated therapeutic effect in a mouse model with little toxicity. Further study should be done before its application inside the human body. PMID- 19446330 TI - Isolated CNS lymphoid blast crisis in a patient with imatinib-resistant chronic myelogenous leukemia: case report and review of the literature. PMID- 19446331 TI - Differential regulation of 11beta-hydroxysteroid dehydrogenase-1 by dexamethasone in glucocorticoid-sensitive and -resistant childhood lymphoblastic leukemia. AB - Glucocorticoid therapy forms a crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However, glucocorticoid resistance is a therapeutic problem with an unclear molecular mechanism. 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) is expressed in glucocorticoid target tissue, where it regenerates active glucocorticoids from inert 11keto-glucocorticoids, amplifying intracellular glucocorticoid levels. Here, we show 11beta-HSD1 expression in leukemic cells from ALL patients (n=14). 11beta-HSD1 was differentially regulated by glucocorticoids between glucocorticoid-sensitive and -resistant ALL cells. Dexamethasone increased 11beta-HSD1 mRNA levels in glucocorticoid-sensitive ALL cells, but decreased levels in the resistant group. Our data suggest that differential induction of 11beta-HSD1 contributes to the glucocorticoid sensitivity in leukemia. PMID- 19446332 TI - Unusual myeloma relapse after thalidomide therapy: the dark side of the moon? PMID- 19446333 TI - Population-level impacts of pesticide-induced chronic effects on individuals depend more on ecology than toxicology. AB - The current method for assessing long-term risk of pesticides to mammals in the EU is based on the individual rather than the population-level and lacks ecological realism. Hence there is little possibility for regulatory authorities to increase ecological realism and understanding of risks at the population level. Here we demonstrate how, using ABM modelling, assessments at the population-level can be obtained even for a pesticide with complex long-term effects such as epigenetic transmission of reproductive depression. By objectively fitting nonlinear models to the simulation outputs it was possible to compare population depression and recovery rates for a range of scenarios in which toxicity and exposure factors were varied. The system was differentially sensitive to the various factors, but vole ecology and behaviour were at least as important predictors of population-level effects as toxicology. This emphasises the need for greater focus on animal ecology in risk assessments. PMID- 19446334 TI - Phthalates in house dust. AB - The main objective of this study was to generate a fast analytical method to determine the five phthalates benzylbutylphthalate (BBP), dibutylphthalate (DBP), di-(2-ethylhexyl)-phthalate (DEHP), di-isodecylphthalate (DIDP), and di isononylphthalate (DINP) in house dust. To achieve this liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS) was used for measurement. The risk of lab- and cross-contamination was nearly eliminated completely as a very short and fast sample preparation including a sieving step and an ultrasonic extraction for the analytes from the dust samples was used. Quantification through internal standard calibration resulted in low limits of determination (DEHP 4 mg kg(-1) to DBP 14 mg kg(-1)). A potential interaction between the analytes DIDP and DINP during chromatographic measurement could be excluded while performing a two level factorial design. Furthermore it was examined to what extend carpet and plastic materials respectively have influence on the total amount of phthalates in dust. It could be shown that apartments in which a minimum of both of these sources appeared revealed the lowest total amount of sum of phthalates in dust (median 362 mg kg(-1)). PMID- 19446335 TI - Primary human hepatocytes are protected against complement by multiple regulators. AB - Inflammatory liver disorders are often associated with a potentially tissue damaging complement activation directly at the main site of complement protein synthesis. As hepatocytes may be the primary target of complement attack, we investigated the expression and protective capacity of soluble and membrane-bound complement regulatory proteins in primary human hepatocytes (PHH). Isolated PHHs were analyzed for their basal and cytokine-induced complement regulator expression by cytofluorometry, rtPCR, confocal laser microscopy and ELISA. Susceptibility to complement-mediated cell lysis was investigated with cytotoxicity tests. In contrast to previous reports, PHHs expressed CD46, CD55, CD59, soluble CD59 (sCD59) and factor H (fH), but not CD35. A low basal expression of CD55 was strongly enhanced by IFN-gamma, IL-1 beta and TNF-alpha. The expression of CD59 could be augmented by IL-1 beta, IL-6 and TNF-alpha but was suppressed by IFN-gamma. CD46 expression was not significantly altered. PHHs synthesized fH and sCD59 and fH was detected on PHH surface after exposure to IL 1 beta. Inhibition experiments revealed that CD59 was most effective in protecting PHHs from complement attack. These data clearly indicate that PHHs are protected by multiple complement regulatory proteins, which are controlled by proinflammatory cytokines. CD59 appears to be pivotal in protecting PHHs against complement-mediated lysis. PMID- 19446336 TI - Chicken scavenger receptors and their ligand-induced cellular immune responses. AB - The scavenger receptors (SRs) comprise structurally and functionally divergent groups of cell surface and secreted proteins that play an important role in innate immune defenses. Searching translated chicken genomic databases revealed many proteins homologous to mammalian SRs. SR mediated immune functions (oxidative burst, degranulation, phagocytosis, nitric oxide (NO) production, and cytokine expression) were evaluated in chicken heterophils, peripheral blood mononuclear cells (PBMC), and a chicken macrophage cell line (HD11) using various SR class A and B ligands. Results showed that the SR-A ligands, fucoidan, poly(I) and poly(G), but not SR-B ligands, phosphatidylserine and LDL, stimulated dose dependent NO production in HD11 cells. However, SR-A ligands failed to induce NO in chicken monocytes. Quantitative RT-PCR indicated that SR ligands differentially regulated the gene expression of cytokines and chemokine in HD11 cells with a strong up-regulation of the cytokines IL-1 beta and IL-6 and the chemokine MIP-1 beta, but had no effect on IL-4, IL-12, IFN-gamma, and IFN-beta. SR-B ligands did not alter expression of these genes. SR-A ligands had no stimulatory effect on functional response in heterophils. However, LDL, a SR-B ligand stimulated oxidative burst in both heterophils and PBMC. Additionally, results indicate that SRs are involved in bacterial binding in macrophages. PMID- 19446337 TI - Molecular characterization of tumor necrosis factor receptors 1 and 2 of the goldfish (Carassius aurutus L.). AB - Tumor necrosis factor alpha (TNFalpha) is a pleotropic cytokine that mediates its effects by binding to one of two TNF receptors, TNF-R1 or TNF-R2. We have recently identified the cDNA sequences of both goldfish TNF-R1 and TNF-R2. In silico analyses revealed conserved cysteine rich domains, predicted docking sites for TNFR-specific downstream signaling factors for both receptors and a conserved death domain for TNF-R1. The expression of these receptors in tissues and various immune cell types was investigated by Q-PCR. The TNF-R2 expression was substantially higher than that of TNF-R1 in all tissues. Both receptors were most robustly expressed in monocytes where as the mRNA levels of TNF-R1 were the lowest in mature macrophages and those of TNF-R2 in peripheral blood leukocytes. Treatment of goldfish macrophages with recombinant goldfish (rg) TNFalpha-2, rgIFN gamma or rgTGF beta differentially altered the expression of both TNF receptors. The rgTNF alpha-2 up-regulated the expression of TNF-R2 but down regulated the expression of TNF-R1. The rgIFN gamma increased the expression of both TNF receptors while rgTGF beta caused a time-dependent decreases in mRNA of goldfish TNF-R1 and TNF-R2. In vitro binding studies using recombinant TNFalpha-1 and TNFalpha-2 revealed that either isoform was capable of interacting with the recombinant forms of the extracellular domains of either TNF-R1 or TNF-R2. Functional significance of these ligand-receptor interactions was confirmed by experiments showing that goldfish TNF-R1 and TNF-R2 down-regulated the rgTNF alpha-1 or rgTNF alpha-2-primed respiratory burst response of goldfish macrophages. PMID- 19446338 TI - The human CD6 gene is transcriptionally regulated by RUNX and Ets transcription factors in T cells. AB - CD6 is a lymphocyte surface receptor involved in lymphocyte activation and differentiation processes that is constitutively expressed on developing and mature T cells and on the B1a cells. To define the molecular basis for the tissue specific expression of CD6 we have identified the transcription factors that control the activity of the proximal regulatory region of the human CD6 gene. The TATA-less CD6 promoter contains multiple transcriptional start sites, and its preferential activity in human T lymphocytes is dependent on RUNX- and Ets binding sites located within a highly conserved region. RUNX and Ets-1 factors transactivated the CD6 promoter through recognition of the -215 and -230 binding sites, respectively. Chromatin immunoprecipitation assays revealed that RUNX1 constitutively occupies the CD6 promoter in vivo, and knockdown experiments demonstrated that the steady-state level of CD6 mRNA is dependent on the expression of RUNX1, RUNX3 and Ets-1 transcription factors. Therefore, RUNX1/3 and Ets1 control the expression of CD6 in human T lymphocytes, thus expanding the range of T-cell specific and developmentally regulated lymphocyte gene targets involved in T-cell activation and differentiation. PMID- 19446339 TI - A pseudotype baculovirus-mediated vaccine confers protective immunity against lethal challenge with H5N1 avian influenza virus in mice and chickens. AB - Baculovirus has emerged recently as a novel and attractive gene delivery vehicle for mammalian cells. In this study, baculovirus pseudotyped with vesicular stomatitis virus glycoprotein was used as a vector to express the hemagglutinin (HA) protein of highly pathogenic H5N1 avian influenza virus, A/Chicken/Hubei/327/2004 (HB/327). The resultant recombinant baculovirus (BV-G HA) mediated gene delivery and HA expression efficiently in mammalian cells. Mice immunized with 1 x 10(9)PFU of BV-G-HA developed significantly higher levels of H5-specific antibodies and cellular immunity than those that received 100 microg of DNA vaccines expressing HA, and were completely protected from lethal challenge with HB/327. Different vaccination doses were further tested in chickens, and these experiments demonstrated that 1 x 10(8)PFU of BV-G-HA offered complete protection from challenge with 100 LD(50) of HB/327. These data indicate that the pseudotype baculovirus-mediated vaccine could be utilized as an alternative strategy against the pandemic spread of H5N1 influenza virus. PMID- 19446340 TI - Vaccination coverage rates in eleven European countries during two consecutive influenza seasons. AB - OBJECTIVES: This study assessed influenza vaccination coverage rates in eleven European countries during seasons 2006/07 and 2007/08. The aims were to analyse vaccine uptake rates in the general population and in high-risk groups, including children, as well as to understand the principal drivers and barriers towards vaccination. METHODS: Community-based face-to-face interviews, telephone surveys or mailed surveys were conducted in UK, Germany, Italy, France, Spain, Austria, Czech Republic, Finland, Ireland, Poland and Portugal. Approximately 2000 representative adult individuals per country and season were interviewed. Data on the vaccination status of children were obtained by proxy interviews. For the analysis, five target groups were defined. RESULTS: Vaccination coverage levels in the general population ranged from 9.5% (Poland) to 28.7% (UK) during season 2007/08. In comparison with the previous season, only minor increases were visible. The coverage in the elderly target group was highest at 70.2% in the UK and lowest at 13.9% in Poland. The vaccination rate of chronically ill persons ranged from 11.1% (Poland) to 56.0% (UK). Vaccination levels among health care workers were generally low. Vaccine uptake in children was lowest in Ireland (4.2%) and highest in Germany (19.3%). Respondents from all countries were aware of the seriousness of influenza as a disease. People who had never been vaccinated regarded being infected as unlikely. The advice from a family doctor or a nurse was deemed as the main encouraging factor for vaccination. CONCLUSIONS: During 2007/08, influenza vaccination coverage rates differed widely between countries, not only in the general population but also in the predefined at-risk groups. Generally, the increases in coverage compared to the previous season were marginal. Overcoming the barriers and implementing the driving forces identified by our surveys may help to increase vaccine uptake and to reach the corresponding WHO goals. PMID- 19446341 TI - Attachment representations in mothers of preterm infants. AB - The aim of the study was to assess attachment representations in mothers of preterm infants using the Working Model of Child Interview (WMCI) at the 12 months of the infant's corrected age. In addition, the relation between WMCI representation categories and the Edinburgh Postnatal Depression Scale score at 6 months of the infant's corrected age was studied. There were 38 mothers of preterm infants (<1500 g or <32 gestational weeks) and 45 mothers of full-term infants. The results showed no differences between the study groups in the distribution of the three main representation categories (balanced, disengaged and distorted). However, there were qualitative differences in representations between the groups. Furthermore, maternal depression symptoms were associated with distorted representation category. We suggest that despite the qualitative differences in the mothers' representations, mothers of preterm infants are as likely to form balanced attachments with their infants as mothers of full-term infants. PMID- 19446342 TI - Health related quality of life in recurrent depression: a comparison with a general population sample. AB - BACKGROUND: In the acute phase major depressive disorder (MDD) is a disabling disease. We compared HRQOL in patients with remitted MDD (rMDD) with a community sample and longitudinally assessed the relation between depressive symptoms and HRQOL in recurrently depressed patients. METHODS: We used 12-month data of patients from the Depression Evaluation Longitudinal Therapy Assessment (DELTA) study. HRQOL was assessed with the Medical Outcome Short Form (SF-36). Remission was determined with the Structured Clinical Interview for DSM-IV and depressive symptoms were assessed with the Beck Depression Inventory. Patients' mean SF-36 scores were compared with those of an age- and sex-matched Dutch reference population. The longitudinal relation between levels of SF-36 and levels of depressive symptomatology was assessed with a repeated measures linear regression analysis using the mixed models module. RESULTS: In patients with rMDD in the remitted phase, especially in women, both physical and mental HRQOL was lower than in a Dutch population sample. An increase in the level of depressive symptoms corresponded to a decrease in all scales of the SF-36. CONCLUSION: Also in remitted rMDD patients, especially in women, HRQOL is lower than in the general population which emphasizes that also in this phase of recurrent depression HRQOL deserves attention. Furthermore, in patients with rMDD a higher depressive symptom severity level is associated with a lower HRQOL. These findings imply that residual symptoms should be treated aggressively and HRQOL enhancement therapies should be developed. PMID- 19446343 TI - Regionally-specific changes in levels of tumour necrosis factor in the dorsolateral prefrontal cortex obtained postmortem from subjects with major depressive disorder. AB - BACKGROUND: From studies in the periphery, changed levels of tumour necrosis factor (TNF) have been implicated in the pathophysiology of major depressive disorders (MDD). Therefore we decided to determine whether TNF was altered in the frontal cortex (Brodmann's areas (BA) 24 and 46) from 10 subjects with MDD and 10 control subjects. METHODS: Tissue homogenates were prepared from the left hemisphere and levels of TNF trans-membrane (tmTNF) and TNF soluble (sTNF) forms measured by Western blots. RESULTS: tmTNF was significantly increased in BA 46 (mean+/-SEM: 7.70+/-0.92 vs. 3.18+/-0.87 Ratio Internal Control, p<0.001), but not BA 24, from subjects with MDD, there was no change in levels of sTNF in either CNS region. LIMITATIONS: As the report of tmTNF in postmortem CNS from subjects with MDD, our findings need to be replicated in another group of cases. CONCLUSIONS: Our data supports the hypothesis that changes in pro-inflammatory pathways may be involved in the pathophysiology of MDD. Targeting these pathways may be a new approach to treating the disorder. PMID- 19446344 TI - TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. AB - This study was undertaken to determine the effect of toll-like receptor-3 (TLR3) on the regulation of osteoclastogenic activity in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). The expression of receptor activator of nuclear factor kappa B ligand (RANKL) mRNA and protein in RA-FLS after TLR3 activation was determined using RT-PCR, real-time PCR, western blot analysis, and immunohistochemistry. Human monocytes were cocultured with RA-FLS that had been prestimulated by the TLR3 ligand polyriboinosinic-polyribocytidylic acid and then stained for tartrate-resistant acid phosphatase (TRAP) activity. Other markers of osteoclasts were measured using RT-PCR and real-time PCR. The expression of TLR3 and RANKL was much higher in the RA synovium than in the osteoarthritis (OA) synovium. TLR3 activation induced RANKL expression in RA-FLS, but not in OA-FLS or in normal skin fibroblasts. TLR3 activation also induced the production of IL 1beta but had no effect on IL-17 or TNF-alpha production in RA-FLS. Inhibition of IL-1beta reversed the TLR3-induced upregulation of RANKL expression. Coculture of human monocytes with TLR3-activated RA-FLS or TLR3 ligand-stimulated human monocytes increased the expression of TRAP, RANK, cathepsin K, calcitonin receptor, and MMP-9, reflecting the differentiation of monocytes into osteoclasts. Our results suggest that TLR3 promotes osteoclastogenesis in the RA synovium both directly and indirectly. TLR3 stimulates human monocytes directly to promote osteoclast differentiation. TLR3 induces RANKL expression indirectly in RA-FLS, and the expression of RANKL promotes the differentiation of osteoclasts in the RA synovium. Targeting the TLR3 pathway may be a promising approach to preventing inflammatory bone destruction in RA. PMID- 19446345 TI - Increased rat serum corticosterone suggests immunomodulation by stimulation of the vagal nerve. AB - The role of the vagal nerve within the immune system has not been fully elucidated. Vagal afferents connect to several central nervous system structures, including the hypothalamus. We investigated the effect of vagal nerve stimulation (VNS) on serum corticosterone levels in rats. Corticosterone levels were measured following 1 h of high frequency (30 Hz) or low frequency (1 Hz) VNS in awake animals. There was a significant increase (p < 0.05) in serum corticosterone levels following 30 Hz VNS compared to 1 Hz VNS or sham stimulation. These results suggest an immediate effect of VNS on the hypothalamic pituitary-adrenal (HPA) axis and support the role of the vagal nerve in immunomodulation. PMID- 19446346 TI - The biology of PGC-1alpha and its therapeutic potential. AB - In eukaryotes, cellular and systemic metabolism is primarily controlled by mitochondrial activity. The peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is an important regulator of mitochondrial biogenesis and function. Furthermore, PGC-1alpha controls many of the phenotypic adaptations of oxidative tissues to external and internal perturbations. By contrast, dysregulated metabolic plasticity is involved in the etiology of numerous diseases. Accordingly, modulation of PGC-1alpha levels and activity has recently been proposed as a therapeutic option for several pathologies. However, pharmacological interventions aimed at PGC-1alpha have to overcome inherent limitations of targeting a coactivator protein. Here, I focus on the recent breakthroughs in the identification of physiological and pathophysiological contexts involving PGC-1alpha. In addition, perspectives regarding the therapeutic importance of PGC-1alpha-controlled cellular and systemic metabolism are outlined. PMID- 19446347 TI - Potential pharmacological control of the NF-kappaB pathway. AB - Nuclear factor (NF)-kappaB governs the expression of numerous genes that are important for various cellular responses. Its activation is induced by a wide variety of stimuli including stress, cigarette smoke, viral and bacterial products, cytokines, free radicals, carcinogens and tumor promoters to name a few. Deregulation of the NF-kappaB pathway has been observed in and attributed to the development of a variety of human ailments including cancers, autoimmune disorders, pulmonary, cardiovascular, neurodegenerative and skin diseases. Efforts to develop modulators of NF-kappaB have yielded several candidates, some of which are currently in Phase I/II of clinical trials. In addition, it is now becoming apparent that several of the approved drugs being currently used also work, in part, owing to their ability to influence the NF-kappaB pathway. In this article, we focus on the druggable components of the NF-kappaB signaling system and on the recent development of novel therapeutics that target NF-kappaB in various diseases. PMID- 19446348 TI - Functional imaging of the human dopaminergic midbrain. AB - Invasive recording of dopamine neurons in the substantia nigra and ventral tegmental area (SN/VTA) of behaving animals suggests a role for these neurons in reward learning and novelty processing. In humans, functional magnetic resonance imaging (fMRI) is currently the only non-invasive event-related method to measure SN/VTA activity, but it is debated to what extent fMRI enables inference about dopaminergic responses within the SN/VTA. We consider the anatomical and functional parcellation of the primate SN/VTA and find that its homogeneity suggests little variation in the regional specificity of fMRI signals for reward related dopaminergic responses. Hence, these responses seem to be well captured by the compound fMRI signal from the SN/VTA, which seems quantitatively related to dopamine release in positron emission tomography (PET). We outline how systematic investigation of the functional parcellation of the SN/VTA in animals, new developments in fMRI analysis and combined PET-fMRI studies can narrow the gap between fMRI and dopaminergic neurotransmission. PMID- 19446349 TI - CA125 levels among patients with advanced heart failure: an emerging independent predictor for survival. AB - Serum CA125, a high-molecular weight glycoprotein, is a tumor marker widely used for the diagnosis and follow-up of patients with ovarian cancer in clinical practice. Recently, increased serum CA125 values, in parallel with catecholamines and natriuretic peptides, have also been documented in patients with heart failure. As far as the relationship between CA125 and cardiac dysfunction is concerned; interleukin-6, interleukin-10, and tumor necrosis factor-alpha, which are all elevated in heart failure, might play a pivotal role, since there are data suggesting that the proliferation of CA125-producing cells is induced by proinflammatory cytokine network. However, little is known about the biologic role of this substance: whether it simply reflects the increased activation of the cytokine pathway (or other pathophysiologic pathways), or whether CA125 is an active substance truly responsible for myocardial and/or peripheral dysfunction. Further insight to the precise determinants for increased CA125 levels in this population would help establish the clinical usefulness of this emerging marker in predicting survival. PMID- 19446350 TI - Negative pressure pulmonary edema complicating an electrophysiological study. AB - We report on a case of acute non-cardiogenic negative-pressure pulmonary edema developed during an ablation procedure of an accessory pathway in a patient with no structural heart disease. That potentially serious complication has not been previously reported during an interventional cardiology procedure. PMID- 19446351 TI - Determination of the essential nutrient requirements of wine-related bacteria from the genera Oenococcus and Lactobacillus. AB - Wine lactic acid bacteria (LAB) are responsible for the malolactic fermentation (MLF) in wine production. Wine LAB have fastidious nutrient requirements but their auxotrophies remain little studied. The ability of specific wine nutrients to meet the nutritional requirements of wine LAB, and thus support MLF, remains unclear. This work investigated the essential growth requirements of four strains of wine LAB from the genera Oenococcus and Lactobacillus using the single omission technique with a suitable chemically defined medium. For the determination of auxotrophies, at least 3 (and up to 15) subcultures in deficient media were made, and intra- and extracellular nutrient carry over was reduced by small inoculation rates and washing cells 3 times between transfers. This careful methodology revealed more auxotrophies than those described for wine LAB in the literature. The essential bacterial nutrient requirements were found to be strain specific. 10 compounds were essential for all wine LAB tested, the carbon and phosphate source, manganese, as well as several amino acids (proline, arginine and the branched amino acids valine, leucine and isoleucine) and vitamins (nicotinic acid and pantothenic acids). Nucleotides were not essential for any of the bacteria studied. The two Oenococcus oeni strains revealed a larger number of auxotrophies (18 and 21) and had a higher degree of nutritional similarity (86%) defined as percentage of common requirements per maximum total requirements. The two Lactobacillus strains only had 11 and 14 auxotrophies and the similarity was 79%, but both were auxotroph for riboflavin, which was not needed by the O. oeni strains. Data on the common requirements may be used to further study the ability of wines or commercial nutrients to support MLF and to consider the microbiological stability of finished wines. The results indicate that absence of riboflavin in oenological nutrient preparations may allow to create a specific advantage for indigenous or inoculated O. oeni, which are generally desired for MLF. PMID- 19446352 TI - Bacteriocin production by Pediococcus pentosaceus isolated from marula (Scerocarya birrea). AB - Strain ST44AM, isolated from marula, was identified as Pediococcus pentosaceus based on biochemical tests, sugar fermentation reactions (API 50CHL), PCR with species-specific primers and 16S rDNA sequencing. Strain ST44AM produces a 6.5 kDa class IIa bacteriocin, active against lactic acid bacteria, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Listeria innocua, Listeria ivanovii subsp. ivanovii and Listeria monocytogenes. The peptide is inactivated by proteolytic enzymes, but not when treated with alpha-amylase, Triton X-100, Triton X-114, SDS, Tween 20, Tween 80, urea, NaCl and EDTA. No change in activity was recorded after 2 h at pH values between 2.0 and 12.0, and after treatment at 100 degrees C for 120 min or 121 degrees C for 20 min. The mode of activity against L. ivanovii susbp. ivanovii ATCC19119 and Enterococcus faecium HKLHS is bactericidal, resulting in cell lyses and enzyme- and DNA-leakage. No significant differences in cell growth and bacteriocin production were observed when strain ST44AM was cultured in MRS broth at 26 degrees C, 30 degrees C and 37 degrees C for 24 h and tested against the same target strain. L. ivanovii subsp. ivanovii ATCC 19119 and E. faecium HKLHS did, however, differ in sensitivity to bacteriocin ST44AM (3.3x10(6) AU/mL and 2.6x10(4) AU/mL, respectively). Peptide ST44AM adsorbs at high levels (1600 AU/mL) to producer cells. Bacteriocin ST44AM may be a derivative of pediocin PA-1. This is the first report on the presence of P. pentosaceus in marula and a pediocin PA-1 derivative produced by this species. We are also the first to report on the synergetic effect ciprofloxacin has on a pediocin-like bacteriocin. PMID- 19446353 TI - Microalgae and terrestrial biomass as source for fuels--a process view. AB - Due to increasing oil prices and climate change concerns, biofuels have become more important as potential alternative energy sources. It is an open question which kind of biofuels with which yield potentials, characteristic properties and environmental consequences should give the largest contributions. Microalgae offer novel aquatic biomass systems with higher fuel yield potential and lower water demand than terrestrial biomass. They allow the direct generation of desired end products like biooil, hydrogen, or of materials to be processed afterwards (like starch, biomass). Research and development activities at present include fundamentals of algae strain improvement, reactor design and process integration, with auxiliary power requirements and specific reactor cost being addressed as most critical issues. PMID- 19446355 TI - Glucose tolerance in pregnancy and the long-term risk of cardiovascular disease. AB - BACKGROUND: Studies demonstrate an association between high but non-diabetic blood glucose levels and cardiovascular morbidity and mortality. Pregnancy alters glucose metabolism and results in a continuum of glucose tolerance, it is not known whether this continuum is associated with a continuum of risk of CVD in later life. OBJECTIVES: To examine the long-term risk of CVD associated with the continuum of maternal glucose tolerance. PARTICIPANTS: Nine hundred and seventeen participants assessed during pregnancy and followed over 20 years. MEASUREMENTS: Smoking behaviour, BMI at index pregnancy and follow-up, and gestational HbA1c. MAIN OUTCOME: Requiring medication for hypertension and CVD, and hospital admissions for CVD as ascertained by record linkage over 20-year period. RESULTS: Fifty-one women had a history of CVD, 85 women had hypertension and 17 women (2.3%) were admitted for CVD. There was a significant increase in the risk for CVD, hypertension and hospitalisation for CVD across the quartiles of gestational HbA1c after adjustment for known risk factors. This increased risk reached statistical significance in the highest quartile although confidence intervals were wide. CONCLUSION: Sub-clinical HbA1c during pregnancy was associated with a dose-related increase in the presence of medication and hospital admission for CVD. The magnitude of these effects is of note. PMID- 19446354 TI - Near-optimal glycemic control in Chilean women with pregestational type-2 diabetes: persistent macrosomia relates to maternal pre-pregnancy overweight. AB - After a 10-year program intending to improve glycemic control in diabetic pregnancies, we evaluated whether factors underlying macrosomia are similar for type-1 and -2 pregestational diabetic women. PATIENTS AND METHODS: Twenty-three pregnancies in type-1 diabetics (PDM1, age 28.3+/-1.1 years) and 51 pregnancies in type-2 diabetics (PDM2, age 32.8+/-0.6 years) were followed and treated with intensified insulin therapy. Several factors potentially influencing macrosomia were evaluated. STATISTICS: chi-square, Fisher's exact, Student's "t" and Mann Whitney "U" tests, and ROC analysis. RESULTS: In PDM1 and PDM2, respectively, large-for-gestational-age (LGA) frequencies were 26.08% and 37.25% (NS), antepartum HbA1c values were 6.5+/-0.32 and 6.1+/-0.16 (NS), and pre-pregnancy body mass indexes (BMI) were 23.03+/-0.66 and 30.01+/-0.89 (p<0.0001). In PDM1 the main predictor of LGA was an antepartum HbA1c> or =6.8% (p=0.046), whereas in PDM2 pregestational BMI> or =24 the variable associated (p=0.032) with LGA newborns. CONCLUSIONS: PDM1 and PDM2 differ in the underlying factors related to macrosomia. Whereas in PDM1 the antepartum HbA1c emerged as the most significant variable, suggesting that glycemic control largely determines macrosomia, in PDM2 with near-optimal glycemic control, macrosomia related to pregestational BMI. PMID- 19446356 TI - Activity-based costing evaluation of a [(18)F]-fludeoxyglucose positron emission tomography study. AB - OBJECTIVE: The aim of the study is to use the activity-based costing approach to give a better insight in the actual cost structure of a positron emission tomography procedure (FDG-PET) by defining the constituting components and by simulating the impact of possible resource or practice changes. METHODS: The cost data were obtained from the hospital administration, personnel and vendor interviews as well as from structured questionnaires. A process map separates the process in 16 patient- and non-patient-related activities, to which the detailed cost data are related. One-way sensitivity analyses shows to which degree of uncertainty the different parameters affect the individual cost and evaluate the impact of possible resource or practice changes like the acquisition of a hybrid PET/CT device, the patient throughput or the sales price of a 370MBq (18)F-FDG patient dose. RESULTS: The PET centre spends 73% of time in clinical activities and the resting time after injection of the tracer (42%) is the single largest departmental cost element. The tracer cost and the operational time have the most influence on cost per procedure. The analysis shows a total cost per FDG-PET ranging from 859 Euro for a BGO PET camera to 1142 Euro for a 16 slices PET-CT system, with a distribution of the resource costs in decreasing order: materials (44%), equipment (24%), wage (16%), space (6%) and hospital overhead (10%). CONCLUSIONS: The cost of FDG-PET is mainly influenced by the cost of the radiopharmaceutical. Therefore, the latter rather than the operational time should be reduced in order to improve its cost-effectiveness. PMID- 19446357 TI - Understanding the neurogenetics of sleep: progress from Drosophila. AB - Most behaviors manifest themselves through interactions with environments. Sleep, however, is characterized by immobility and reduced responsiveness. Although nearly all animals sleep, the purpose of sleep remains an enduring puzzle. Drosophila melanogaster exhibits all the behavioral characteristics of mammalian sleep, enabling the use of powerful genetic approaches to dissect conserved fundamental neurogenetic aspects of sleep. Drosophila studies over the past four years have identified novel genes and pathways modulating sleep, such as Shaker and sleepless, and candidate brain regions known to function in circadian regulation and learning and memory. Advances in systems genetics coupled with the ability to target specific brain regions enable the characterization of transcriptional networks and neural circuits contributing to phenotypic variation in sleep. PMID- 19446358 TI - A multidimensional segmentation evaluation for medical image data. AB - Evaluation of segmentation methods is a crucial aspect in image processing, especially in the medical imaging field, where small differences between segmented regions in the anatomy can be of paramount importance. Usually, segmentation evaluation is based on a measure that depends on the number of segmented voxels inside and outside of some reference regions that are called gold standards. Although some other measures have been also used, in this work we propose a set of new similarity measures, based on different features, such as the location and intensity values of the misclassified voxels, and the connectivity and the boundaries of the segmented data. Using the multidimensional information provided by these measures, we propose a new evaluation method whose results are visualized applying a Principal Component Analysis of the data, obtaining a simplified graphical method to compare different segmentation results. We have carried out an intensive study using several classic segmentation methods applied to a set of MRI simulated data of the brain with several noise and RF inhomogeneity levels, and also to real data, showing that the new measures proposed here and the results that we have obtained from the multidimensional evaluation, improve the robustness of the evaluation and provides better understanding about the difference between segmentation methods. PMID- 19446359 TI - Altered miRNA expression in sputum for diagnosis of non-small cell lung cancer. AB - Analysis of molecular genetic markers in biological fluids has been proposed as a useful tool for cancer diagnosis. MicroRNAs (miRNAs) are small regulatory RNAs that are frequently dysregulated in lung cancer and have shown promise as tissue based markers for its prognostication. The aim of this study was to determine whether aberrant miRNA expression can be used as a marker in sputum specimen for the diagnosis of non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: expressions of mature miRNAs, mir-21 and mir-155, were examined by real-time reverse transcription polymerase chain reaction (RT-PCR) and normalized to that of control miRNA, U6B, in sputum of 23 patients with NSCLC and 17 cancer-free subjects. The data was compared with conventional sputum cytology for the diagnosis of lung cancer. All endogenous miRNAs were present in sputum in a remarkably stable form and sensitively and specifically detected by real-time RT PCR. Mir-21 expression in the sputum specimens was significantly higher in cancer patients (76.32+/-9.79) than cancer-free individuals (62.24+/-3.82) (P<0.0001). Furthermore, overexpression of mir-21 showed highly discriminative receiver operator characteristic (ROC) curve profile, clearly distinguishing cancer patients from cancer-free subjects with areas under the ROC curve at 0.902+/ 0.054. Detection of mir-21 expression produced 69.66% sensitivity and 100.00% specificity in diagnosis of lung cancer, as compared with 47.82% sensitivity and 100.00% specificity by sputum cytology. The measurement of altered miRNA expression in sputum could be a useful noninvasive approach for the diagnosis of lung cancer. PMID- 19446360 TI - Serglycin proteoglycan is not implicated in localizing exocrine pancreas enzymes to zymogen granules. AB - Storage and release of proteins from granules forms the basis of cellular functions as diverse as cell mediated cytotoxicity, neuronal communication, activation of muscle fibres, and release of hormones or digestive enzymes from endocrine and exocrine glands, such as the pancreas. Serglycin is the major intracellular proteoglycan of haematopoietic cells. Serglycin is important for localization of proteins in granules of different haematopoietic cell types. Previous reports have indicated a role for serglycin in granule formation and localization of zymogens in granules of the exocrine pancreas in rat. We here present data showing that serglycin is not present at the protein level in human or murine pancreas. Furthermore, the amount and localization of three exocrine pancreas zymogens (amylase, trypsinogen, and carboxypeptidase A) is not affected by the absence of serglycin in a serglycin knock-out mouse model. PMID- 19446361 TI - Cathepsin X prevents an effective immune response against Helicobacter pylori infection. AB - Cathepsin X, a cysteine protease, has been shown to regulate an immune response by activating beta-2 integrin receptors. In this study we demonstrate its role in regulating the immune response to infection with H. pylori. The level of cathepsin X was determined in THP-1 monocyte cells primed with H. pylori antigens isolated from subjects suffering from gastritis, who had either eradicated or not the disease after the antibiotic therapy. We show that the specific clinical outcome of H. pylori eradication therapy correlates strongly with the membrane expression of cathepsin X in stimulated THP-1 cells, being significantly higher after stimulation with H. pylori strains from those subjects who did not respond to antibiotic therapy. The same antigens elicit a more vigorous immune response, increased expression of MHC II, however trigger inadequate cytokine profile (IFN gamma and IL-4) to eradicate the pathogen. We propose that cathepsin X mediated activation of beta-2 integrin receptor Mac-1 suppresses the stimulatory signal in the form of cytokines. Cathepsin X co-localizes on the membrane of THP-1 cells with Mac-1 integrin receptor and its inhibition increases homotypic aggregation and mononuclear cell proliferation, events that are associated with low Mac-1 activity. Our study highlights the diversity of the innate immune response to H. pylori antigens leading to either successful eradication of the infection or maintenance of chronic inflammation, revealing cathepsin X location and activity as a regulator of the effectiveness of H. pylori eradication. PMID- 19446362 TI - Peptides modeled after the alpha-domain of metallothionein induce neurite outgrowth and promote survival of cerebellar granule neurons. AB - Metallothionein (MT) is a metal-binding protein capable of preventing oxidative stress and apoptotic cell death in the central nervous system of mammals, and hence is of putative therapeutic value in the treatment of neurodegenerative disorders. Recently, we demonstrated that a peptide modeled after the beta-domain of MT, EmtinB, induced neurite outgrowth and increased neuronal survival through binding to receptors of the low-density lipoprotein receptor family (LDLR). The present study identified two MT alpha-domain-derived peptide sequences termed EmtinAn and EmtinAc, each consisting of 14 amino acids, as potent stimulators of neuronal differentiation and survival of primary neurons. In addition, we show that a peptide derived from the N-terminus of the MT beta-domain, EmtinBn, promotes neuronal survival. The neuritogenic and survival promoting effects of EmtinAc, similar to MT and EmtinB but not EmtinAn, were dependent on the functional integrity of LDLR. Moreover, EmtinAn and EmtinAc induced activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt). We suggest that multiple functional sites of MT serve to cross-link MT receptor(s), thereby transducing signals leading to an increase in neurite outgrowth and survival. PMID- 19446363 TI - Effect of physical desiccation on plant regeneration efficiency in rice (Oryza sativa L.) variety super basmati. AB - This experiment assessed the effect of partial physical desiccation on plant regeneration efficiency in scutellum-derived embryogenic calluses of rice (Oryza sativa L.) variety Super basmati. A number of callusing cultures were developed, and efficient callus induction was observed on MS (Murashige and Skoog) basal medium supplemented with 2.0mg/L 2,4-dichlorophenoxy acetic acid. The calluses were proliferated on the same medium for 3 weeks and then shifted to dehydration desiccation treatment for 72h. The desiccated calluses were cultured on different media for somatic embryogenesis and plant regeneration. A medium with 2.0mg/L alpha-napthaleneacetic acid, 10.0mg/L abscisic acid , 2.0mg/L kinetin was best for somatic embryogenesis only, but not for further plant development. After 10d, differentiated calluses were sub-cultured on medium with various concentrations and types of carbohydrates (carbon source) in (1)MS(2j) medium. A large number of plantlets (14.51+/-2.81 and 8.56+/-2.90 plants/callus) were regenerated via chemical desiccation, on MS with 3% maltose+3% sorbitol and 6% sucrose, respectively. Under dehydration on only simple MS (3% sucrose), 11.23+/-3.22 plants/callus were developed. Under conditions of dehydration and chemical desiccation, plant regeneration rates were higher than the calluses cultured on simple MS medium in the presence of plant growth regulator. After somatic embryogenesis, >25% plants were sterile. The protocol used here may allow maximum regeneration of normal and fertile plantlets of super basmati rice within 3 months. PMID- 19446364 TI - Detection of community-associated MRSA as a result of the unmasking effect of antibiotic treatment. PMID- 19446365 TI - Are hospitals too clean to trigger good hand hygiene? AB - Compliance with hand hygiene in the healthcare setting is generally low. The aim of the present study was to investigate the degree of compliance with hand hygiene after toilet visits inside and outside the hospital. We observed hospital/laboratory staff, participants of the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2007, and users of public lavatories. Compliance with hand hygiene after toilet visits was 46% for hospital staff, 84% for conference participants and 75% for members of the public. Healthcare workers show different behaviour regarding hand hygiene inside and outside the healthcare setting. Perhaps the feeling of a 'miasmic' environment such as public toilets triggers better hand hygiene, whereas the relatively clean hospital environment may block the trigger for hand disinfection. PMID- 19446366 TI - Should laparoscopic surgeons wear masks? PMID- 19446367 TI - Variation in infection incidence between neonatal intensive care units can depend on the measures used. PMID- 19446368 TI - Sero-epidemiology of hepatitis A virus infection among healthcare workers in Korean hospitals. AB - Hepatitis A virus (HAV) has been increasingly reported in Korea as has an outbreak in Korean healthcare workers (HCWs). This 2008 study evaluated the sero epidemiology of HAV infections among 3696 HCWs in four Korean hospitals. HCWs were tested for immunoglobulin G anti-HAV antibodies using commercially available kits. Data including demographic characteristics, occupation, workplace and serological status for other hepatitis viruses were collected. Statistical analyses were conducted to identify variables related to HAV seropositivity. Among the 3696 participants, 2742 (74%) were women and the majority (96%) were aged 20-39 years (median: 28; range: 19-68). Eighteen percent were physicians, 46% nurses, 10% nurses' aides, 11% paramedical technicians and 15% administrative staff. Seropositivity for HAV significantly increased with age (P<0.001): 1.8% for < or =24 years, 14.7% for 25-29 years, 41.8% for 30-34 years, 75.5% for 35-39 years, and 93.7% for > or =40 years. Among those aged 20-39 years, age-specific HAV seroprevalence was significantly lower in physicians than in the other occupational groups (P<0.001). In Korea, mass vaccination to HCWs aged < or =29 years or screening for seropositivity and vaccinating non-immune subjects aged 30 39 years should be considered, especially in physicians. PMID- 19446369 TI - Protection against Abeta-mediated rapid disruption of synaptic plasticity and memory by memantine. AB - Soluble amyloid-beta protein (Abeta) may cause cognitive impairment in Alzheimer's disease in the absence of significant neurodegeneration. Here, the ability of the NMDA receptor (NMDAR) antagonist memantine to prevent synthetic Abeta-mediated rapid functional deficits in learned behavior and synaptic plasticity was assessed in the rat. In vitro, pretreatment with a clinically relevant, NMDAR blocking concentration of memantine partially inhibited the induction of long-term potentiation (LTP) in the dentate gyrus and prevented further inhibition caused by exposure to Abeta(1-42). Whereas systemic injection with memantine alone inhibited LTP in the CA1 area in vivo, a subthreshold dose partially abrogated the inhibition of LTP by intracerebroventricular soluble Abeta(1-42). Similarly, systemic treatment with memantine alone impaired performance of an operant learning task and a subthreshold dose prevented the Abeta(1-42)-mediated increase in perseveration errors. The acute protection afforded by memantine, albeit in a narrow dose range, against the rapid disruptive effects of soluble Abeta(1-42) on synaptic plasticity and learned behavior strongly implicate NMDAR-dependent reversible dysfunction of synaptic mechanisms in Abeta-mediated cognitive impairment. PMID- 19446370 TI - Brain atrophy associated with baseline and longitudinal measures of cognition. AB - The overall goal was to identify patterns of brain atrophy associated with cognitive impairment and future cognitive decline in non-demented elders. Seventy one participants were studied with structural MRI and neuropsychological testing at baseline and 1-year follow-up. Deformation-based morphometry was used to examine the relationship between regional baseline brain tissue volume with baseline and longitudinal measures of delayed verbal memory, semantic memory, and executive function. Smaller right hippocampal and entorhinal cortex (ERC) volumes at baseline were associated with worse delayed verbal memory performance at baseline while smaller left ERC volume was associated with greater longitudinal decline. Smaller left superior temporal cortex at baseline was associated with worse semantic memory at baseline, while smaller left temporal white and gray matter volumes were associated with greater semantic memory decline. Increased CSF and smaller frontal lobe volumes were associated with impaired executive function at baseline and greater longitudinal executive decline. These findings suggest that baseline volumes of prefrontal and temporal regions may underlie continuing cognitive decline due to aging, pathology, or both in non-demented elderly individuals. PMID- 19446371 TI - The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats. AB - NMDA receptor (NMDAR) activity has been strongly implicated in both in vitro and in vivo learning models and the decline in cognitive function associated with aging and is linked to a decrease in NMDAR functional expression. GLYX-13 is a tetrapeptide (Thr-Pro-Pro-Thr) which acts as a NMDAR receptor partial agonist at the glycine site. GLYX-13 was administered to young adult (3 months old) and aged (27-32 months old) Fischer 344 X Brown Norway F1 rats (FBNF1), and behavioral learning tested in trace eye blink conditioning (tEBC), a movable platform version of the Morris water maze (MWM), and alternating t-maze tasks. GLYX-13 (1mg/kg, i.v.) enhanced learning in both young adult and aging animals for MWM and alternating t-maze, and increased tEBC in aging rats. We previously showed optimal enhancement of tEBC in young adult rats given GLYX-13 at the same dose. Of these learning tasks, the MWM showed the most robust age related deficit in learning. In the MWM, GLYX-13 enhancement of learning was greater in the old compared to the young adult animals. Examination of the induction of long-term potentiation (LTP) and depression (LTD) at Schaffer collateral-CA1 synapses in hippocampal slices showed that aged rats showed marked, selective impairment in the magnitude of LTP evoked by a sub-maximal tetanus, and that GLYX-13 significantly enhanced the magnitude of LTP in slices from both young adult and aged rats without affecting LTD. These data, combined with the observation that the GLYX-13 enhancement of learning was greater in old than in young adult animals, suggest that GLYX-13 may be a promising treatment for deficits in cognitive function associated with aging. PMID- 19446372 TI - No association of PGRN 3'UTR rs5848 in frontotemporal lobar degeneration. AB - Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has been claimed that homozygosity of the SNP rs5848 located in the 3'UTR of progranulin increases risk for FTLD. We have attempted to replicate the association of rs5848 in three independent FTLD cohorts. No association of rs5848 with FTLD was observed in any individual cohort nor was any observed when the data was combined. These data argue that rs5848 is not a risk factor for FTLD. PMID- 19446373 TI - [Treatment of hypertension in the very elderly]. PMID- 19446374 TI - [Cryptogenic pneumonia organized in the elderly]. PMID- 19446375 TI - [Psychometric properties of the satisfaction with life scale in active elderly women]. AB - OBJECTIVE: The present study analyzes the psychometric properties of the Spanish version of the Satisfaction with Life Scale. METHODS: The sample of 310 active elderly women with primary school education and living in their own homes. The scale's reliability was examined with Cronbach's alpha and the exploratory factor analysis. RESULTS: The reliability show a value of 0.75. Principal components analysis showed a single factor solution accounting for 51.32% of the variance. Item 5 "The conditions of my life are excellent" explained the highest percentage of variance in the data. CONCLUSION: These analyses showed acceptable internal consistency. PMID- 19446376 TI - [Aging negative stereotypes and their relationship with sociodemographic variables over 65 elderly]. AB - INTRODUCTION: The aim of the present study was to determine whether there are any associations between the degree of belief in negative stereotypes of aging in 65- to 96-year-old and the following sociodemographic variables: gender, age, marital status and educational level. MATERIALS AND METHODS: The sample consisted of 757 non-institutionalized people divided into four age groups. Gender was homogeneously distributed in all groups. During an interview, the participants responded to a questionnaire that was organized in two parts. The first part collected data on age, educational level, gender and marital status. The second part consisted of a scale of negative stereotype of aging (Cuestionario de Estereotipos Negativos hacia la Vejez [CENVE]), with three factors: health, social-motivational and character-personality. RESULTS: Significant differences were found in relation to age but not in relation to gender. In relation to the health factor, participants aged more than 80 showed weaker stereotypes than the remaining age groups. In relation to the social-motivational factor, the older the participants, the stronger the negative stereotypes in relation to a decrease in interests in life. Persons with lower educational level scored higher on the health and character-personality factors of the CENVE. CONCLUSIONS: The results are discussed in relation to their potential applications in psychosocial interventions. PMID- 19446377 TI - [Human life and aging]. PMID- 19446378 TI - Global serotype distribution among Streptococcus pneumoniae isolates causing otitis media in children: potential implications for pneumococcal conjugate vaccines. AB - Acute otitis media (AOM) is the most common infection following pneumococcal colonization of the upper respiratory tract. Streptococcus pneumoniae causes 30 60% of AOM cases worldwide. However, not all pneumococcal serotypes cause disease and an association exists with nasopharyngeal colonization by certain serotypes and their propensity to cause AOM. This review examines the global serotype distribution relationship between pneumococcal serotypes and AOM in children aged <18 years and demonstrates that the most common pneumococcal serotypes causing AOM globally are 3, 6A, 6B, 9V, 14, 19A, 19F, and 23F. PMID- 19446379 TI - Vertical distribution of anthropogenic radionuclides in cores from contaminated floodplains of the Yenisey River. AB - The Mining and Chemical Industrial Combine, Zheleznogorsk (MCIC, previously known as Krasnoyarsk-26) on the River Yenisey has contaminated the surrounding environment with anthropogenic radionuclides as a result of discharges of radioactive wastes. The purpose of this study was to investigate the vertical distribution of anthropogenic contamination ((137)Cs and plutonium) within floodplain areas at different distances from the discharge point. Sites were chosen that display different characteristics with respect to periodic inundation with river water. Cs-137 activity concentrations were in the range 23-3770 Bq/kg (dry weight, d.w.); Pu-239,240 activity concentrations were in the range <0.01 14.2 Bq/kg (d.w.). Numerous sample cores exhibited sub-surface maxima which may be related to the historical discharges from the MCIC. Possible evidence indicating the deposition of earlier discharges at MCIC in deeper core layers was observed in the (238)Pu:(239,240)Pu activity ratio data: a Pu signal discernible from global fallout could be observed in numerous samples. Cs-137 and Pu-239,240 activity concentrations were correlated with the silt fraction (% by mass <63 microm) though no significant correlation was observed between (grain-size) normalised (137)Cs activity concentrations and distance downstream from the MCIC. PMID- 19446380 TI - Oral filariasis--a case report. AB - Filarial worms are nematodes that dwell in the subcutaneous tissues and lymphatics of human hosts. In India, filariasis is predominantly caused by a species of nematode called Wuchereria bancrofti. The disease is transmitted through the bite of blood sucking mosquitoes. The salient clinical feature of the disease is lymphangitis leading to elephantiasis of the legs, arms, scrotum and breast. Oral or perioral involvement is very rare. We report a case of filariasis which was diagnosed after biopsy of an innocuous cheek nodule. PMID- 19446381 TI - Postoperative management of the airway with a Ravussin cricothyroid cannula in head and neck surgery. PMID- 19446382 TI - National study group sessions using web-based teaching software: a new concept for training. PMID- 19446383 TI - Heavy metal deposition in the Italian "triangle of death" determined with the moss Scorpiurum circinatum. AB - In this study, a biomonitoring project using the moss Scorpiurum circinatum was carried out to evaluate the deposition and biological effects of heavy metals in the area of Acerra (Naples, S Italy), one of the vertices of the sadly called "Italian triangle of death" owing to the dramatic increase in tumours. The results clearly indicated that the study area is heavily polluted by heavy metals, a large proportion of which is likely present in the atmosphere in particulate form. The ultrastructural organization of exposed samples was essentially preserved, but cell membrane pits, cytoplasm vesicles and concentric multilamellar/multivesicular bodies, probably induced by pollution, were found, which may be involved in the tolerance mechanisms to metal pollution in this moss species. Although severe biological effects were not found at the ultrastructural level in the exposed moss, effects on humans, especially after long-term exposure, are to be expected. PMID- 19446384 TI - Zinc accumulation potential and toxicity threshold determined for a metal accumulating Populus canescens clone in a dose-response study. AB - The effect of increasing soil Zn concentrations on growth and Zn tissue concentrations of a metal-accumulating aspen clone was examined in a dose response study. Plants were grown in a soil with a low native Zn content which was spiked with Zn salt solutions and subsequently aged. Plant growth was not affected by NH(4)NO(3)-extractable soil Zn concentrations up to 60 microg Zn g( 1) soil, but it was completely inhibited at extractable concentrations above 90 microg Zn g(-1) soil. From these data an effective concentration of 68.5 microg extractable Zn g(-1) soil was calculated at which plant growth was reduced by 50%. The obtained information on toxicity threshold concentrations, and the relation between plant Zn accumulation and extractable soil Zn concentrations may be used to assess the suitability of the investigated Populus canescens clone for various phytoremediation strategies. The potential risk of metal transfer into food webs associated with P. canescens stands on Zn-polluted sites may also be estimated. PMID- 19446385 TI - Molecular characterization of copper in soils using X-ray absorption spectroscopy. AB - Bioavailability of Cu in the soil is a function of its speciation. In this paper we investigated Cu speciation in six soils using X-ray absorption near edge structure (XANES), extended X-ray absorption fine structure (EXAFS), and synchrotron-based micro X-ray fluorescence (mu-XRF). The XANES and EXAFS spectra in all of the soils were the same. mu-XRF results indicated that the majority of the Cu particles in the soils were not associated with calcium carbonates, Fe oxides, or Cu sulfates. Principal component analysis and target transform of the XANES and EXAFS spectra suggested that Cu adsorbed on humic acid (HA) was an acceptable match. Thus it appears that Cu in all of the soils is primarily associated with soil organic matter (SOM). Theoretical fitting of the molecular structure in the soil EXAFS spectra revealed that the Cu in the soils existed as Cu atoms bound in a bidentate complex to O or N functional groups. PMID- 19446386 TI - [Information and assent: presentation of 32 information cards concerning plastic and aesthetic surgery]. AB - Obligation to deliver full information and obtaining enlightened assent are now, for the whole French practitioner, a necessary preliminary to each operation. Henceforth, in case of suit, the practitioner must prove the reality and the quality of preoperative information. The authors propose 32 information cards corresponding to the most currently operations of plastic and aesthetic surgery. They will being clear and simple, with a large agreement, strictly informative and yearly up to date. They have the label and therefore the scientific guaranty of the French Society of Plastic Reconstructive and Aesthetic Surgery. PMID- 19446387 TI - Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. AB - INTRODUCTION: The efficacy of repeated administration of vasopressin alone during prolonged cardiopulmonary resuscitation (CPR) remains unconfirmed. This study was conducted to estimate the effectiveness of the repeated administration of vasopressin vs. epinephrine for cardiopulmonary arrest (CPA) patients receiving prolonged CPR. METHODS: We conducted a prospective randomized controlled study on patients who experienced out-of-hospital CPA. The patients were randomly assigned to receive a maximum of four injections of either 40IU of vasopressin (vasopressin group) or 1mg of epinephrine (epinephrine group) immediately after emergency room (ER) admission. Patients who received vasopressors before ER admission or suffered non-cardiogenic CPA were excluded after randomization. RESULTS: In total, 336 patients were enrolled (vasopressin group, n=137; epinephrine group, n=118). No differences were found between these groups (vasopressin group vs. epinephrine group) in the rates of return of spontaneous circulation (ROSC) (28.7% vs. 26.6%), 24-h survival (16.9% vs. 20.3%), or survival to hospital discharge (5.6% vs. 3.8%). In a subgroup analysis by the Fisher's exact test, the rate of ROSC was higher in the vasopressin group than in the epinephrine group, among the patients whose arrests were witnessed (48.1% vs. 27.8%, p=0.010) or who received bystander CPR (68.0% vs. 38.5%, p=0.033). When the independent predictors of ROSC were calculated in the subgroup analysis, however, vasopressin administration (Odds ratio: 0.87-0.28) did not affect the outcome. CONCLUSIONS: This is the first report of a possible vasopressin-alone resuscitation without additional epinephrine. However, repeated injections of either vasopressin or epinephrine during prolonged advanced cardiac life support resulted in comparable survival. PMID- 19446388 TI - Electrical injury during "hands on" defibrillation-A potential risk of internal cardioverter defibrillators? AB - Despite clear guidance for the need for rescuers to avoid contact with a patient during external defibrillation, the advice regarding the potential dangers of rescuer contact during the firing of an internal cardioverter defibrillator [ICD] generally implies that such contact is safe. This case report describes documented nerve injury to a rescuer by a shock delivered from an ICD during chest compression on a patient in cardiac arrest. The authors also discuss the existing literature on the subject and make suggestions for future management. PMID- 19446389 TI - The complexity of neurobiological processes in acute ischemic stroke. AB - There is an urgent need for improved diagnostics and therapeutics for acute ischemic stroke. This is the focus of numerous research projects involving in vitro studies, animal models and clinical trials, all of which are based on current knowledge of disease mechanisms underlying acute focal cerebral ischemia. Insight in the chain of events occurring during acute ischemic injury is essential for understanding current and future diagnostic and therapeutic approaches. In this review, we summarize the actual knowledge on the pathophysiology of acute ischemic stroke. We focus on the ischemic cascade, which is a complex series of neurochemical processes that are unleashed by transient or permanent focal cerebral ischemia and involves cellular bioenergetic failure, excitotoxicity, oxidative stress, blood-brain barrier dysfunction, microvascular injury, hemostatic activation, post-ischemic inflammation and finally cell death of neurons, glial and endothelial cells. PMID- 19446390 TI - Higher mean platelet volume determined shortly after the symptom onset in acute ischemic stroke patients is associated with a larger infarct volume on CT brain scans and with worse clinical outcome. AB - OBJECTIVE: Mean platelet volume (MPV) determined shortly after the onset of acute ischemic stroke represents the pre-stroke values. Data on its relationship to stroke severity/outcome have been conflicting. We related MPV to infarct volume on CT brain scans and risk of death/dependence 7 days and 3 months post-stroke. METHODS: MPV (within 30h since stroke onset), infarct volume (13-83h since stroke onset) and clinical outcomes were evaluated in 81 consecutive patients (32 men, age 52-91 years, 10 small artery occlusion, 10 large artery atherosclerosis, 29 cardioembolic, 32 multiple probable/possible etiology). RESULTS: Higher MPV was independently associated with larger ln-infarct volume [estimate 0.259, 95% confidence interval (CI) 0.004-0.513, P=0.046], greater risk of death/dependence 7 days post-stroke [relative risk (RR)=1.077, 95% CI 1.005-1.115, P=0.036], and greater risk of death/dependence 3 months post-stroke (RR=1.077, 95% CI 1.001 1.158, P=0.048). Considered covariates: stroke etiology, CT scan timing, platelet count and other hematological parameters, demographic variables, history of cerebrovascular, cardiac or cardiovascular diseases, diabetes, serum chemistry, previous antiplatelet and statin use and treatments delivered after the index event. CONCLUSIONS: Data support the view about MPV as a determinant of severity/outcome of the acute ischemic stroke. PMID- 19446391 TI - Selective recovery of Cr and Cu in leachate from chromated copper arsenate treated wood using chelating and acidic ion exchange resins. AB - The purpose of this study was to selectively remove chromium and copper from CCA treated wood acid leachates (initial concentrations of 447-651 mg As l(-1), 374 453 mg Cu l(-1) and 335-622 mg Cr l(-1)) using ion exchange resins and precipitation techniques. Batch experiments revealed that the chelating resin Dowex M4195 had a high copper selectivity in the presence of chromium while the Amberlite IR120 resin had a high chromium sorption capacity. Combining M4195 and IR120 resins in four successive columns, made with Plexiglas tube, led to 96% copper extraction and 68% chromium extraction. NH(4)OH (4M) efficiently eluted copper from the chelating resin while H(2)SO(4) (10%v/v) was used for IR120 resin elution. Copper and chromium recovery by elution reached 94% and 81%, respectively. Successive sorption and elution steps using M4195 and IR120 ion exchange resins presented similar metal removal capacities over the five cycles. No resin deterioration was observed but the results suggested arsenic bulk diffusion into the M4195 resin. Successive treatments of CCA-treated wood leachate with M4195 and IR120 allowed for copper and chromium removal while arsenic could be extracted by coagulation treatment with ferric chloride and precipitation with Ca(OH)(2) at pH 5.7. This final process led to 99.9% arsenic removal. The final effluent contained less than 1 mg l(-1) of arsenic, chromium and copper. PMID- 19446392 TI - Reduction of hexavalent chromium mediated by micro- and nano-sized mixed metallic particles. AB - A variety of micron-scale mixed metallic particles (Pd/Fe, Ag/Fe, Cu/Fe, Zn/Fe, Co/Fe, Mg/Fe, Ni/Fe, Al/Fe, Si/Fe, Pd/Cu and Pd/Zn; and Pd/Cu/Fe, Pd/Zn/Fe and Zn/Cu/Fe) and selected nano-sized bimetallic analogs (Pd/Fe, Cu/Fe and Pd/Cu) were evaluated for reducting activity with Cr(VI) in a surfactant preparation (Tween 20) under a variety of reaction conditions. Relative to the reactivity of the zero-valent iron, the tested bimetallic mixtures (Pd/Fe>Pd/Zn>Ag/Fe>Ni/Fe>Zn/Fe>Pd/Cu>Cu/Fe) appreciably increased the pseudo first-order rate constant. The Zn/Cu/Fe represented a cost-effective preparation providing comparable or improved kinetic parameters relative to the more expensive palladized bimetallic mixtures. The Pd/Fe, Cu/Fe and Pd/Cu nano-sized particles proved to be more reactive (up to 100-fold) for the reductive remediation of Cr(VI). The results were comparable when working with nano-sized Cu and Fe particles, suggesting that the cementation of a noble metal serves not only as a reaction catalyst but also provides protection to the metallic surface, impeding its rapid inactivation. PMID- 19446393 TI - Selection of sorbent for removing pesticides during water treatment. AB - This paper presents research on phenoxyacid pesticides removal using sorption methods on activated carbons. It was noted, that physico-chemical properties of adsorbent and adsorbate as well as parameters of the process have influence on adsorption of pesticides, derivatives of phenoxyacetic acid on carbon. The experimental data were analyzed by the Freundlich isotherm. The best for remove from water on carbon NP-5 was 2,4-D. Equilibrium data fitted well with the Freundlich model with maximum adsorption capacity of NP-5 carbon. The exemplary sorption capacity at equilibrium concentration 10 mg L(-1) were: 2,4-D 70 mg g( 1), MCPA 2 mg g(-1), MCPP 0.5 mg g(-1). The results indicated that coconut shell based NP-5 carbon is most effective for the adsorption of phenoxyacetic acid from aqueous solutions. PMID- 19446394 TI - Diffusion of hexavalent chromium in chromium-containing slag as affected by microbial detoxification. AB - An electrochemical method was used to determine the diffusion coefficient of chromium(VI) in chromium-containing slag. A slag plate was prepared from the original slag or the detoxified slag by Achromobacter sp. CH-1. The results revealed that the apparent diffusion coefficient of Cr(VI) was 4.4 x 10(-9)m(2)s( 1) in original slag and 2.62 x 10(-8)m(2)s(-1) in detoxified slag. The results implied that detoxification of chromium-containing slag by Achromobacter sp. CH-1 could enhance Cr(VI) release. Meanwhile, the results of laboratory experiment showed that the residual total Cr(VI) in slag decreased from an initial value of 6.8 mg g(-1) to 0.338 mg g(-1) at the end of the detoxification process. The Cr(VI) released from slag was also reduced by Achromobacter sp. CH-1 strain since water soluble Cr(VI) in the leachate was not detected after 4 days. Therefore, Achromobacter sp. CH-1 has potential application for the bio-detoxification of chromium-containing slag. PMID- 19446395 TI - Multivariate statistical study of organic pollutants in Nanjing reach of Yangtze River. AB - Multivariate statistical approach was used to identify the source apportionment of 25 semi-volatile compounds (SVOCs) in surface water in Nanjing reach of Yangtze River, China. Surface water samples were collected from six sites in January 2007. Concentrations of SVOCs were determined by gas chromatography equipped with a mass spectrometry detector (GC-MS). Cluster analysis (CA) and principal component analysis-multiple linear regression (PCA-MLR) were used for evaluation of contamination status, distribution and source apportionment. The results of CA showed that the six sites in this study could be divided into two significant groups, i.e. low and high pollutant groups. PCA-MLR results suggested that four source types were identified, explaining about 84.5% of the total variance. Of four sources, industrial and domestic sewage sources contributed 43.5-64.8% of various SVOCs in six sites, precipitance and runoff sources 4.22 42.87%, shipping sources 4.22-23.49%, and other miscellaneous sources 1.05-8.97%. These results indicated that point source pollutants affected the water quality of this region. High correlation coefficient (R(2)=0.973) between the measured and predicted concentrations of SVOCs suggested the applicability of the PCA-MLR for estimation of source contribution to the SVOCs in water. PMID- 19446396 TI - Preparation, non-isothermal decomposition kinetics, heat capacity and adiabatic time-to-explosion of NTOxDNAZ. AB - NTOxDNAZ was prepared by mixing 3,3-dinitroazetidine (DNAZ) and 3-nitro-1,2,4 triazol-5-one (NTO) in ethanol solution. The thermal behavior of the title compound was studied under a non-isothermal condition by DSC and TG/DTG methods. The kinetic parameters were obtained from analysis of the DSC and TG/DTG curves by Kissinger method, Ozawa method, the differential method and the integral method. The main exothermic decomposition reaction mechanism of NTOxDNAZ is classified as chemical reaction, and the kinetic parameters of the reaction are E(a)=149.68 kJ mol(-1) and A=10(15.81)s(-1). The specific heat capacity of the title compound was determined with continuous C(p) mode of microcalorimeter. The standard mole specific heat capacity of NTOxDNAZ was 352.56 J mol(-1)K(-1) in 298.15K. Using the relationship between C(p) and T and the thermal decomposition parameters, the time of the thermal decomposition from initialization to thermal explosion (adiabatic time-to-explosion) was obtained. PMID- 19446397 TI - Unfolding study of native bacteriorhodopsin under acidic condition. AB - In this study, we measured the structural properties of "blue membrane", which is specific formation of a purple membrane (PM) upon acid titration or removal of cations, by the force curve measurement mode of an atomic force microscopy. The PM fragments were immobilized on a glass substrate and force curve measurements were carried out on the fragments under neutral (pH 7.2) and acidic (pH 2.4) condition. The results revealed that peak positions of the unfolding spectra obtained under acidic condition were shifted to the shorter extension region than those at neutral pH and that the relative position of only the first peak was changed by about 5nm. These results suggest the possibility that the specific secondary structure is formed at the site from its C-terminus to helices F in acidified PM. PMID- 19446398 TI - Comparative efficacy of spinosad with conventional acaricides against hard and soft tick populations from Antalya, Turkey. AB - The acaricidal efficacy of ceramic tiles treated at field application rates with either spinosad (Mozkill 120 SC, 0.01 g ai/m(2)), deltamethrin (Impotek Deltamethrin EW, 0.01 g ai/m(2)), permethrin+esbiothrin (Chrysamed, 0.1 g ai/m(2)), chlorpyrifos-methyl (Chlortoks EC 50, 0.2 g ai/m(2)) or a mixture of alpha-cypermethrin/tetramethrin/piperonyl butoxide (Ecorex Alfa SE, 0.01 g ai/m(2)), against larval Rhipicephalus turanicus and Argas persicus ticks was determined in laboratory bioassays. All ticks were initially exposed to treated tiles for 15 min then removed to non-treated containers and mortality evaluated for 15 min, 1 h, 6 h, and 24 h postexposure. Generally, A. persicus proved to be the most susceptible of the two species to all treatments. The alpha cypermethrin/tetramethrin/piperonyl butoxide mixture was the quickest acting acaricide against larval A. persicus where 100% mortality was observed 15 min postexposure. For the rest of the treatments complete mortality was obtained at 1 h except for permethrin/esbiothrin which occurred at 6 h postexposure. Complete mortality of larval R. turanicus occurred to deltamethrin and spinosad at 1 h postexposure with all acaricides providing 100% control at 6 h except permethrin/esbiothrin which only achieved 92% control through the end of the study (i.e. 24 h). Our results showed that spinosad would be a useful addition in a tick control program as an alternative for pyrethroids and organic phosphorus acaricides against both tick species. PMID- 19446399 TI - Evidence of Fasciola hepatica infection in Radix peregra and a mollusc of the family Succineidae in Ireland. AB - Worldwide molluscs of the genera Lymnaea, Pseudosuccinea, Galba and Stagnicola act as intermediate hosts of the common liver fluke, Fasciola hepatica. Galba truncatula is the only recorded intermediate host of F. hepatica within Ireland and is the principle intermediate host within Europe. To investigate the transmission of liver fluke on the Teagasc hill sheep farm, Co. Mayo, Ireland, snail species other than G. truncatula, were collected from the lowland pasture (snail sp. 'A') in May (n=23) and from the hill area (snail sp. 'B') in March, April and May 2008 (n=78, 53 and 36 respectively). Morphological characteristics identified snail sp. 'A' as a Succinea sp. and snail sp. 'B' as Radix peregra. PCR and subsequent sequencing of the 18S gene and internal transcribed spacer 2 (ITS-2) region of the snail rDNA were used for molecular identification. The 18S ribosomal DNA (rDNA) sequences revealed a 99% similarity with Omalonyx matheroni (Succineidae) for snail sp. 'A', and for snail sp. 'B' a 99% and 98% similarity with Radix auricularia and R. peregra, respectively. The ITS-2 sequences of snail sp. 'B' revealed a 100% similarity with R. peregra. Using PCR F. hepatica DNA was identified in 73.9% (n=17) of snail sp. 'A' collected during May and 10.3% (n=8), 60.4% (n=32) and 61.1% (n=22) of snail sp. 'B' collected during March, April and May, respectively. A priori knowledge of habitat preference and environmental tolerances of G. truncatula has failed to explain the prevalence of infection recorded in the hill sheep flock on Teagasc hill sheep farm. These findings may explain the presence of infection in sheep populations grazing hill habitats considered too acidic to maintain G. truncatula populations. PMID- 19446400 TI - Trypanosoma cruzi: dehydroepiandrosterone (DHEA) and immune response during the chronic phase of the experimental Chagas' disease. AB - Dehydroepiandrosterone (DHEA) has long been considered as a precursor for many steroid hormones. It also enhances the immune responses against a wide range of viral, bacterial, and parasitic pathogens. The aims of this work were to evaluate the influences of exogenous DHEA treatment on Wistar rats infected with the Y strain of Trypanosoma cruzi during the acute and its influence on the chronic phase of infection. Animals were subcutaneous treated with 40 mg/kg body weight/day of DHEA. DHEA treatment promoted increased lymphoproliferative responses as well as enhanced concentrations of NO and IL-12. So, we point in the direction that our results validate the utility of the use of DHEA as an alternative therapy candidate against T. cruzi. PMID- 19446401 TI - Pituitary response to metyrapone in Gulf War veterans: relationship to deployment, PTSD and unexplained health symptoms. AB - OBJECTIVE: Gulf War deployment has been associated with a distinct neuroendocrine profile characterized by low 24h basal ACTH levels and enhanced cortisol and ACTH suppression to low-dose dexamethasone. The metyrapone stimulation test was performed to further characterize hypothalamic-pituitary activity in Gulf War veterans (GWV) and its relationship to unexplained medical symptoms and post traumatic stress disorder (PTSD). METHOD: Eleven GWV without PTSD, 18 GWV with PTSD and 15 healthy subjects not exposed to the Gulf War theater (non-exposed) underwent the metyrapone stimulation test, which inhibits cortisol synthesis, impairs cortisol-mediated negative feedback inhibition and in turn increases levels of ACTH and 11-deoxycortisol, a cortisol precursor. These hormones were measured at baseline (7:00 a.m.) and at intervals (from 8:00 a.m. to 4:00 p.m.) following the administration of metyrapone 750mg orally at 7:05 a.m. and at 10:05 a.m. RESULTS: There were group differences in the ACTH response despite similar cortisol and 11-deoxycortisol responses to metyrapone. GWV without PTSD had a significantly attenuated ACTH response compared to non-exposed subjects; GWV with PTSD had a significantly higher ACTH response than GWV without PTSD but did not differ from non-exposed subjects. Among GWV, unexplained medical health symptoms (e.g., neurological, musculoskeletal, cardiac, and pulmonary symptoms) and PTSD symptoms were significantly positively associated with the ACTH response to metyrapone. CONCLUSION: Gulf War deployment is associated with a substantially lower ACTH response to metyrapone. In contrast, unexplained health symptoms and PTSD in Gulf War veterans are associated with relatively greater hypothalamic pituitary activity which may reflect increased CRF activity and is evident only in consideration of deployment effects. This pattern of differences suggests either that Gulf War deployment and its associated exposures results in enduring changes in pituitary function or that reduced hypothalamic-pituitary activity protects against the development of PTSD and other deployment-related health problems. PMID- 19446402 TI - Randomized controlled trial of the ACTION smoking cessation curriculum in tobacco growing communities. AB - We conducted a group randomized trial of an interactive, games-based, tobacco cessation program (ACTION) designed to help adolescents who live in tobacco growing communities to stop using tobacco. More than 260 high school students participated in this study, in 14 schools across three states. We collected self reported measures of cigarette and smokeless tobacco use and conducted biochemical validation of self-reported use at three time points (pre-test, immediate post-test, and 90-day follow-up). We used multi-level modeling to account for intraclass clustering at the school and classroom levels, and we analyzed our results using an intent-to-treat approach and a per protocol approach. Using the per protocol analytic approach, ACTION participants were more likely than comparison participants to achieve abstinence at 90-day follow-up. We found no program effects on our secondary outcomes or mediating factors. This study suggests that ACTION has promise as a relatively effective adolescent cessation program, although the overall limited effectiveness of cessation programs for adolescents must be acknowledged. PMID- 19446403 TI - Serous oligocystic adenoma (SOIA) of the pancreas--first reported case of a genetically fixed association in a patient with hereditary non-polyposis colorectal cancer (HNPCC). AB - Cystic tumor lesions of the pancreas are relatively uncommon. Advances in imaging and pathohistology, including immunohistochemistry, have led to the detection and classification of novel tumor entities. A promoting aspect is the extended indication profile in pancreatic surgery, in particular, because of lower perioperative morbidity and mortality. One of these classified cystic neoplasms of the pancreas is serous oligocystic adenoma (SOIA), a rare and benign tumor lesion. We report on a 41-year-old man with a cystic lesion within the pancreatic head. Therefore, he underwent pylorus-preserving cephal duodenopancreatectomy. Pathohistologic investigation revealed a SOIA. He had a medical history significant for subtotal colectomy because of a synchronous double colonic carcinoma. Both tumor tissue specimens had been characterized for a high level of microsatellite instability (MSI) and loss of hMLH1, as well as for a corresponding germ line mutation in hMLH1 gene, leading to the diagnosis of hereditary non-polyposis associated colon cancer (HNPCC). The case is remarkable since the SOIA revealed MSI and loss of hMLH1 protein in the tumor cells that has never been reported for this tumor type. In addition, there is a rare and extraordinary association between SOIA and HNPCC, which has never been published before, since SOIA, in this case, could have been developed in the setting of HNPCC syndrome. PMID- 19446404 TI - Factors influencing histological response after neoadjuvant chemoradiation therapy for rectal carcinoma. AB - Neoadjuvant chemoradiation therapy is one of the standard therapeutic regimens for rectal carcinoma. Nevertheless, chemoradiation therapy is not completely devoid of adverse effects, and it would be interesting to try to predict which patient will respond to neoadjuvancy. This study aimed at analyzing factors influencing pathological response after therapy. We reviewed the clinical and morphological data of 39 patients after neoadjuvant chemoradiation therapy. We performed immunohistochemistry for p53, cyclin D1, MIB-1 (Ki67), and bcl-2 protein in paraffin-embedded tissue. In our series, 12 patients did not respond to neoadjuvant therapy, 12 showed a complete response, and 15 a partial response. There was a statistically significant association between response and cardiomyopathy (p=0.02) and tenesmus (p=0.02) and a trend towards significance for age (p=0.08), preoperative TNM (p=0.08), peritumoral inflammatory response (p=0.07), and preoperative CEA (p=0.08). As for immunohistochemistry, we only found a trend towards significance for cyclin D1 (p=0.08). In our series of patients with rectal carcinoma receiving preoperative chemoradiation therapy, few factors were predictive of a histological response. The histological response seems to improve survival and reduce relapses. PMID- 19446405 TI - E-cadherin expression in upper urothelial carcinoma in Balkan Endemic Nephropathy and non-endemic regions. AB - There is a high incidence of upper urothelial carcinoma (UUC) in regions affected by Balkan Endemic Nephropathy (BEN). The aim of this study was to compare E cadherin expression in UUC, in regions affected by BEN, and in control rural and city populations free of BEN. Another aim was to determine the influence of some morphological parameters on the E-cadherin status. In the samples of 85 UUC patients, of whom 40 lived in BEN settlements and 45 served as control subjects, immunoreactions were performed using monoclonal anti-human E-cadherin antibody. Aberrant expression of E-cadherin was more frequent in BEN tumors than in control tumors (p<0.01). Decreased E-cadherin expression was linked to high grade and solid growth in control and BEN tumors (p<0.0001 and <0.05 versus p<0.05 and <0.05, respectively), and to the stage in control tumors (p<0.01). However, BEN low grade and low stage tumors showed aberrant expression more often than did control tumors (p<0.05 and <0.005, respectively). In control tumors, using univariate analysis, E-cadherin status was found to be influenced by grade, stage, and tumor growth (p=0.001, 0.017, 0.015, respectively). In the same group, only the grade was significant according to multistep logistic regression analysis (Wald=6.429 and p=0.011). The growth pattern had a predominant influence on E-cadherin expression in BEN tumors (p=0.005). A significant influence on normal membranous or abnormal cytoplasmic expression of E-cadherin in UUC is exerted by tumor grade, stage, growth, and metaplastic change (p=0.002, 0.048, 0.019, 0.011, respectively), but only by tumor grade in the multistep logistic regression model. These results suggest that decreased expression of E-cadherin in BEN tumors may be linked to tumor growth, while expression of E-cadherin in control tumors may be associated with tumor grade. PMID- 19446406 TI - Mast cell burden and reticulin fibrosis in the myeloproliferative neoplasms: a computer-assisted image analysis study. AB - The mast cell has been associated with fibrosis in many different tissues, organs, and different disease processes including hematopoietic malignancies. Mast cells are often increased in the bone marrow of patients with primary bone marrow disorders, and patients with systemic mastocytosis often have a second concomitant neoplastic disease of the bone marrow. The goals of the current study were to determine the role the mast cell has in the pathogenesis of myeloproliferative neoplasms (MPN) and to correlate the mast cell burden with the degree of reticulin fibrosis. We used computer-assisted image analysis of bone marrow core biopsies stained for mast cell tryptase from patients with myeloproliferative neoplasms [31 cases: 12 chronic myelogenous leukemia (CML), 6 primary myelofibrosis (PMF), 4 essential thrombocythemia (ET), 4 polycythemia vera (PV), and 5 chronic myeloproliferative disorder, unclassifiable (CMPD-U)]. Although the number of cases of some subtypes of MPN was small, the results suggested that PMF and ET each had significantly more mast cells than both CML and control cases (P<0.01 and 0.05, respectively, Mann-Whitney test). CMPD-U and PV showed no significant differences from the control cases, but the CML cases had significantly fewer mast cells than our control cases (P=0.02, Mann-Whitney test). In addition, the quantity of mast cells seen in the bone marrows of MPN patients correlated with reticulin fibrosis (P=0.04, Mann-Whitney test). Our studies highlight the different mast cell quantities in different myeloproliferative neoplasms and suggest a direct role for the mast cell in intramedullary fibrosis. Further studies are warranted to confirm our observation and to study the mechanisms by which mast cells contribute to fibrosis in the MPN setting. PMID- 19446407 TI - Temporal horizon: modulation by smoking status and gender. AB - Recently, delay discounting has been argued to be conceptually consistent with the notion of temporal horizon [Bickel, W.K., Yi, R., Kowal, B.P., Gatchalian, K.M., 2008. Cigarette smokers discount past and future rewards symmetrically and more than controls: is discounting a measure of impulsivity? Drug Alcohol Depend. 96, 256-262]. Temporal horizon refers to the temporal distance over which behavioral events or objects can influence behavior. Here we examine the results on two putative measures of temporal horizon, future time perspective (FTP) and delay discounting, collected over three separate studies (n=227), to determine the influence of smoking and gender on temporal horizon. By comparing the results on these temporal horizon measures we address our population of interest: women who smoke. One of the measures of FTP indicates that smoking women have a shorter temporal horizon than their nonsmoking counterparts. Additionally, the story completion measures of FTP are positively correlated with delay discounting. In contrast, results of delay discounting measures showed no difference between smoking women and nonsmoking women, while results of delay discounting measures indicated smoking men have a shorter temporal horizon than non-smoking men. Additionally, the results of the FTP story completion measure indicated that lower third income earners had a shortened temporal horizon compared to upper third income earners. A possible explanation for these results is explored, and the implications of the modulation of temporal horizon by gender and smoking are discussed. PMID- 19446408 TI - Sedative and hypothermic effects of gamma-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: assessment using biotelemetry. AB - The recreational drug gamma-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH) and various antagonist drugs. GHB (1000mg/kg) caused profound sedation for more than 2h and a complex triphasic effect on body temperature: an initial hypothermia (5-40min), followed by hyperthermia (40 140min), followed again by hypothermia (140-360min). A lower GHB dose (500mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6h. The dopamine D(1) receptor antagonist SCH 23390 (1mg/kg), the opioid antagonist naltrexone (1mg/kg), the benzodiazepine antagonist flumazenil (10mg/kg), and the 5-HT(2A/2C) receptor antagonist ritanserin (1mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000mg/kg). However the GABA(B) antagonist SCH 50911 (50mg/kg) prevented the hyperthermia induced by GHB (1000mg/kg). Repeated daily administration of GHB (1000mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA(B) receptor agonist baclofen (10mg/kg). A high ambient temperature of 28 degrees C prevented the hypothermia obtained with GHB (500mg/kg) at 20 degrees C, while GHB (500mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5mg/kg) or METH (1mg/kg) at 28 degrees C. These results further confirm a role for GABA(B) receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these drugs. PMID- 19446410 TI - Behavioral problems and the occurrence of tobacco, cannabis, and coca paste smoking in Chile: evidence based on multivariate response models for school survey data. AB - BACKGROUND: In this study we estimate suspected links between youthful behavioral problems and smoking of tobacco, cannabis, and coca paste. METHODS: In the Republic of Chile, school-attending youths were sampled from all 13 regions of the country, with sample size of 46,907 youths from 8th to 12th grades. A Generalized Estimating Equations (GEE) approach to multiple logistic regression was used to address three interdependent response variables, tobacco smoking, cannabis smoking, and coca paste smoking, and to estimate associations. RESULTS: Drug-specific adjusted slope estimates indicate that youths at the highest levels of behavioral problems are an estimated 1.1 times more likely to have started smoking tobacco, an estimated 1.6 times more likely to have started cannabis smoking, and an estimated 2.0 times more likely to have started coca paste smoking, as compared to youths at the lowest level of behavioral problems (p<0.001). CONCLUSION: In Chile, there is an association linking behavioral problems with onsets of smoking tobacco and cannabis, as well as coca paste; strength of association is modestly greater for coca paste smoking. PMID- 19446411 TI - Depleting proteins from the growth medium of Mycoplasma capricolum unmasks bacterium-derived enzymatic activities. AB - Mycoplasma constitutes a unique group of bacteria best characterized as lacking peptidoglycan and having one of the smallest genomes of all free-living prokaryotes. Members of this group also represent important pathogens of humans, animals, and plants. Our understanding of the interaction between these pathogens and their hosts is limited, partly due to our inadequate knowledge of the secreted enzymes and virulence factors of these pathogens. Analysis of secreted proteins of mycoplasma has been hampered by their fastidious growth requirements where protein-rich growth supplements are required. Simple ultrafiltration of the complete medium through a 10kDa cut-off membrane successfully removed virtually all of the polypeptides in the medium and supported the growth of Mycoplasma capricolum (type California kid). This modification (AM medium) exposed the activities of a number of enzymes produced by this bacterium during growth including; acid and alkaline phosphatase, gelatinase, and beta-lactamase activities. We also show that the spent culture medium contained hemolysin activity. PMID- 19446409 TI - A prospective study of familial conflict, psychological stress, and the development of substance use disorders in adolescence. AB - BACKGROUND: Exposure to adverse family environments in childhood can influence the risk trajectory for developing substance use disorders in adolescence. Evidence for this is largely based on cross-sectional studies which have been unable to establish the temporality of this association and investigate underlying pathways. METHODS: The sample consisted of 1421 adolescents from the Project on Human Development in Chicago Neighborhoods, a three wave longitudinal study conducted between 1994 and 2001 that followed children from ages 10 to 22. Logistic regression analyses with multiple imputation were conducted to examine the relation between familial conflict in childhood and substance use disorders in late adolescence and emerging adulthood. We conducted mediational analyses to determine if internalizing and externalizing problems explain this relationship, and we investigated whether external social support mitigates the adverse effects of familial conflict on the development of substance use disorders. RESULTS: Familial conflict was significantly associated with the risk of substance use disorders during adolescence (odds ratio: 1.23; 95% CI: 1.02-1.47), and 30% of this effect was due to higher levels of externalizing problems (but not internalizing problems). External social support in childhood did not buffer the effects of familial conflict on substance use disorders during adolescence. CONCLUSION: Exposure to familial conflict early in life increases the risk of substance use disorders during late adolescence and emerging adulthood, due partly to higher levels of externalizing problems, but not internalizing problems. Future research is needed to identify additional pathways underlying this association, and the extent to which these pathways are modifiable. PMID- 19446412 TI - Placental transfusion insult in the predisposition for SIDS: a mathematical study. AB - A difference has been observed between the newborn hearing screening tests of thirty-one SIDS cases versus control infants that survived the first year of life [Rubens DD, Vohr BV, Tucker R, O'Neil CA, Chung W. Newborn oto-acoustic emission hearing screening tests. Preliminary evidence for a marker of susceptibility to SIDS. Early Hum Dev 2008;84(4);225-9]. This study is motivated by the hypothesis that the predisposition for SIDS may be caused by inner ear and brainstem damage from a high venous pressure insult at birth that disrupts an infant's ability to detect rising CO(2) levels following the first month of life. The injury is not immediately lethal due to the persistence of fetal physiological responses during the early postnatal period [Guntheroth WG. Crib death, the Sudden Infant Death Syndrome. Armonk NY: Futura Publishing Co.; 1995. p. 291]. Elastic vessels are assumed in the umbilical vein and newborn venous circulation at the time of a potential high pressure placental transfusion insult and pulse wave propagation is simulated using the nonlinear one-dimensional equations of blood flow in elastic vessels. Peak pressures in the auricular veins increase with the amplitude and length of the umbilical surge, reaching over 60 mm Hg when two consecutive surges separated by 100 ms, of a peak pressure of 100 mm Hg, and a pulse interval of 200 ms are propagated in a network with low peripheral reflections. Our findings support the proposed mechanism for inner ear damage in SIDS and the potential benefit of a newborn hearing screening test in identifying susceptibility and early preventative measures following birth. PMID- 19446413 TI - A sperm cryopreservation protocol for the loach Misgurnus anguillicaudatus and its applicability for other related species. AB - The aim of the present study was to establish a protocol of sperm cryopreservation in Misgurnus anguillicaudatus and verify the applicability of the obtained protocol in other loach species. We evaluated the following parameters: inseminating dose, thawing temperatures (20, 25 and 30 degrees C for 10s), extenders (loach or cyprinid extenders), internal cryoprotectants (dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), glycerol (Gly), ethylene glycol (EG), and methanol (MeOH) at 0, 5, 10 and 15%), external cryoprotectants (bovine serum albumin 1 and 2%; sucrose 0.5 and 1%; glucose 0.5 and 1%; glycine 0.5 and 1%), activating solutions (distilled water, dechlorinated tap water, 25mM NaCl and 50mM NaCl), and hatchability of the eggs when fertilized with fresh or cryopreserved sperm. After the evaluation of these parameters, we optimized the cryopreservation using the following procedure: thawing temperature at 25 degrees C for 10s; loach or cyprinid extenders; methanol at 10 or 15% as internal cryoprotectants; glycine 0.5% or bovine serum albumin 1% as external cryoprotectants and 50mM NaCl for sperm activation. Using this procedure, the fertilizability of the post-thawed sperm was 47% in comparison to the fresh sperm, at the minimum inseminating dose (687.65 spermatozoa egg(-1)mL(-1)). Based on this protocol, sperm from other loach species Lefua nikkonis, Misgurnus mizolepis and Barbatula toni were cryopreserved successfully. PMID- 19446414 TI - Cordysinocan, a polysaccharide isolated from cultured Cordyceps, activates immune responses in cultured T-lymphocytes and macrophages: signaling cascade and induction of cytokines. AB - Cordyceps sinensis, a well-known traditional Chinese medicine, possesses activities in anti-tumor, anti-oxidation and stimulating the immune response; however, the identity of active component(s) is not determined. A strain of Cordyceps sinensis, namely UST 2000, has been isolated. By using activity-guided purification, a novel polysaccharide of molecular weight approximately 82 kDa was isolated from the conditioned medium of cultured Cordyceps. The isolated exo polysaccharide, namely cordysinocan, contains glucose, mannose, galactose in a ratio of 2.4:2:1. In cultured T-lymphocytes, application of cordysinocan induced the cell proliferation and the secretion of interleukin-2, interleukin-6 and interleukin-8. In addition, the phosphorylation of extracellular signal-regulated kinases (ERK) was induced transiently by the treatment of cordysinocan. Moreover, application of cordysinocan in cultured macrophages increased the phagocytosis activity and the enzymatic activity of acid phosphatase. These results therefore verify the important role of Cordyceps polysaccharide in triggering such immune responses. PMID- 19446415 TI - A geometric-morphometric study of the Cretan humerus for sex identification. AB - Various scholars have pioneered sex assessment from different parts of the skeleton based on metrical or qualitative morphological characteristics. Lately though, a new technique which combines both traditional methods is becoming popular in forensic anthropology. Geometric-morphometrics is a field of multivariate statistical biometric analysis which allows the quantification of the shape and size components of morphological variation. The purpose of this investigation is to assess sex from the humerus in a contemporary Greek population using geometric-morphometric analysis of shape data derived from digital radiographs. The study population consists of 97 well-preserved adult humeri from two cemeteries of Heraklion, Crete. The left humeri are radiographed using digital radiograph machine (TCA 4R PLUS). Assuming fragmentary patterns, the proximal and distal ends are studied separately. Five landmarks are selected on the radiograph of the proximal epiphysis and seven landmarks on the distal. Generalised Procrustes analysis (GPA) and thin-plate splines are used to obtain the shape and size variables for statistical analysis. Then three discriminant function analyses were carried out: one uses the PC scores from Procrustes shape space, the second the centroid size alone and the third the PC scores of GPA residuals plus lnCS for analysis in Procrustes form space. Results indicate the existence of shape differences between the sexes. In females the greater tubercle is smoother, with its superior border less pronounced. Additionally, females have a relatively squared distal epiphysis, while males exhibit a more rectangular shape. Shape differences between genders, for the cross-validated data, give slightly better classification results in the proximal humerus (73%) compared with the distal humerus (71%). Size alone performed better (86.5% for proximal and 85.6% for distal humerus). As anticipated, the classification accuracy improves (89.6% for proximal and 89.7% for distal epiphysis) when both size and shape are combined. From the forensic standpoint, the usefulness of this study rests on the identification of sex based on shape differences observed on radiographs of fragmentary humeri that could not be assessed with traditional methods. The analysis of humeral radiographs by geometric-morphometric techniques offers an alternative way to identify the sex of unknown skeletal remains. Whether this is statistically better than simply using traditional osteometric methods is a question that needs to be tested in a meta-statistical approach. PMID- 19446416 TI - Xanthogranulomatous cholecystitis: diagnostic performance of CT to differentiate from gallbladder cancer. AB - PURPOSE: To retrospectively evaluate CT findings of xanthogranulomatous cholecystitis (XGC) and to measure diagnostic performance for distinguishing it from gallbladder (GB) cancer. METHODS AND MATERIALS: Our institutional review board approved this retrospective study. Three blinded radiologists, first independently and then in consensus, retrospectively evaluated postcontrast CT images of 35 patients with histopathologically proved XGC and GB cancer, all of whom subsequently had cholecystectomy. These included 18 patients with XGC (13 male, 5 female; age range, 35-84, mean 63 years) and 17 with GB cancer (6 male, 11 female; age range, 45-95, mean 69). Differences in CT findings between XGC and GB cancer and diagnostic performances for each CT finding were calculated. Sensitivity, specificity, and accuracy were calculated for each radiologist and observer performance was also determined by receiver-operating-characteristic curve analysis. RESULTS: Five CT findings showed significant differences between XGC and GB cancer. Sensitivity, specificity, and accuracy of each finding for the differentiation of XGC were 89%, 65%, 77% with diffuse GB wall thickening, 67%, 82%, 74% with a continuous mucosal line, 61%, 71%, 66% with intra-mural hypo attenuated nodules, 72%, 77%, 74% with absence of macroscopic hepatic invasion, and 67%, 71%, 69% with absence of intra-hepatic bile duct dilatation, respectively. When at least three of these five CT findings were observed in combination, sensitivity, specificity, and accuracy were 83%, 100% and 91%, respectively. Sensitivities, specificities and Az values for the differentiation of XGC from GB cancer were 83%, 88%, 0.94 for reader 1, 78%, 88%, 0.93 for reader 2, and 78%, 82%, 0.84 for reader 3. CONCLUSIONS: The combination of three of the five CT findings that are common with XGC can provide excellent accuracy for the differentiation of XGC and GB cancer. PMID- 19446417 TI - Incidental lung nodules on CT examinations of the abdomen: prevalence and reporting rates in the PACS era. AB - OBJECTIVES: To retrospectively evaluate prevalence, reporting rates and clinical implications of incidental pulmonary nodules detected in multidetector computed tomography (MDCT) abdominal studies. MATERIALS AND METHODS: Abdominal MDCT studies of 243 consecutive patients, 94 of whom had a history of cancer, were evaluated. Lung bases included in the scan were reviewed on a PACS workstation with different window settings and post-processing techniques. Nodules were classified according to their density (calcified, solid noncalcified, non-solid, part-solid) and size (<4mm; 4-6mm; 6-8mm; >8mm). The study findings were compared with the corresponding radiologic reports. Previous of following CT studies, when available from the PACS, were also reviewed to evaluate changes in number and size of the detected nodules. RESULTS: An average of 8.2 cm of lung parenchyma was imaged in each patient. 213 noncalcified nodules (NCNs) were identified in 95 patients (39.1%) but only 8 patients (8.4%) had it mentioned in the final report. Comparison CT studies were available for 44 out of the 95 positive patients showing disappearance of the nodules in 2 cases, no interval change in 26 and progression in size and/or number in 16 patients, in whom a final diagnosis of metastasis or primary lung cancers was achieved. CONCLUSION: Radiologists tend to overlook lung portions on abdominal CT studies. Underreporting may affect patient care and have medico-legal implications since images are permanently stored in digital format on PACS and CD-ROMs. Management of the discovered nodules should be tailored to the clinical situation of the patient, and particular care should be reserved to patients with oncologic history. PMID- 19446418 TI - Unusual malignant tumors of the breast: MRI features and pathologic correlation. AB - Unusual malignant breast tumors are well-differentiated subtypes of invasive ductal carcinoma, including mucinous, tubular, medullary and papillary carcinomas, and account for about 10% of malignant breast tumors. They are increasingly being encountered during magnetic resonance imaging (MRI) examinations of the breast. Therefore, breast radiologists should be aware of their appearance on MRI. This review provides an overview of MRI characteristics of a range of unusual tumors (mucinous carcinoma, medullary carcinoma, tubular carcinoma, intraductal papillary carcinoma, intracystic papillary carcinoma and invasive papillary carcinoma), highlighting specific clues for diagnosis and correlating MRI and pathologic features. Many unusual breast tumors exhibit MRI features similar to those of benign or low suspicious lesions (oval shape, well defined margins, high signal intensity on T2-weighted images, continuous increase kinetics, i.e. type I dynamic curve), leading to a possible misdiagnosis. Nevertheless, an understanding of pathologic features of these tumors, especially tissue content (mucinous, fibrous) and growth pattern, can help to define some specific clues for their diagnosis. PMID- 19446419 TI - In situ detection of antibiotic-resistance elements in single Bacillus cereus spores. AB - Rapid detection of Bacillus spores is a challenging task in food and defense industries. In situ labeling of spores would be advantageous for detection by automated systems based on single-cell analysis. Determination of antibiotic resistance genes in bacterial spores using in situ labeling has never been developed. Most of the in situ detection schemes employ techniques such as fluorescence in situ hybridization (FISH) that target the naturally amplified ribosomal RNA (rRNA). However, the majority of antibiotic-resistance genes has a plasmidic or chromosomal origin and is present in low copy numbers in the cell. The main challenge in the development of low-target in situ detection in spores is the permeabilization procedure and the signal amplification required for detection. This study presents permeabilization and in situ signal amplification protocols, using Bacillus cereus spores as a model, in order to detect antibiotic resistance genes. The permeabilization protocol was designed based on the different layers of the Bacillus spore. Catalyzed reporter deposition (CARD)-FISH and in situ polymerase chain reaction (PCR) were used as signal amplification techniques. B. cereus was transformed with the high copy number pC194 and low copy number pMTL500Eres plasmids in order to induce resistance to chloramphenicol and erythromycin, respectively. In addition, a rifampicin-resistant B. cereus strain, conferred by a single-nucleotide polymorphism (SNP) in the chromosome, was used. Using CARD-FISH, only the high copy number plasmid pC194 was detected. On the other hand, in situ PCR gave positive results in all tested instances. This study demonstrated that it was feasible to detect antibiotic-resistance genes in Bacillus spores using in situ techniques. In addition, in situ PCR has been shown to be more sensitive and more applicable than CARD-FISH in detecting low copy targets. PMID- 19446420 TI - Determination of losartan, telmisartan, and valsartan by direct injection of human urine into a column-switching liquid chromatographic system with fluorescence detection. AB - Column-switching high-performance liquid chromatographic (HPLC) method has been developed and validated for quantification of losartan, telmisartan, and valsartan in human urine. Urine samples were diluted on the extraction mobile phase (1:4, v/v) and a volume of 20 microL of this mixture were directly injected onto the HPLC system. The analytes were extracted from the matrix using an on line solid-phase extraction procedure involving a precolumn packed with 25 microm C(18) alkyl-diol support (ADS), and a solution 2% methanol in 5mM phosphate buffer (pH 3.8) at a flow-rate of 0.8 mL/min for isolation and preconcentration of losartan, telmisartan, and valsartan. The enriched analytes were back-flushed after, onto the analytical column with a mixture of 5mM phosphate buffer (pH 3.8) acetonitrile-methanol (65:20:15, v/v/v) at a flow-rate of 3.0 mL/min and detected by fluorescence at 259 and 399 nm as excitation and emission wavelength respectively. The separation of losartan, telmisartan, and valsartan was achieved on a Chromolith RP-18e monolithic column. The method provides extraction recoveries from spiked urine samples greater than 93%. Intra-day and inter-day precision were generally acceptable; the intra-day-assay C.V. was <3.5 for all compounds and the inter-day-assay C.V. was < 3.7%. The estimated calibration range was 0.001-2.5 microg/mL(-1) with excellent coefficient of determination (>0.9981). The detection limits for losartan, telmisartan, and valsartan at a signal-to-noise ratio of 5:1 were 0.002, 0.0002 and 0.001 microg/mL(-1) when a sample volume of 20 microL was injected. The proposed method permitted the simultaneous determination of losartan, telmisartan, and valsartan in 8 min, with an adequate precision and sensitivity. However, the overlap of the sample cleanup step with the analysis increases the sampling frequency to 12 samples/h. The developed column-switching method was successfully applied for the determination of these analytes in human urine samples of patients submitted at ARA-IIs therapy. PMID- 19446421 TI - Isolation and analysis of bioactive diterpenoids in Salvia species (Salvia chionantha and Salvia kronenburgiii) by micellar electrokinetic capillary chromatography. AB - In the present work, we isolated two bioactive diterpenoids, horminone and 7-O acetylhorminone and developed a micellar electrokinetic chromatography (MEKC) method for the simultaneous quantitative analysis of them in Turkish Salvia species. The optimal separation electrolyte was 50 mmol/L SDS and 25% methanol at pH 11.5. The limits of detection (S/N=3) were 3.269 and 4.518 microg/mL for horminone and 7-O-acetylhorminone, respectively. The method has been applied successfully to analyze these two components in Salvia chionantha and Salvia kronenburgii acetone extracts. PMID- 19446422 TI - Quantitative analysis of diclofenac sodium powder via near-infrared spectroscopy combined with artificial neural network. AB - A method for quantitative analysis of diclofenac sodium powder on the basis of near-infrared (NIR) spectroscopy is investigated by using of orthogonal projection to latent structures (O-PLS) combined with artificial neural network (ANN). 148 batches of different concentrations diclofenac sodium samples were divided into three groups: 80 training samples, 46 validation samples and 22 test samples. The average concentration of diclofenac sodium was 27.80%, and the concentration range of all the samples was 15.01-40.55%. O-PLS method was applied to remove systematic orthogonal variation from original NIR spectra of diclofenac sodium samples, and the filtered signal was used to establish ANN model. In this model, the concentration of diclofenac sodium was determined. The degree of approximation was employed as selective criterion of the optimum network parameters. In order to compare with O-PLS-ANN model, principal component artificial neural network (PC-ANN) model and calibration models that use different preprocessing methods (first derivative, standard normal variate (SNV) and multiplicative scatter correction (MSC)) of the original spectra were also designed. In addition, partial least squares regression (PLS) models were also established to compare with ANN models. Experimental results show that O-PLS-ANN model is the best. PMID- 19446423 TI - A direct HPLC method for the resolution and quantitation of the R-(-)- and S-(+) enantiomers of vigabatrin (gamma-vinyl-GABA) in pharmaceutical dosage forms using teicoplanin aglycone chiral stationary phase. AB - A direct chiral high-performance liquid chromatography (HPLC) method was developed and validated for the resolution and quantification of antiepileptic drug enantiomers, R-(-)- and S-(+)-vigabatrin (gamma-vinyl-gamma-aminobutyric acid) in pharmaceutical products. The separation was optimized on a macrocyclic glycopeptide antibiotic chiral stationary phase (CSP) based on teicoplanin aglycone, chirobiotic (TAG), using a mobile phase system containing ethanol-water (80:20, v/v), at a flow rate of 0.4ml/min and UV detection set at 210nm. The stability of vigabatrin enantiomers under different degrees of temperature was also studied. The enantiomers of vigabatrin were separated from each other. The calibration curves were linear over a range of 100-1600microg/ml (r=0.999) for both enantiomers. The overall recoveries of R-(-)- and S-(+)-vigabatrin enantiomers from pharmaceutical products were in the range of 98.3-99.8% with %RSD ranged from 0.48 to 0.52%. The limit of quantification (LOQ) and limit of detection (LOD) for each enantiomer were 100 and 25microg/ml, respectively. No interferences were found from commonly co-formulated excipients. PMID- 19446424 TI - The physiology behind intubation and ventilation: it is never too late to learn. PMID- 19446425 TI - Sunflower-seed oil, rapidly-degradable starch, and adiposity up-regulate leptin gene expression in lactating goats. AB - We conducted experiments to evaluate the effects of lipid supplementation and the nature of starchy concentrate on the regulation of leptin synthesis in lactating goats. Multiparous goats in mid- to late lactation received diets based on different forages and containing plant oil or seeds rich in either 18:1c9, 18:2n 6 or 18:3n-3 corresponding to 3%-7% dry matter (DM) as lipid supplements, or diets based on concentrate as either rapidly or slowly degradable starch. The isoenergetic replacement of a part of the concentrate by either oleic sunflower seed oil, formaldehyde-treated linseeds, or linseed oil did not modify leptinemia and the leptin mRNA concentration in adipose tissues, suggesting a lack of effect of 18:1c9, 18:3n-3, or their biohydrogenation products. Conversely, leptinemia and the leptin mRNA abundance were increased (by 20% and 140%, respectively, P<0.05) in goats fed sunflower-seed oil under a grassland hay-based diet but not a maize silage-based diet, at similar energy intakes and adiposity. Thus, 18:2n-6 per se may up-regulate leptin gene expression, but the effect could be blunted by other fatty acids formed during the ruminal digestion of sunflower-seed oil when combined with maize silage. Consumption of rapidly but not slowly degradable starch increased (by 17%, P<0.05) leptinemia. Moreover, during lactation, plasma leptin was positively correlated (P<0.05) to adiposity parameters and negatively correlated to fiber intake. The results suggest that leptinemia responds poorly to nutritional factors in lactating goats, thus highlighting the physiological need to sustain hypoleptinemia during lactation. PMID- 19446426 TI - Fatal intraurethral foreign body. PMID- 19446427 TI - [Is it valuable to screen for peripheral arterial disease in patients with coronary artery diseases?]. AB - Peripheral arterial disease (PAD), symptomatic or not, is a marker of poor prognosis which is considered as an equivalent of secondary prevention. In patients with coronary artery disease, PAD is often ignored, despite it could be a marker of worsened outcome. It seems interesting to screen for PAD in patients with coronary artery disease in order to detect a particularly high risk sub group of patients who will benefit of an adapted adjustment of the therapeutic strategy. PMID- 19446428 TI - [Hepatitis E initially serologically silent with prolonged evolution in a patient treated for a lymphoma]. PMID- 19446429 TI - [Laptop computer-induced erythema Ab Igne]. PMID- 19446430 TI - [Angioedema with acquired C1-inhibitor deficiency associated with low grade lymphoproliferative syndrome presenting a facial pseudo-paralysis in 82 years old patient]. PMID- 19446431 TI - [Drug treatment for hypertrophic cardiomyopathy]. AB - Drug treatment of hypertrophic cardiomyopathy is the first-line treatment, at the onset of clinical signs and symptoms. Beta-blockers are proposed for symptomatic patients with no gradient or with a gradient that appears only on exertion. Verapamil is the standard second-line drug,when the beta-blockers are insufficient or ineffective but must be avoided when there is blockage at rest with severe symptoms. Disopyramide is indicated for patients with obstruction who do not respond to beta blockers and/or verapamil. Treatment with anticoagulants is widely prescribed because this disease is highly emboligenic. PMID- 19446432 TI - What have we learned from pre-clinical juvenile toxicity studies? AB - Juvenile toxicity studies have assumed a higher priority within the pharmaceutical industry following recent changes in regulations. The requirement and designs of these studies should be on a 'case-by-case' basis. Discussions have suggested that recently the regulatory agencies have requested a more standard design incorporating multiple parameters, despite the disparity in the data available and the mode of action and indication of the respective drugs. In addition, the general perception was that studies were generating nothing new; there was no clear indication of novel toxicity or sensitivity; and the findings observed were predictable from what was already known. Clarity was therefore required both in terms of the study designs used and their usefulness and ability to generate meaningful data. This paper discusses the contributions from 10 pharmaceutical companies of 39 studies to clarify what has been learned and whether this has contributed to our greater understanding. Juvenile toxicity studies should be designed to fulfil a scientific rationale, only after first deciding what useful toxicological information might be obtained. Should a study be conducted, the endpoints must be assessed for both practicality and interpretability. Only when using appropriately designed studies can we adequately identify potential safety or pharmacokinetic issues, suggest additional clinical endpoints and/or contribute to the product label. PMID- 19446433 TI - Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA's ToxRefDB. AB - As the primary source for regulatory developmental toxicity information, prenatal studies characterize maternal effects and fetal endpoints including malformations, resorptions, and fetal weight reduction. Results from 383 rat and 368 rabbit prenatal studies on 387 chemicals, mostly pesticides, were entered into the U.S. Environmental Protection Agency's (EPA) Toxicity Reference Database (ToxRefDB) using harmonized terminology. An initial assessment of these data was performed with the goal of profiling environmental chemicals based on maternal and fetal endpoints for anchoring in vitro data provided in the EPA's ToxCast research program. Using 30 years worth of standard prenatal studies, maternal and fetal effects were culled from the database and analyzed by target-description fields and lowest effect levels (LELs). Focusing on inter-species comparison, the complexity of fetal target organ response to maternal dosing with environmental chemicals during the period of major organogenesis revealed hierarchical relationships. Of 283 chemicals tested in both species, 53 chemicals (18.7%) had LELs on development (dLEL) that were either specific, with no maternal toxicity (mLEL), or sensitive (dLEL